Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development

In postmortem brains of humans with AUD, nociceptin mRNA decreases in the amygdala.

“In postmortem brains of humans with AUD, nociceptin mRNA decreased in the amygdala (Kuzmin et al., 2009).”

• cites Kuzmin et al., 2009 sourceDisputed

  The Results (section 2; page not provided) report lower pronociceptin (PNOC) mRNA in the hippocampus, with no evident PNOC difference in the other regions analyzed, including the central amygdala. The mRNA found to be lower in the central amygdala was for the nociceptin receptor (OPRL1), not nociceptin. (LLM, conf=0.91)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

Pain severity is positively associated with higher risk for AUD.

“Indeed, there is a positive association between pain severity and a higher risk for AUD (Lawton and Simpson, 2009;Edlund et al., 2013).”

• cites Lawton and Simpson, 2009 sourceNot checked — no full text of the source
• cites Edlund et al., 2013 sourceDisputed

  The Methods (2.2 Measures; page unavailable) say that pain severity was tested but was not statistically significant after controlling for days with pain and depression. The Discussion (section 4; page unavailable) reports a positive association for pain frequency—not severity—with alcohol abuse/dependence. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

A similar theoretical framework has been proposed for compulsive eating, in which habitual overeating, overeating to relieve a negative emotional state, and overeating despite aversive consequences reflect the three functional domains outlined in drug addiction.

“Note that a similar theoretical framework has been proposed for compulsive eating, in which habitual overeating, overeating to relieve a negative emotional state, and overeating despite aversive consequences reflect the three functional domains that are outlined in drug addiction (Moore et al., 2017(Moore et al., , 2019)).”

• cites Moore et al., 2017 sourceSupported
• cites Moore et al., 2019 sourceNot checked — no full text of the source

Hyperkatifeia can be considered an emotional parallel to hyperalgesia observed with repeated administration of chronic opioids and alcohol.

“Hyperkatifeia can be considered an emotional parallel to hyperalgesia (i.e., greater sensitivity to physical pain) that is observed with repeated administration of chronic opioids and alcohol (Shurman et al., 2010;Koob, 2019).”

• cites Shurman et al., 2010 sourcePartly supported

  The Introduction describes hyperkatifeia as hypersensitivity to emotional distress, analogous to hyperalgesia as hypersensitivity to pain. It links both to excessive opioid exposure that disrupts homeostasis, but says they are less likely when opioids effectively relieve pain. Our copy does not extend this pairing to repeated alcohol administration. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Koob, 2019Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Using the Addictions Neuroclinical Assessment, five subdomains of negative emotional states that can be operationally measured in human laboratory settings and paralleled by animal models were outlined.

“Using the Addictions Neuroclinical Assessment, five subdomains of negative emotional states that can be operationally measured in human laboratory settings and paralleled by animal models were outlined (Kwako et al., 2016).”

• cites Kwako et al., 2016 sourcePartly supported

  The Introduction’s ANA Domains section identifies negative emotionality as one of three main domains and discusses measurable features such as dysphoria and hypohedonia. The Introduction also says the framework draws on humans and model organisms. Our copy does not outline five subdomains of negative emotional states or establish that each has a human-laboratory measure paralleled by an animal model (pages not provided). (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Direct statistical intergroup comparisons and analysis of changes in hub status indicated a reshaping of networks known to process information of negative valence.

“Direct statistical intergroup comparisons and an analysis of changes in hub status indicated a reshaping of networks that are known to process information of negative valence.”

• cites Mechling et al., 2016 sourceSupported

In a subsequent study, the three neurofunctional domains proposed to be critical for the addiction cycle (incentive salience, negative emotionality, and executive function) were validated using a factor analysis of a deeply phenotyped clinical sample.

“In a subsequent study, the three neurofunctional domains that were proposed to be critical for the addiction cycle (incentive salience, negative emotionality, and executive function) were validated using a factor analysis of a deeply phenotyped clinical sample (Kwako et al., 2019; Fig. 3).”

• cites Kwako et al., 2019 sourcePartly supported

  The Results (Factor Structure) report that factor analysis identified three factors aligning well with the proposed domains in a clinical sample. But the Abstract (Conclusions) says the findings suggest the domains are relevant for AUD and that more work is required to validate and standardize their measures, so saying the domains were validated overstates the finding. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

The negative valence network that evolved included structures such as the periaqueductal gray, hippocampus, amygdala, cingulate cortex, median raphe, and habenula.

“The negative valence network that evolved included such structures as the periaqueductal gray, hippocampus, amygdala, cingulate cortex, median raphe, and habenula (Mechling et al., 2016).”

• cites Mechling et al., 2016 sourcePartly supported

  The Results and Discussion identify the periaqueductal gray, hippocampal region, amygdala, anterior cingulate areas, and habenula among nodes with prominent connectivity changes in an aversion-related network. They identify the remaining region as the midbrain reticular nucleus (MRN), not the median raphe. The paper describes network reshaping after gene deletion, rather than a network that evolved. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

In a connectome imaging study using hypothesis-free analysis of combined resting-state functional magnetic resonance imaging diffusion tractography, m-opioid receptor gene (Oprm1) inactivation produced dramatic changes in aversion/pain-related connectivity and less so in reward connectivity.

“The authors showed that m-opioid receptor gene (Oprm1) inactivation produced dramatic changes in aversion/ pain-related connectivity and less so in reward connectivity (Mechling et al., 2016).”

• cites Mechling et al., 2016 sourceSupported

Dopaminergic function is compromised during acute alcohol withdrawal in animal models of chronic administration or compulsive-like drinking.

“Dopaminergic function is also compromised during acute alcohol withdrawal in animal models of chronic administration or compulsive-like drinking (Diana et al., 1993;Weiss et al., 1996).”

• cites Diana et al., 1993 sourceNot checked — no full text of the source
• cites Weiss et al., 1996 sourceSupported

Acute opioid effects activate G proteins through the mu-opioid receptor and modulate second messengers and cellular effectors that generate short-term and long-term neuroadaptations relevant to a blunted hedonic response to the drug (tolerance).

“For the acute effects of opioid drugs, G proteins are activated through the m-opioid receptor and modulate the activity of several second messengers and cellular effectors that generate both short-term and long-term neuroadaptations that are relevant to a blunted hedonic response to the drug (i.e., tolerance; Cahill et al., 2016).”

• cites Cahill et al., 2016 sourceSupported

Electrical stimulation of the lateral habenula output caused conditioned place aversions.

“Consistent with these observations, electrical stimulation of the lateral habenula output caused conditioned place aversions (Stamatakis and Stuber, 2012).”

• cites Stamatakis and Stuber, 2012 sourcePartly supported

  The passage indexed under Abstract reports conditioned place aversion in mice after stimulation of the LHb-to-RMTg pathway. However, it specifies optogenetic stimulation, not electrical stimulation; the Online Methods also describe laser stimulation. No page numbers are supplied in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Significant evidence has emerged for a role for the lateral habenula-VTA circuit in driving aversive responses to the loss of reward and mediating and encoding aversive states.

“Significant evidence has also emerged for a role for the lateral habenula-VTA circuit in driving aversive responses to the loss of reward and mediating and encoding aversive states (Hikosaka, 2010).”

• cites Hikosaka, 2010 sourcePartly supported

  In “Avoidance of punishment” (page unavailable), the review says the lateral habenula signals negative stimulus value to dopamine neurons in the VTA and may contribute to suppressing movements leading to aversive outcomes. “Reward-based decision-making” describes responses to smaller-than-expected rewards. These passages support a role in encoding negative outcomes and responding to aversive stimuli, but the claim that the circuit *drives* aversive responses to reward loss states the proposed behavioral role more firmly than the source does. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Alcohol withdrawal is characterized by a hyperglutamatergic state that is opposite to the acute effects of alcohol.

“In contrast, alcohol withdrawal is characterized by a hyperglutamatergic state that is opposite to the acute effects of alcohol (Hwa et al., 2017).”

• cites Hwa et al., 2017 sourcePartly supported

  The Introduction and Heavy drinking and withdrawal sections describe increased glutamate activity during withdrawal. But the claim that this is opposite to the acute effects of alcohol is too broad: the Introduction says an acute ethanol injection also increases glutamate in the nucleus accumbens. The Low-level drinking section reports reduced prefrontal excitability after acute alcohol, indicating that acute effects vary by measure and region. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

In humans, oral doses of alcohol increased extracellular dopamine concentrations during intoxication in healthy volunteers, based on PET measures.

“In humans, consistent with animal studies, oral doses of alcohol increased extracellular dopamine concentrations during intoxication in healthy volunteers, based on positron emission tomography measures (Boileau et al., 2003;Urban et al., 2010).”

• cites Boileau et al., 2003 sourceNot checked — no full text of the source
• cites Urban et al., 2010 sourceSupported

The lateral habenula may play a role in modulating motivated behavior and addiction by modulating dopamine neurotransmission via actions on dopamine neurons in the VTA.

“The lateral habenula may play a role in modulating motivated behavior and addiction by modulating dopamine neurotransmission via actions on dopamine neurons in the VTA (Hikosaka, 2010;Velasquez et al., 2014;Boulos et al., 2017).”

• cites Hikosaka, 2010 sourcePartly supported

  The Reward-based decision-making section says the lateral habenula inhibits dopamine neurons in the VTA, and Towards a unified theory of habenula function links that inhibition to reduced motivation. The paper discusses nicotine addiction, but attributes the withdrawal-related mechanism to the medial habenula and interpeduncular nucleus; it does not support the claim that the lateral habenula modulates addiction through VTA dopamine neurons. Page numbers were not available in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Velasquez et al., 2014 sourceSupported
• cites Boulos et al., 2017 sourcePartly supported

  The ADDICTION section links the lateral habenula to cocaine reward and dependence, while the SCHIZOPHRENIA section describes lateral habenula stimulation altering dopamine-related risk/reward decisions. The DEPRESSION > Rodents section mentions lateral habenula neurons projecting to the VTA, but our copy does not establish that its role in addiction operates by modulating VTA dopamine neurons. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

In humans, PET imaging studies reported lower baseline dopamine D2 receptor availability in the dorsal striatum in psychostimulant abusers and opioid-dependent subjects compared with control subjects.

“In humans, positron emission tomography imaging studies reported lower baseline dopamine D 2 receptor availability in the dorsal striatum in psychostimulant abusers and opioid-dependent subjects compared with control subjects (Wang et al., 1997;Ashok et al., 2017).”

• cites Wang et al., 1997 sourceNot checked — no full text of the source
• cites Ashok et al., 2017 sourcePartly supported

  The Results section, “Dopamine receptor availability” (page unavailable), reports lower D2/3 receptor availability in stimulant users than in healthy controls. The paper analyzes the whole striatum rather than specifically the dorsal striatum, and its Discussion notes that the tracers generally cannot distinguish D2 from D3 receptors. It does not study opioid-dependent subjects; the citing sentence also cites Wang et al. for that broader claim. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

The mesolimbic dopamine system becomes compromised after chronic administration of virtually all drugs of abuse, including opioids and alcohol.

“Nevertheless, what is also evident is that the mesolimbic dopamine system becomes compromised after the chronic administration of virtually all drugs of abuse, including opioids and alcohol (Koob and Volkow, 2010;Diana, 2011).”

• cites Koob and Volkow, 2010 sourcePartly supported

  The Withdrawal/Negative Affect Stage section reports reduced mesolimbic dopamine activity during acute withdrawal from all major drugs of abuse in animal studies. It also describes compromised dopamine function as a hypothesis concerning particular phases of addiction. The claim omits the withdrawal and animal-study qualifiers, presenting the effect as a general consequence of chronic administration. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Diana, 2011 sourceSupported

Antagonism of CRF receptors in the extended amygdala blocked the aversive stimulus effects of drug withdrawal.

“The antagonism of CRF receptors in the extended amygdala blocked the aversive stimulus effects of drug withdrawal (Koob, 2015).”

• cites Koob, 2015 sourceSupported

Activation of CRF neurons in the CeA during alcohol withdrawal that projected to the BNST may mediate dependence-induced excessive alcohol intake.

“An optogenetic study showed that activation of CRF neurons in the CeA during alcohol withdrawal that projected to the BNST may mediate dependenceinduced excessive alcohol intake (de Guglielmo et al., 2016(de Guglielmo et al., , 2019)).”

• cites de Guglielmo et al., 2016 sourcePartly supported

  The Discussion reports that a CeA neuronal ensemble recruited during abstinence is required for excessive drinking in alcohol-dependent rats. But the study used Daun02 to inactivate that ensemble; our copy does not identify it as CRF neurons, test a projection to the BNST, or report an optogenetic experiment. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites de Guglielmo et al., 2019 sourceSupported

Systemic injections of small-molecule CRF1 receptor antagonists blocked the increase in alcohol intake associated with acute withdrawal and protracted abstinence.

“Systemic injections of small-molecule CRF 1 receptor antagonists blocked the increase in alcohol intake that was associated with acute withdrawal (Knapp et al., 2004;Overstreet et al., 2004a;Funk et al., 2007) and protracted abstinence (Gehlert et al., 2007).”

• cites Knapp et al., 2004 sourcePartly supported

  The Methods (section 2.2; page not supplied) describe intraperitoneal injections of the nonpeptide CRF antagonist CRA1000 during acute ethanol withdrawal. The Discussion (section 4; page not supplied) reports that CRA1000 blocked withdrawal-related social interaction deficits, an anxiety-like behavior—not an increase in alcohol intake. Protracted abstinence is attributed to a different citation in the citing sentence. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Overstreet et al., 2004aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Funk et al., 2007 sourceNot checked — no full text of the source

Systemic CRF1 receptor antagonist administration blocked anxiety-like responses to alcohol withdrawal.

“Systemic CRF 1 receptor antagonist administration blocked anxiety-like responses to alcohol withdrawal (Knapp et al., 2004;Overstreet et al., 2004b;Breese et al., 2005).”

• cites Knapp et al., 2004 sourceSupported
• cites Overstreet et al., 2004bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Breese et al., 2005 sourceSupported

Rats made dependent using the chronic intermittent alcohol vapor model exhibit a blunted corticosterone response.

“Similar effects have been observed in animal models in which rats that are made dependent using the chronic intermittent alcohol vapor model exhibit a blunted corticosterone response (Richardson et al., 2008).”

• cites Richardson et al., 2008 sourceSupported

The effects of k-opioid receptor blockade on high compulsive-like alcohol intake may be mediated by the extended amygdala, including the CeA and shell of the NAc.

“These effects may be mediated by the extended amygdala, including the CeA and shell of the NAc (Nealey et al., 2011).”

• cites Nealey et al., 2011 sourcePartly supported

  The Discussion reports that blocking κ-opioid receptors in the nucleus accumbens shell attenuated excessive ethanol self-administration in dependent rats. It does not identify the central amygdala (CeA) or establish the extended amygdala as the mediating circuit; it also describes excessive intake rather than specifically compulsive-like intake. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Systemic and intracerebral k-opioid receptor antagonist administration blocks high compulsive-like drug intake associated with extended access to and dependence on alcohol.

“Both systemic and intracerebral k-opioid receptor antagonist administration blocked high compulsivelike drug intake that was associated with extended access to and dependence on alcohol (Hölter et al., 2000;Walker and Koob, 2008).”

• cites Hölter et al., 2000 sourceNot checked — no full text of the source
• cites Walker and Koob, 2008 sourcePartly supported

  The Drugs and Results sections report that systemic nalmefene reduced ethanol self-administration and intracerebral nor-BNI selectively reduced it in ethanol-dependent rats. But nalmefene is not a selective κ-opioid antagonist, and the study reports reduced—not completely blocked—intake after ethanol-vapor-induced dependence. It does not establish the claimed effect under extended-access drinking conditions. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Dynorphin has long been known to be activated by chronic psychostimulant and opioid administration and self-administration and alcohol self-administration.

“It has long been known to be activated by chronic psychostimulant and opioid administration and self-administration (Nestler, 2004;Koob, 2008) and alcohol self-administration (Karkhanis and Al-Hasani, 2020).”

• cites Nestler, 2004 sourceNot checked — no full text of the source
• cites Koob, 2008Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Karkhanis and Al-Hasani, 2020 sourceSupported

Alcohol withdrawal is associated with increases in the release of CRF in the CeA and BNST.

“Alcohol withdrawal is associated with increases in the release of CRF in the CeA (Merlo-Pich et al., 1995) and BNST (Olive et al., 2002).”

• cites Merlo-Pich et al., 1995 sourceSupported
• cites Olive et al., 2002 sourceSupported

In a 12-week, multisite, randomized clinical trial in 150 alcohol-dependent individuals, the selective V1b receptor antagonist ABT-436 significantly increased the percentage of days abstinent compared with placebo.

“In a 12-week, multisite, randomized clinical trial in 150 alcohol-dependent individuals, the selective V 1b receptor antagonist ABT-436 significantly increased the percentage of days abstinent compared with placebo (Ryan et al., 2017).”

• cites Ryan et al., 2017 sourceSupported

Direct injections of nociceptin in the CeA attenuate escalation of intravenous oxycodone self-administration in a high addiction index subset of outbred rats.

“Perhaps more compelling for the present thesis, direct injections of nociceptin in the CeA attenuated the escalation of intravenous oxycodone self-administration in a high addiction index subset of outbred rats (Kallupi et al., 2020).”

• cites Kallupi et al., 2020 sourceSupported

Alcoholic liver disease involves inflammation, in part through an alcohol-induced increase in gut permeability to endotoxins such as lipopolysaccharide that activate innate immune cells in the liver.

“Alcoholic liver disease involves inflammation, in part through an alcohol-induced increase in the permeability of the gut to endotoxins, such as lipopolysaccharide, that activate innate immune cells in the liver (Szabo et al., 2011).”

• cites Szabo et al., 2011 sourceSupported

Ex vivo electrophysiological recordings in the CeA indicate that oxytocin blocks the facilitatory effects of alcohol on GABA release in the CeA in dependent rats but not in nondependent rats.

“Ex vivo electrophysiological recordings in the CeA indicated that oxytocin blocked the facilitatory effects of alcohol on GABA release in the CeA in dependent rats but not in nondependent rats (Tunstall et al., 2019).”

• cites Tunstall et al., 2019 sourceSupported

Oxytocin administration intranasally or directly in the brain blocks the increase in drinking in alcohol-dependent rats.

“Oxytocin administration intranasally or directly in the brain blocked the increase in drinking in alcohol-dependent rats (Tunstall et al., 2019).”

• cites Tunstall et al., 2019 sourceSupported

Proinflammatory cytokines expressed in astrocytes in the periaqueductal gray may play an important role in the pathogenesis of the morphine withdrawal response.

“These findings support the hypothesis that proinflammatory cytokines that are expressed in astrocytes in the periaqueductal gray may play an important role in the pathogenesis of the morphine withdrawal response (Hao et al., 2011).”

• cites Hao et al., 2011 sourceSupported

Interactions between the immune system and stress system associated with the withdrawal/negative affect stage involve both microglia and astrocytes.

“Interactions between the immune system and stress system that are associated with the withdrawal/negative affect stage involve both microglia and astrocytes (Crews et al., 2017).”

• cites Crews et al., 2017 sourcePartly supported

  Section 3 says stress affects both microglia and astrocytes, and Section 5 says immune signaling contributes to the withdrawal/negative affect stage. The paper does not specifically link both cell types to immune–stress interactions during that stage. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Intraventricular Hcrt-1 elevates intracranial self-stimulation thresholds, suggesting an aversive effect of excessive activation of the Hcrt system.

“Additional studies demonstrate that intraventricular Hcrt-1 elevates intracranial self-stimulation thresholds, suggesting an aversive effect of excessive activation of the Hcrt system (Boutrel et al., 2005).”

• cites Boutrel et al., 2005 sourceSupported

Using a chronic morphine, intermittent, escalating-dose procedure, Hcrt mRNA levels in the lateral hypothalamus increase during the aversive state of acute morphine withdrawal.

“Using a chronicmorphine, intermittent, escalating-dose procedure, Hcrt mRNA levels in the lateral hypothalamus increased during the aversive state of acute morphine withdrawal (Zhou et al., 2010).”

• cites Zhou et al., 2010 sourceSupported

Chronic alcohol treatment in mice induces proinflammatory gene expression in the brain that persists for at least 1 week of abstinence.

“For alcohol, chronic alcohol treatment in mice induced proinflammatory gene expression in the brain that persisted for at least 1 week of abstinence (Qin et al., 2007).”

• cites Qin et al., 2007 sourceCould not verify

  The Materials and Methods describe a single LPS or TNFα injection in mice, not chronic alcohol treatment. The Results report elevated brain TNFα one week after LPS, but our copy does not address proinflammatory gene expression after a week of alcohol abstinence (searched: chronic alcohol treatment, alcohol, ethanol, abstinence). (LLM, conf=0.75)

  Experimental — accuracy not yet measured

Neuroinflammatory signaling pathways in the central nervous system contribute to neuroadaptive processes that mediate dysregulation of hyperkatifeia associated with the withdrawal/negative affect stage of the addiction cycle.

“Neuroinflammatory signaling pathways in the central nervous system are also hypothesized to contribute to neuroadaptive processes that mediate the dysregulation of hyperkatifeia that is associated with the withdrawal/negative affect stage of the addiction cycle (Koob and Volkow, 2010;Crews and Vetreno, 2016).”

• cites Koob and Volkow, 2010 sourcePartly supported

  The Withdrawal/Negative Affect Stage section describes neuroadaptations involving brain stress systems and negative emotional states during withdrawal. It does not identify neuroinflammatory signaling pathways as contributors to those processes or use the term “hyperkatifeia”; the molecular-plasticity passages discuss other signaling mechanisms instead. Pages are not available in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Crews and Vetreno, 2016 sourcePartly supported

  The sections on brain neuroimmune signaling and blood-derived innate immune signals link alcohol-related inflammation to altered neural activity, depression, and alcohol craving. The copy does not specifically connect these pathways to hyperkatifeia or identify them as mediating negative affect in the withdrawal stage of the addiction cycle. Page numbers were not available in the indexed passages. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Female rodents drink more alcohol than males.

“Female rodents also drink more alcohol than males (Eriksson and Pikkarainen, 1968;Becker and Koob, 2016).”

• cites Eriksson and Pikkarainen, 1968 sourceNot checked — no full text of the source
• cites Becker and Koob, 2016 sourceSupported

Repeated opioid administration in animal models produces a gradual, dose-dependent decrease in nociceptive thresholds that lasts for several weeks after drug administration.

“In animal models, repeated opioid administration (e.g., once daily for 2 weeks) produces a gradual and dose-dependent decrease in nociceptive thresholds that lasts for several weeks after drug administration (Célèrier et al., 2001;Simonnet and Rivat, 2003).”

• cites Célèrier et al., 2001 sourcePartly supported

  The Results section ('Changes in pain sensitivity associated with once-daily administration of heroin'; page unavailable) reports a gradual decrease in nociceptive threshold after 12 daily injections, with a larger decrease at the higher heroin dose. It does not support the claim that the lowered basal threshold lasted several weeks after treatment: it returned to the control value 8 days after the lower-dose course and on day 21, about 9 days after the higher-dose course. The two-month finding concerns hyperalgesia precipitated by naloxone, not a continuously lowered basal threshold. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites Simonnet and Rivat, 2003 sourceNot checked — no full text of the source

The dynorphin/k-opioid receptor system may be engaged in negative emotional states associated with chronic pain.

“The dynorphin/k-opioid receptor system may also be engaged in negative emotional states that are associated with chronic pain (Cahill et al., 2014;Massaly et al., 2016Massaly et al., , 2019)).”

• cites Cahill et al., 2014 sourceSupported
• cites Massaly et al., 2016 sourceSupported
• cites Massaly et al., 2019 sourcePartly supported

  The Discussion reports that dynorphin-containing neurons and kappa opioid receptor activity drive negative affect associated with inflammatory pain. This supports engagement of the system in pain-related negative emotional states, but the study’s findings are specifically in rodent models of inflammatory pain, not chronic pain generally. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Little work has focused on preclinical studies of gender differences in animal models of hyperkatifeia and negative reinforcement with opioids.

“To date, little work has focused on preclinical studies of gender differences in animal models of hyperkatifeia and negative reinforcement with opioids (Becker and Koob, 2016).”

• cites Becker and Koob, 2016 sourceSupported

Individuals with a history of opioid addiction show heightened pain perception.

“In humans, heightened pain perception has long been observed in individuals with a history of opioid addiction (Ho and Dole, 1979;Ren et al., 2009).”

• cites Ho and Dole, 1979 sourceNot checked — no full text of the source
• cites Ren et al., 2009 sourceSupported

A study failed to observe a reduction in the amount of benzodiazepines required for alcohol withdrawal treatment with oxytocin.

“Another study failed to observe such a reduction of the amount of benzodiazepines that were required for alcohol withdrawal treatment (Melby et al., 2019).”

• cites Melby et al., 2019 sourceSupported

Selectively bred lines exhibit faster acquisition of alcohol self-administration.

“Selectively bred lines exhibited the faster acquisition of self-administration (Li and Lumeng, 1984;Moore and Lynch, 2015).”

• cites Li and Lumeng, 1984 sourceNot checked — no full text of the source
• cites Moore and Lynch, 2015 sourceCould not verify

  The Introduction says female rats and mice acquire ethanol self-administration more quickly than males, but does not attribute faster acquisition to selectively bred lines. The Methods (§2.4) describe training selectively bred P rats to self-administer ethanol, and the Results (§3.3) report their intake; neither compares their acquisition speed with another line. Searched for faster and rapid acquisition in P rats and selectively bred lines. (LLM, conf=0.74)

  Experimental — accuracy not yet measured

Withdrawal from chronic opioid self-administration produces hyperalgesia (lower pain thresholds) in humans and animal models.

“In humans and animal models, withdrawal from chronic opioid self-administration produces hyperalgesia (i.e., lower pain thresholds; Tilson et al., 1973;Angst and Clark, 2006).”

• cites Tilson et al., 1973 sourceNot checked — no full text of the source
• cites Angst and Clark, 2006 sourcePartly supported

  The Human Studies section describes increased pain sensitivity during opioid withdrawal, and Small and Anecdotal Reports describes lower heat-pain tolerance in patients undergoing withdrawal. The Animal Studies section reports withdrawal hyperalgesia in rodents. These passages do not establish the claim specifically for chronic opioid self-administration; the animal studies described used administered opioids, and the human quantitative finding concerns pain tolerance rather than threshold. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Systemic CRF1 receptor antagonist blocks withdrawal hyperalgesia in animals with extended access to heroin.

“Consistent with this observation, hyperalgesia during withdrawal in animals that developed compulsive-like responding with extended access to heroin was blocked by the systemic administration of a CRF 1 receptor antagonist (Edwards et al., 2012b;Park et al., 2015).”

• cites Edwards et al., 2012bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Park et al., 2015 sourceSupported

Some physical signs of opioid withdrawal are more pronounced in male mice than in female mice.

“and some physical signs of opioid withdrawal are more pronounced in male mice than in female mice (Diaz et al., 2005).”

• cites Diaz et al., 2005 sourceSupported

In males with alcohol use disorder (AUD), oxytocin peptide mRNA is significantly elevated in the prefrontal cortex compared with controls.

“In a postmortem study of males with AUD, oxytocin peptide mRNA was significantly elevated in the prefrontal cortex in subjects with AUD compared with controls (Lee et al., 2017).”

• cites Lee et al., 2017 sourceSupported

Pain serves as a situational motivator of alcohol consumption, partly as a function of pain-induced negative affect.

“Here, pain serves as a situational motivator of alcohol consumption, partly as a function of pain-induced negative affect (Zale et al., 2015).”

• cites Zale et al., 2015 sourcePartly supported

  In “Pain as a Situational Motivator of Alcohol Use,” the review reports evidence that some people drink to cope with pain, but describes pain-related negative affect as a possible mechanism. The “Integrative Conceptualization” likewise says pain may motivate drinking through negative reinforcement. The claim presents that proposed mechanism more definitively than the source does. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Experimentally induced pain increases urge and intention to drink, mediated by pain-induced negative affect.

“In a study that tested the effects of experimentally induced pain on proximal antecedents of alcohol consumption as proxies for ad libitum alcohol consumption and investigated pain-induced negative affect as a mechanism of action, participants in the pain condition subsequently endorsed a greater urge and intention to drink, and these effects were mediated by paininduced negative affect (Moskal et”

• cites Moskal et al., 2018 sourceSupported

Abstinence from chronic alcohol consumption produces hyperalgesia in animal studies.

“As with opioids, although acute alcohol administration in animal studies may confer analgesic effects, abstinence from chronic alcohol consumption produces hyperalgesia (Gatch et al., 1999;Gatch, 2009;Egli et al., 2012).”

• cites Gatch et al., 1999 sourceNot checked — no full text of the source
• cites Gatch, 2009 sourceNot checked — no full text of the source
• cites Egli et al., 2012 sourceSupported

Rodent models of alcohol withdrawal reliably show hyperalgesia in multiple pain assays.

“For example, rodent models of alcohol withdrawal have reliably observed hyperalgesia in multiple pain assays (Gatch et al., 1999;Gatch, 2009;Egli et al., 2012).”

• cites Gatch et al., 1999 sourceNot checked — no full text of the source
• cites Gatch, 2009 sourceNot checked — no full text of the source
• cites Egli et al., 2012 sourceSupported

The Addictions Neuroclinical Assessment framework allows identification of individuals with phenotypes that signal dysregulation in the hyperkatifeia domain.

“From a nosology perspective, the Addictions Neuroclinical Assessment framework allows the identification of individuals with phenotypes that signal dysregulation in this domain (Kwako et al., 2016).”

• cites Kwako et al., 2016 sourcePartly supported

  The Introduction and ANA Summary propose assessing negative emotionality to distinguish individuals by their profiles of vulnerability. The paper describes ANA as a heuristic framework intended to enable this work, rather than demonstrating that it already identifies such phenotypes; our copy also does not call the domain “hyperkatifeia.” (LLM, conf=0.79)

  Experimental — accuracy not yet measured

Physical pain is a significant predictor of alcohol use, heavy alcohol use, and relapse to drinking after a period of abstinence.

“Perhaps more compelling, physical pain appears to be a significant predictor of alcohol use and heavy alcohol use and relapse to drinking after a period of abstinence (Larson et al., 2007;Caldeiro et al., 2008;Witkiewitz et al., 2015).”

• cites Larson et al., 2007 sourceNot checked — no full text of the source
• cites Caldeiro et al., 2008 sourcePartly supported

  The Discussion and Substance use outcomes sections report that veterans with persistent pain had worse alcohol-use severity and were less likely to be abstinent from alcohol or drugs at 12 months than those with low pain. The paper does not report heavy alcohol use as a separate outcome or test relapse to drinking after a documented period of abstinence; its findings also concern persistent pain in veterans receiving outpatient addiction treatment, not physical pain generally. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Witkiewitz et al., 2015 sourcePartly supported

  The Results report that pain significantly predicted heavy-drinking lapses in both trials and any-drinking lapses following treatment in COMBINE. But the Introduction defines a lapse as drinking beyond a limit after either abstinence or a moderate-drinking goal, so the study does not establish that these lapses followed abstinence. Its findings also concern people treated for alcohol use disorder, rather than alcohol use generally. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

nor-BNI fails to block lactic acid-induced elevations of brain reward thresholds and decrease in NAc dopamine in rats.

“Moreover, the k-opioid receptor antagonist nor-BNI failed to block lactic acidinduced elevations of brain reward thresholds and the decrease in NAc dopamine in rats (Leitl et al., 2014).”

• cites Leitl et al., 2014 sourceSupported

Dynorphin-containing neurons and k-opioid receptor activity in the NAc shell are necessary and sufficient to drive pain-induced negative affective states.

“Even more compelling, using a series of pharmacological, optogenetic, and chemogenetic approaches, the authors showed that both dynorphin-containing neurons and k-opioid receptor activity in the NAc shell were necessary and sufficient to drive pain-induced negative affective states (Massaly et al., 2019).”

• cites Massaly et al., 2019 sourceSupported

Systemic JDtic fails to block conditioned place aversion produced by visceral and acid-induced pain in mice.

“However, systemic doses of the k-opioid receptor antagonist (3R)-7-hydroxy-N-{(2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1yl]-3-methylbutan-2-yl}-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (JDtic) failed to block conditioned place aversion that was produced by visceral and acid-induced pain in mice (Bagdas et al., 2016).”

• cites Bagdas et al., 2016 sourceSupported

A meta-analysis of 18 controlled studies supports the analgesic effects of alcohol.

“A meta-analysis of 18 controlled studies that compared pain in people who were given alcohol versus no alcohol provided support for the analgesic effects of alcohol (Thompson et al., 2017).”

• cites Thompson et al., 2017 sourceSupported

nor-BNI prevents loss of the diffuse noxious inhibitory control response in the rat hindpaw after morphine-primed stress.

“and nor-BNI significantly prevented loss of the diffuse noxious inhibitory control response (i.e., a pain-inhibiting pain response) in the rat hindpaw after morphine-primed stress (Nation et al., 2018).”

• cites Nation et al., 2018 sourceSupported

Comorbidity is linked to extended amygdala neural substrates mediating negative affect and hyperkatifeia.

“Such comorbidity has been particularly linked to the neural substrates of the extended amygdala that mediate common elements of negative affect and hyperkatifeia (Centanni et al., 2019).”

• cites Centanni et al., 2019 sourceSupported

Polymorphisms of the k-opioid receptor and prodynorphin genes are associated with higher risk for opioid addiction.

“Polymorphisms of the genes that encode the human k-opioid receptor (Yuferov et al., 2004;Gerra et al., 2007) and prodynorphin (Clarke et al., 2012) have also been associated with a higher risk for opioid addiction.”

• cites Yuferov et al., 2004 sourceSupported
• cites Gerra et al., 2007 sourceNot checked — no full text of the source
• cites Clarke et al., 2012 sourceSupported

In rhesus monkeys, extended opioid exposure and subsequent opioid withdrawal increased the reinforcing strength of heroin in choice responding, supporting negative reinforcement as a source of motivation.

“Studies did show that changes in choice responding in rhesus monkeys during extended opioid exposure and subsequent opioid withdrawal reflected an increase in the reinforcing strength of heroin in a manner that supports the hypothesis that negative reinforcement is a source of motivation (Negus and Banks, 2018).”

• cites Negus and Banks, 2018 sourceSupported

Early-onset adolescent exposure to alcohol, tobacco, and drugs predicts later AUD, substance use disorder, and related problems.

“Early-onset adolescent exposure to alcohol, tobacco, and drugs of abuse also predicts later AUD and substance use disorder and alcohol-and drug-related problems (Grant et al., 2001;Englund et al., 2008;Enoch, 2011).”

• cites Grant et al., 2001 sourceNot checked — no full text of the source
• cites Englund et al., 2008 sourcePartly supported

  The Logistic regression models section (page not available) reports that higher alcohol use at age 16 predicted current alcohol use disorder at age 28 in men. The paper measured adolescent alcohol-use level, not age of first exposure, and these findings do not establish the claimed predictions for tobacco or other drugs, non-alcohol substance use disorders, or drug-related problems. (LLM, conf=0.89)

  Experimental — accuracy not yet measured
• cites Enoch, 2011 sourcePartly supported

  The section on early life stress and early-onset problem drinking (page unavailable) says that alcohol use before age 15 predicts adult alcohol dependence, and that adolescent binge drinking predicts adult alcohol dependence and illicit drug use. It does not establish that early adolescent exposure to tobacco or drugs predicts later substance use disorder or drug-related problems. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Significant hyperkatifeia is associated with psychostimulant, tobacco, and cannabinoid addiction.

“Significant hyperkatifeia is also associated with psychostimulant, tobacco, and cannabinoid addiction from the perspectives of phenotypes and neurocircuitry/neurotransmitter systems (Baker et al., 1987(Baker et al., , 2004;;Diana, 2011;Cook et al., 2015;Koob, 2015;Ashok et al., 2017).”

• cites Baker et al., 1987Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Baker et al., 2004 sourceNot checked — no full text of the source
• cites Diana, 2011 sourcePartly supported

  The Transcranial Magnetic Stimulation section (page unavailable) describes neural changes associated with psychostimulants and cannabis dependence, and Dopamine as a Possible Therapeutic Target (page unavailable) discusses dopaminergic changes after cannabinoid withdrawal. These passages support a neurocircuitry-related aspect of the claim, but they do not establish significant hyperkatifeia—a heightened negative emotional state—for psychostimulant, tobacco, and cannabinoid addiction. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Neurocircuitry dysregulations contribute to links between neural mechanisms of hyperkatifeia and hyperalgesia.

“The argument is that these specific neurocircuitry dysregulations contribute to the links that have been hypothesized to exist between the neural mechanisms that are responsible for hyperkatifeia and hyperalgesia (Shurman et al., 2010;Koob, 2019).”

• cites Shurman et al., 2010 sourceSupported
• cites Koob, 2019Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Cumulative effect of childhood trauma on substance dependence risk: each additional type of violent crime/abuse experience nearly doubles odds of dependence on alcohol, cocaine, and/or opioids.

“For example, there is a cumulative effect of childhood trauma on the risk of substance dependence, in which for every unit increase in the number of types of violent crime/abuse experiences, the odds of a person developing dependence on alcohol, cocaine, and/or opioids almost doubled (Douglas et al., 2010; Fig. 6).”

• cites Douglas et al., 2010 sourceSupported

Optogenetic shutdown of CRF neurons in the CeA selectively suppresses alcohol-dependent drinking in dependent animals.

“More recently, also as noted above, optogenetically shutting off CRF neurons in the CeA selectively suppressed alcohol-dependent drinking, but only in dependent animals (de Guglielmo et al., 2019).”

• cites de Guglielmo et al., 2019 sourceSupported

No clinical studies to date have found efficacy of CRF1 antagonists for other stress-related psychiatric disorders.

“Additionally, no clinical studies to date have found efficacy of CRF 1 receptor antagonists for the treatment of other stress-related psychiatric disorders, such as major depression, generalized anxiety disorder, social anxiety, or posttraumatic stress disorder (Griebel and Holsboer, 2012;Dunlop et al., 2017).”

• cites Griebel and Holsboer, 2012 sourceNot checked — no full text of the source
• cites Dunlop et al., 2017 sourcePartly supported

  The Introduction reports that larger trials found no efficacy for major depression, generalized anxiety disorder, or social anxiety disorder, and the Abstract’s Conclusions report a negative PTSD trial. But the Introduction also says an early human trial suggested efficacy for major depression, so the absolute claim that no clinical study had found efficacy overstates the source. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Hcrt-2 receptor mRNA levels increased in the CeA in long-access rats.

“Additionally, an increase in Hcrt-2 receptor mRNA levels in the CeA in longaccess rats was observed by quantitative polymerase chain reaction.”

• cites Schmeichel et al., 2015 sourcePartly supported

  The Results section reports that Hcrtr2 mRNA increased in the amygdala of long-access rats, measured by qPCR. The Reverse Transcription and Quantitative PCR section says amygdala substructures were not assessed, so the paper does not establish an increase specifically in the CeA. Page numbers are unavailable in our copy. (LLM, conf=0.92)

  Experimental — accuracy not yet measured

Gabapentin reversed sleep disturbances in AUD.

“Notably, gabapentin reversed sleep disturbances in AUD (Mason et al., 2014).”

• cites Mason et al., 2014 sourcePartly supported

  The Discussion reports that participants’ pretreatment sleep disturbances significantly improved with gabapentin relative to placebo, and the Results report a dose-dependent improvement in sleep quality. Neither passage establishes that the disturbances were fully reversed; the claim is stronger than the reported finding. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Hcrt-1 receptor antagonist blocked stress-induced reinstatement of alcohol seeking.

“An Hcrt-1 receptor antagonist also blocked the stress (yohimbine)induced reinstatement of alcohol seeking(Richards et al., 2008).”

• cites Richards et al., 2008 sourceSupported

Systemic administration of an Hcrt-2 receptor antagonist dose-dependently decreased heroin self-administration in long-access but not short-access animals.

“The systemic administration of an Hcrt-2 receptor antagonist dose-dependently decreased heroin self-administration in long-access but not in shortaccess animals in an extended-access procedure(Schmeichel et al., 2015).”

• cites Schmeichel et al., 2015 sourceSupported

Acamprosate blocked sleep disturbances associated with protracted abstinence in humans.

“Acamprosate also blocked sleep disturbances that were associated with protracted abstinence in humans (Perney et al., 2012), again linking its therapeutic actions to the reversal of hyperkatifeia.”

• cites Perney et al., 2012 sourcePartly supported

  The Discussion (page unavailable) reports that acamprosate improved sleep disturbances more quickly than placebo after alcohol withdrawal, with a significant benefit over six months. The Conclusion (page unavailable) also describes improved sleep problems, but neither passage says acamprosate blocked or prevented the disturbances; the paper describes a smaller improvement after accounting for abstinence duration. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Hcrt-1 receptor antagonist dose-dependently decreased alcohol intake, particularly in alcohol-dependent mice.

“The Hcrt-1 receptor antagonist dosedependently decreased alcohol intake, particularly in alcohol-dependent mice(Lopez et al., 2016).”

• cites Lopez et al., 2016 sourcePartly supported

  The Results report that GSK1059865 reduced ethanol intake at every tested dose in ethanol-dependent mice, but only at the highest dose in non-dependent controls. This supports the greater sensitivity of dependent mice; the Results do not establish that intake decreased progressively as dose increased. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Chronic systemic mifepristone during alcohol vapor exposure in rats blocked escalation of drinking during withdrawal.

“Similarly, the chronic administration of mifepristone, a glucocorticoid and progesterone receptor antagonist, when administered systemically in rats during the course of alcohol vapor exposure, blocked the escalation of drinking during withdrawal that developed during dependence induction (Vendruscolo et al., 2012).”

• cites Vendruscolo et al., 2012 sourceSupported

Classically, with opioids and alcohol, individuals with a substance use disorder may start with recreational use during the binge/intoxication stage and progress to the withdrawal/negative affect stage as negative reinforcement evolves.

“Classically, with opioids and alcohol, individuals with a substance use disorder may start with recreational use of the drug during the binge/intoxication stage and progress to the withdrawal/negative affect stage as negative reinforcement evolves (Koob et al., 2019; Fig. 2).”

• cites Koob et al., 2019 sourceNot checked — no full text of the source

Much of the misuse of opioids and alcohol develops because negative reinforcement may be the initial starting point either via self-medication or chronic pain.

“However, much of the misuse of opioids and alcohol also develops because negative reinforcement may be the initial starting point either via selfmedication or chronic pain (Ballantyne et al., 2019).”

• cites Ballantyne et al., 2019 sourceNot checked — no full text of the source

Engagement of neuroadaptations by the addiction cycle triggers a break from hedonic homeostasis and compensatory responses in brain reward and stress systems that generate the withdrawal/negative affect stage.

“The argument here is that such engagement ultimately triggers a break from hedonic homeostasis and subsequent compensatory responses in brain reward and stress systems to generate the withdrawal/negative affect stage (Koob and Le Moal, 1997).”

• cites Koob and Le Moal, 1997 sourceNot checked — no full text of the source

Entrance into the three-stage addiction cycle at any stage can engage neuroadaptations that lead to hyperkatifeia.

“From a physiologic perspective, entrance into the three-stage cycle at any stage can engage neuroadaptations that lead to hyperkatifeia.”

An individual can enter the addiction cycle at different stages.

“Consistent with the spectrum and allostatic framework, an individual can enter the addiction cycle at different stages.”

The theoretical basis of hyperkatifeia as a driving force in negative reinforcement in addiction has its roots in opponent process theory.

“The theoretical basis of hyperkatifeia as a driving force in negative reinforcement in addiction has its roots in opponent process theory.”

In alcohol addiction or AUD, a broader spectrum of drug misuse evolves ranging from binges to constant drinking for fear of withdrawal.

“In alcohol addiction or AUD, a broader spectrum of drug misuse evolves that can range from binges of alcohol intake that can be daily episodes or prolonged days of heavy drinking to constant drinking for fear of withdrawal, similar to opioids.”

In terms of motivation for drug seeking, a new source of acquired motivation is generated, termed negative reinforcement.

“In terms of the motivation for drug seeking, a new source of acquired motivation is generated, termed negative reinforcement (Ahmed and Koob, 2005).”

• cites Ahmed and Koob, 2005 sourceNot checked — no full text of the source

A negative feedforward control construct was theorized that keeps mood in homeostatic balance even with strong perturbations.

“A negative feedforward control construct was theorized that keeps mood in homeostatic balance, even with strong perturbations.”

As a result, a greater amount and more frequent use of the previously rewarding drug is needed to maintain or approach euthymia (tolerance).

“As a result, a greater amount and more frequent use of the previously rewarding drug is needed to maintain or approach euthymia (i.e., tolerance).”

For opioid use disorder, approved treatments targeting hyperkatifeia are mostly opioid drugs that substitute for opioids.

“For opioids, they are mostly drugs that are opioids themselves and substitute for opioids.”

Such a framework has generated significant evidence to suggest that powerful nondrug reinforcers, such as food, can also dysregulate the same motivational constructs and circuits outlined in drug addiction.

“Such a framework has generated significant evidence to suggest that powerful nondrug reinforcers, such as food, can also dysregulate the same motivational constructs and circuits that are outlined herein.”

Masking of the a-process results in apparent tolerance.

“Masking of the a-process results in what has been termed”

• cites Colpaert, 1996 sourceNot checked — no full text of the source
• cites Laulin et al., 1999 sourceNot checked — no full text of the source

Opponent process theory was proposed as a key theory.

“A key theory that was proposed was called opponent process theory (Solomon andCorbit, 1973, 1974;D'Amato, 1974;Hoffman and Solomon, 1974;Solomon, 1980;Koob and Bloom, 1988).”

• cites Solomon and Corbit, 1973 sourceNot checked — no full text of the source
• cites Solomon and Corbit, 1974 sourceNot checked — no full text of the source
• cites Koob and Bloom, 1988 sourceNot checked — no full text of the source

As the opponent b-process grows, symptoms such as dysphoria, anxiety, alexithymia, irritability, sleep disturbances, physical and emotional pain, subjective feelings of unease, and simply not feeling hedonically normal become manifest.

“As the opponent b-process grows, such symptoms as dysphoria, anxiety, alexithymia, irritability, sleep disturbances, physical and emotional pain, subjective feelings of unease, and simply not feeling hedonically normal become manifest.”

Under this framework, substance use is compulsively escalated or renewed (in relapse) via negative-reinforcement mechanisms because it transiently prevents or relieves negative emotional symptoms or hyperkatifeia.

“Under this framework, substance use is compulsively escalated or renewed (in relapse) via negative-reinforcement mechanisms because it transiently prevents or relieves negative emotional symptoms or hyperkatifeia (Koob and Le Moal, 1997).”

• cites Koob and Le Moal, 1997 sourceNot checked — no full text of the source

The argument in this review is that there are elements of drug withdrawal and repeated, chronic drug intake that are expressed in common elements across different drugs of abuse.

“Thus, the argument in this review is that there are elements of drug withdrawal and repeated, chronic drug intake that are expressed in common elements across different drugs of abuse.”

Several lines of evidence, ranging from factor analysis of self-report measures and neuropsychological tests in humans with AUD to a connectome imaging study in mice, have validated the importance of the hyperkatifeia construct as a key stage in the development and maintenance of AUD and other substance use disorders.

“Several lines of evidence, ranging from a factor analysis of responses on self-report measures and neuropsychological tests in humans with AUD to a connectome imaging study in mice, have validated the importance of the hyperkatifeia construct as a key stage in the development and maintenance of AUD and other substance use disorders.”

In OUD, a classic pattern evolves in which the individual must administer the drug to avoid severe dysphoria and discomfort associated with abstinence.

“A classic pattern evolves in which the individual must administer the drug to avoid the severe dysphoria and discomfort that are associated with abstinence (Koob et al., 2019).”

• cites Koob et al., 2019 sourceNot checked — no full text of the source

For alcohol use disorder, approved treatments targeting hyperkatifeia are limited to acamprosate.

“For alcohol, these treatments are limited to acamprosate.”

In opponent process theory, many affective control mechanisms in the brain are hypothesized to serve as an emotional stabilization system that counteracts departures from emotional neutrality or equilibrium, regardless of whether they are aversive or pleasant.

“In opponent process theory, many affective control mechanisms in the brain are hypothesized to serve as an emotional stabilization system that counteracts or opposes departures from emotional neutrality or equilibrium, regardless of whether they are aversive or pleasant (Solomon and Corbit, 1974).”

• cites Solomon and Corbit, 1974 sourceNot checked — no full text of the source

Behavioral differences in Oprm1 mutant mice compared with wild-type mice showed that pain and emotional-like and reward-related behaviors correlated predominantly with alterations within reward/aversion pathways.

“Behavioral differences in Oprm1 mutant mice compared with wild-type mice showed that pain and emotional-like and rewardrelated behaviors correlated predominantly with alterations within reward/aversion pathways (Kieffer and Gaveriaux-Ruff, 2002).”

• cites Kieffer and Gaveriaux-Ruff, 2002 sourceNot checked — no full text of the source

The opponent process reduces the hedonic intensity of the a-process.

“This opponent process reduces the hedonic intensity of the a-process (i.e., the state that the input initially activated).”

Development of the b-process reflects the development of hyperkatifeia (or a constellation of negative emotional withdrawal symptoms), masked at least initially by the hedonic properties of the drug.

“Under this framework, development of the b-process reflects the development of hyperkatifeia (or a constellation of negative emotional withdrawal symptoms), masked at least initially by the hedonic properties of the drug.”

Opioids, psychostimulants, and alcohol activate dynorphin, particularly in the shell of the NAc, triggered by cAMP-to-dynorphin activation.

“Another mechanism to explain the hypodopaminergic state is that opioids, psychostimulants, and alcohol activate dynorphin, particularly in the shell of the NAc, triggered by a cascade of molecular events that involve cAMP-to-dynorphin activation (Carlezon et al., 2000;Chavkin and Koob, 2016).”

• cites Carlezon et al., 2000 sourceNot checked — no full text of the source
• cites Chavkin and Koob, 2016 sourceNot checked — no full text of the source

Data to date suggest that non-arrestin 3 signaling drugs retain undesirable constipating and abuse-related effects with repeated exposure, despite their bias for G protein signaling.

“Thus, data to date suggest that such non-arrestin 3signaling drugs retain undesirable constipating and abuse-related effects with repeated exposure, despite their bias for G protein signaling (Altarifi et al., 2017).”

• cites Altarifi et al., 2017 sourceNot checked — no full text of the source

Brain reward systems that involve connections between the medial forebrain bundle and structures such as the VTA and ventral striatum are compromised during withdrawal from drugs of abuse.

“Brain reward systems that involve connections between the medial forebrain bundle and such structures as the ventral tegmental area (VTA) and ventral striatum are compromised during withdrawal from drugs of abuse (Koob and Le Moal, 2005).”

• cites Koob and Le Moal, 2005 sourceNot checked — no full text of the source

Chronic opioid-induced cAMP-dependent increase in the probability of GABA release in the VTA would inhibit dopamine neurons.

“A prominent observation is a chronic opioid-induced cAMP-dependent increase in the probability of GABA release in the VTA, which would inhibit dopamine neurons (Bonci and Williams, 1997).”

• cites Bonci and Williams, 1997 sourceNot checked — no full text of the source

Lower phosphorylated CREB in the CeA and medial nucleus of the amygdala is associated with anxiety-like responses during withdrawal and an increase in alcohol self-administration.

“Lower phosphorylated CREB in the CeA and medial nucleus of the amygdala is associated with anxiety-like responses during withdrawal and an increase in alcohol self-administration.”

The regions that comprise the extended amygdala have cytoarchitectural and circuitry similarities with each other.

“The regions that comprise the extended amygdala have cytoarchitectural and circuitry similarities with each other (Heimer and Alheid, 1991).”

• cites Heimer and Alheid, 1991 sourceNot checked — no full text of the source

In humans, dopamine dysfunction has been repeatedly observed in detoxified alcohol-dependent subjects using brain imaging.

“In humans, dopamine dysfunction has also been repeatedly observed in detoxified alcohol-dependent subjects using brain imaging (Volkow et al., 1996(Volkow et al., , 2002(Volkow et al., , 2007;;Kuikka et al., 2000).”

• cites Volkow et al., 1996 sourceNot checked — no full text of the source
• cites Kuikka et al., 2000 sourceNot checked — no full text of the source

A conceptual framework adopted to explain the neural systems that mediate opponent process adaptation to excessive reward system engagement and drive negative reinforcement involved within-system downregulation of brain reward circuitry and between-system recruitment of brain stress circuitry.

“A conceptual framework that was adopted to explain the neural systems that mediate the long-hypothesized opponent process adaptation to excessive reward system engagement and drive negative reinforcement involved the within-system downregulation of brain reward circuitry and the between-system recruitment of brain stress circuitry (Koob and Bloom, 1988).”

• cites Koob and Bloom, 1988 sourceNot checked — no full text of the source

Neurons in the lateral habenula fire in response to the presentation of unexpected aversive events.

“Neurons in the lateral habenula fire in response to the presentation of unexpected aversive events (Matsumoto and Hikosaka, 2007).”

• cites Matsumoto and Hikosaka, 2007 sourceNot checked — no full text of the source

The focus of between-system neuroadaptations fell on understanding neurocircuitry within the extended amygdala and its role in opponent process, more specifically hyperkatifeia.

“Subsequently, the focus of between-system neuroadaptations fell on understanding neurocircuitry within the extended amygdala and its role in opponent process, more specifically hyperkatifeia (Koob and Bloom, 1988;Koob and Le Moal, 2008;Koob, 2019).”

• cites Koob and Bloom, 1988 sourceNot checked — no full text of the source
• cites Koob and Le Moal, 2008 sourceNot checked — no full text of the source
• cites Koob, 2019Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

All major drugs of abuse produce elevations of reward thresholds (measured by intracranial self-stimulation) during withdrawal from either chronic drug administration or in animal models of drug self-administration with extended access.

“All major drugs of abuse produce elevations of reward thresholds (measured by intracranial self-stimulation) during withdrawal from either chronic drug administration or in animal models of drug self-administration with extended access.”

• cites Schulteis et al., 1995 sourceNot checked — no full text of the source
• cites Ahmed et al., 2002 sourceNot checked — no full text of the source
• cites Jang et al., 2013aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Rapid acute tolerance and opponent process-like actions against the hedonic effects of psychostimulants have been reported in humans.

“Rapid acute tolerance and opponent process-like actions against the hedonic effects of psychostimulants have been reported in humans (Breiter et al., 1997).”

• cites Breiter et al., 1997 sourceNot checked — no full text of the source

The extended amygdala comprises several basal forebrain structures, including the bed nucleus of the stria terminalis (BNST), central nucleus of the amygdala (CeA), sublenticular substantia innominata, and a transition zone in the shell of the NAc.

“The extended amygdala comprises several basal forebrain structures, including the bed nucleus of the stria terminalis (BNST), central nucleus of the amygdala (CeA), sublenticular substantia innominata, and a transition zone in the shell of the NAc (Heimer and Alheid, 1991).”

• cites Heimer and Alheid, 1991 sourceNot checked — no full text of the source

A blunted cortisol response is commonly reported in individuals with AUD.

“Indeed, a blunted cortisol response is commonly reported in individuals with AUD.”

For opioids, vasopressin has parallels to CRF in its role in opioid addiction.

“For opioids, vasopressin has some parallels to CRF in its role in opioid addiction.”

Norepinephrine activation has long been hypothesized to be involved in opioid withdrawal in animals and in humans.

“Norepinephrine activation has long been hypothesized to be involved in opioid withdrawal in animals, based on neurobiological measures and the pharmacology of withdrawal (Maldonado, 1997), and in humans, based largely on pharmacological studies of opioid withdrawal (Gold et al., 1978;Harris and Gewirtz, 2005).”

• cites Maldonado, 1997 sourceNot checked — no full text of the source
• cites Gold et al., 1978 sourceNot checked — no full text of the source
• cites Harris and Gewirtz, 2005 sourceNot checked — no full text of the source

Norepinephrine inhibition with an alpha2-adrenergic receptor agonist blocked naloxone-precipitated conditioned place aversion in opioid-dependent rats.

“Norepinephrine inhibition with an a 2 -adrenergic receptor agonist blocked naloxone-precipitated conditioned place aversion in opioid-dependent rats (Kosten, 1994;Nader and Van der Kooy, 1996).”

• cites Kosten, 1994 sourceNot checked — no full text of the source
• cites Nader and Van der Kooy, 1996 sourceNot checked — no full text of the source

Opioid withdrawal activates central extrahypothalamic CRF signaling, even long into protracted abstinence, which contributes to negative emotional symptoms associated with opioid withdrawal, such as dysphoria and pain.

“In parallel and linked directly to HPA axis overactivity, opioid withdrawal activates central extrahypothalamic CRF signaling, even long into protracted abstinence, which contributes to negative emotional symptoms that are associated with opioid withdrawal, such as dysphoria and pain.”

Vasopressin mRNA levels increase selectively in the amygdala only during early spontaneous withdrawal from chronic heroin exposure and not during late withdrawal.

“Vasopressin mRNA levels increased selectively in the amygdala only during early spontaneous withdrawal from chronic heroin exposure and not during late withdrawal (Zhou et al., 2008).”

• cites Zhou et al., 2008 sourceNot checked — no full text of the source

CRF1 receptor antagonists selectively decreased heroin self-administration in long-access but not short-access rats in an animal model of extended access.

“CRF 1 receptor antagonists selectively decreased heroin self-administration in long-access but not short-access rats in an animal model of extended access (Greenwell et al., 2009a).”

• cites Greenwell et al., 2009aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Precipitated opioid withdrawal increases the release of CRF in the CeA.

“Precipitated opioid withdrawal increases the release of CRF in the CeA (Weiss et al., 2001).”

• cites Weiss et al., 2001 sourceNot checked — no full text of the source

Chronic or acute blockade of glucocorticoid receptor with mifepristone prevented or reversed the escalation of heroin intake associated with extended access in rats, similar to the effect of a CRF receptor antagonist.

“The chronic or acute blockade of glucocorticoid receptor with mifepristone prevented or reversed the escalation of heroin intake that was associated with extended access in rats, similar to the effect of a CRF receptor antagonist (see above; Carmack et al., unpublished results).”

• cites Carmack et al., unpublished resultsNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The alpha1-adrenergic receptor antagonist prazosin dose-dependently reduced intravenous heroin self-administration in long-access rats but not in short-access rats.

“The a 1 -adrenergic receptor antagonist prazosin dose-dependently reduced intravenous heroin self-administration in long-access rats but not in short-access rats in an animal model of extended access to opioid self-administration that produces dependence (Greenwell et al., 2009b).”

• cites Greenwell et al., 2009bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The location of the circuits that mediate hyperkatifeia to a large extent involves elements of the extended amygdala or its connections.

“The location of the circuits that mediate hyperkatifeia to a large extent involves elements of the extended amygdala or its connections (see above and Fig. 5).”

Noradrenergic function is well documented to be activated during alcohol withdrawal in humans.

“Noradrenergic function is well documented to be activated during alcohol withdrawal in humans (Hawley et al., 1981).”

• cites Hawley et al., 1981 sourceNot checked — no full text of the source

Much of the data show the recruitment of brain stress systems, including CRF, norepinephrine, hypocretin, dynorphin, and glucocorticoids, as major key substrates responsible for hyperkatifeia associated with drug withdrawal and thus compulsive-like drug seeking via negative reinforcement.

“Much of the data show the recruitment of brain stress systems, including CRF, norepinephrine, hypocretin, dynorphin, and glucocorticoids, as major key substrates that are responsible for hyperkatifeia that is associated with drug withdrawal and thus compulsivelike drug seeking via negative reinforcement (Koob and Bloom, 1988;Koob, 2019).”

• cites Koob and Bloom, 1988 sourceNot checked — no full text of the source
• cites Koob, 2019Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Vulnerability to hyperkatifeia in driving AUD and substance use disorders may derive not only from activation of prostress neurotransmitter systems but also from antistress neurotransmitter systems.

“The vulnerability to hyperkatifeia in driving AUD and substance use disorders may derive not only from the activation of prostress neurotransmitter systems but also from antistress neurotransmitter systems (see Fig. 5).”

Glial activation may contribute to hyperkatifeia-like responses observed during opioid withdrawal.

“Glial activation may also contribute to hyperkatifeialike responses that are observed during opioid withdrawal.”

Downregulation of nociceptin levels in the CeA may be responsible for the hyper-GABAergic tone in the CeA observed in individuals who develop addiction-like behaviors.

“The same high-addiction subgroup had lower levels of nociceptin in the CeA, and nociceptin normalized GABAergic transmission in the CeA, suggesting that the downregulation of nociceptin levels in the CeA may be responsible for the hyper-GABAergic tone in the CeA that is observed in individuals who develop addiction-like behaviors.”

Hcrt may have antireward/brain stress actions possibly via the CRF system in the extended amygdala.

“Altogether, these results support the hypothesis that Hcrt may have antireward/ brain stress actions possibly via the CRF system in the extended amygdala.”

Elevations of vasopressin release during withdrawal can promote a negative emotional state that facilitates escalation of drinking to alleviate that aversive state.

“Altogether, these results suggest that elevations of vasopressin release during withdrawal can promote a negative emotional state that in turn facilitates the escalation of drinking to alleviate that aversive state.”

Neuroimmune activation contributes to opioid withdrawal and tolerance.

“In parallel, neuroimmune activation contributes to opioid withdrawal and tolerance.”

Amplification of danger signals and glial activation in the amygdala and other components of brain fear/anxiety/stress neurocircuitry contribute to the progression and persistence of the withdrawal/negative affect stage, possibly by interacting with brain stress systems.

“These studies support the hypothesis that the amplification of danger signals and glial activation in the amygdala and other components of brain fear/anxiety/stress neurocircuitry contribute to the progression and persistence of the withdrawal/negative affect stage, possibly by interacting with brain stress systems.”

For opioids, NPY can potentiate their acute rewarding effects.

“For opioids, NPY can potentiate their acute rewarding effects (Robinson and Thiele, 2017).”

• cites Robinson and Thiele, 2017 sourceNot checked — no full text of the source

Women who become addicted to opioids progress from initial use to dependence at a faster rate than men.

“For opioids, clinical reports indicate that women who become addicted to opioids progress through the stages of addiction, from initial use to dependence, at a faster rate than men (Brady and Randall, 1999).”

• cites Brady and Randall, 1999 sourceNot checked — no full text of the source

Individuals who experienced or expressed physical abuse and violent behavior described opioids as helping them feel normal, calm, mellow, soothed, and relaxed.

“Individuals who experienced or expressed physical abuse and violent behavior described the ways in which opioids helped them feel normal, calm, mellow, soothed, and relaxed (Khantzian, 1985).”

• cites Khantzian, 1985 sourceNot checked — no full text of the source

In individuals with opioid addiction, pain is one of the main triggers of relapse.

“In these individuals, pain is one of the main triggers of relapse to addiction (Compton et al., 2001).”

• cites Compton et al., 2001 sourceNot checked — no full text of the source

Increases in GTPγS binding of k-opioid receptor-specific ligands in the amygdala are associated with anxiety produced by chronic pain or neuropathic pain.

“Increases in the GTPgs binding of k-opioid receptor-specific ligands in the amygdala were associated with anxiety that was produced by Complete Freund's Adjuvantinduced chronic pain or sciatic nerve ligation-induced neuropathic pain (Narita et al., 2006).”

• cites Narita et al., 2006 sourceNot checked — no full text of the source

A single injection of heroin in rats produces hyperalgesia.

“Such hyperalgesia has also been observed with a single injection of heroin in rats (Laulin et al., 1998).”

• cites Laulin et al., 1998 sourceNot checked — no full text of the source

Opioid-induced hyperalgesia is reduced in PKCg gene knockout mice.

“Given that protein kinase C (PKC) regulates NMDA receptors, opioid-induced hyperalgesia was also reduced in PKCg gene knockout mice (Célèrier et al., 2004).”

• cites Célèrier et al., 2004 sourceNot checked — no full text of the source

Male rats exhibit greater hangover-like anxiety-like responses during acute alcohol withdrawal.

“Male rats also exhibit greater hangoverlike anxiety-like responses (acute alcohol withdrawal; Varlinskaya and Spear, 2004).”

• cites Varlinskaya and Spear, 2004 sourceNot checked — no full text of the source

Activation of NMDA pronociceptive processes by opioids may be involved in the development of hyperalgesia after chronic opioid treatment.

“Behavioral studies in rodents have shown that the activation of NMDA pronociceptive processes by opioids may be involved in the development of hyperalgesia that is classically observed after chronic opioid treatment (Célèrier et al., 1999;Laulin et al., 2002; see the Within-System Neuroadaptations section above).”

• cites Célèrier et al., 1999 sourceNot checked — no full text of the source
• cites Laulin et al., 2002 sourceNot checked — no full text of the source

Opioid withdrawal-induced hyperalgesia involves activation of the same brain stress systems (CRF and dynorphin) implicated in hyperkatifeia.

“Opioid withdrawal-induced hyperalgesia also includes the activation of the same brain stress systems (e.g., CRF and dynorphin) that are implicated in hyperkatifeia in general.”

Methadone-maintained patients have low pain tolerance.

“Methadone-maintained patients have low pain tolerance (Doverty et al., 2001).”

• cites Doverty et al., 2001 sourceNot checked — no full text of the source

Male rats exhibit greater physical signs of alcohol withdrawal, such as greater seizure susceptibility, compared with female rats.

“Male rats also exhibit greater physical signs of withdrawal, such as greater seizure susceptibility, compared with female rats (Devaud and Chadda, 2001).”

• cites Devaud and Chadda, 2001 sourceNot checked — no full text of the source

NMDA receptor antagonists, such as ketamine, block hyperalgesia in animal models.

“NMDA receptor antagonists, such as ketamine, blocked hyperalgesia in animal models (Célèrier et al., 2000).”

• cites Célèrier et al., 2000 sourceNot checked — no full text of the source

Acute opioid administration can produce hyperalgesia, as shown by naloxone challenge in non-opioid-dependent individuals.

“Non-opioid-dependent individuals who underwent an acute opioid physical dependence challenge with naloxone exhibited the presence of hyperalgesia in response to experimental cold-pressor pain, thus showing that even acute opioid administration can produce hyperalgesia (Compton et al., 2003).”

• cites Compton et al., 2003 sourceNot checked — no full text of the source

Intralateral habenula infusion of serotonin 5-HT2 receptor antagonists or a serotonin reuptake blocker decreases nociceptive sensitivity and alcohol intake in alcohol-withdrawn rats.

“Intralateral habenula infusion of serotonin 5-hydroxytryptamine-2 receptor antagonists or a serotonin reuptake blocker decreased nociceptive sensitivity and alcohol intake in alcohol-withdrawn rats (Zuo et al., 2019).”

• cites Zuo et al., 2019 sourceNot checked — no full text of the source

Glutamate, CRF, the dynorphin/k-opioid receptor system, and the melanocortin system play a role in modulating the interplay between pain, stress, and reward processing.

“Thus, there appears to be some role for glutamate, CRF, the dynorphin/k-opioid receptor system, and the melanocortin system in modulating the interplay between pain, stress, and reward processing.”

Blockade of CRF1 receptors in the CeA inhibits both pain- and anxiety-like behaviors in a model of arthritic pain.

“In a model of arthritic pain, the blockade of CRF 1 receptors in the CeA inhibited both pain-and anxiety-like behaviors (Ji et al., 2007;Fu and Neugebauer, 2008).”

• cites Ji et al., 2007Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Fu and Neugebauer, 2008 sourceNot checked — no full text of the source

There is an association between pain and alcohol use and misuse.

“An association between pain and alcohol use and misuse is supported by clinical studies and metaanalyses.”

Individuals with chronic pain have significantly greater odds of meeting DSM-IV criteria for alcohol abuse/dependence.

“Additionally, individuals with chronic pain had significantly greater odds of also meeting DSM-IV criteria for alcohol abuse/dependence (Demyttenaere et al., 2007).”

• cites Demyttenaere et al., 2007 sourceNot checked — no full text of the source

Optogenetic stimulation of dynorphin-containing neurons in the ventral NAc shell decreases motivation to self-administer sucrose in mice.

“At the microcircuitry level, the stimulation of specifically dynorphin-containing neurons in the ventral NAc shell by selectively expressing channelrhodopsin-2 in dynorphin-Cre+ mice decreased the motivation to selfadminister sucrose.”

Individuals often report consuming alcohol to self-medicate physical and emotional pain.

“Individuals often report consuming alcohol to selfmedicate physical and emotional pain (Holahan et al., 2001;Brennan et al., 2005;Aira et al., 2008;Riley and King, 2009;Zale et al., 2015).”

• cites Holahan et al., 2001 sourceNot checked — no full text of the source
• cites Brennan et al., 2005 sourceNot checked — no full text of the source
• cites Aira et al., 2008 sourceNot checked — no full text of the source

Medications that address both physical and emotional pain may be useful for treating alcohol and drug addiction.

“These findings also suggest that medications that address both physical and emotional pain may be useful for treating alcohol and drug addiction.”

Antisense oligodeoxynucleotide to PKCε blocks alcohol withdrawal-induced hyperalgesia.

“Other molecular targets include PKC«, in which the administration of an antisense oligodeoxynucleotide to PKC« blocked alcohol withdrawal-induced hyperalgesia (Shumilla et al., 2005;Dina et al., 2006).”

• cites Shumilla et al., 2005 sourceNot checked — no full text of the source
• cites Dina et al., 2006 sourceNot checked — no full text of the source

Data showing increases in rewarding effects of opioids or opioid self-administration after chronic pain are limited.

“However, although a few mouse studies have shown some increase in drinking with chronic pain in a neuropathic model of pain (González-Sepúlveda et al., 2016) and osteoarthritis model of pain (Butler et al., 2017), the data to date that show increases in the rewarding effects of opioids or increases in opioid self-administration after chronic pain have been limited (Ozaki et al., 2002;Narita et al.”

• cites Ozaki et al., 2002 sourceNot checked — no full text of the source
• cites Narita et al., 2005 sourceNot checked — no full text of the source
• cites Martin et al., 2007 sourceNot checked — no full text of the source

Early onset of drug use is a significant predictor of subsequent drug abuse.

“When the prevalence of lifetime illicit or nonmedical drug use and dependence was estimated for each year of onset of drug use from the ages of 13 and ,21 years, the early onset of drug use was a significant predictor of the subsequent development of drug abuse (Hingson et al., 2003).”

• cites Hingson et al., 2003 sourceNot checked — no full text of the source

CRF1 SNPs predict greater alcohol consumption in dependent individuals.

“In individuals who were already dependent, CRF 1 SNPs also predicted greater alcohol consumption (Treutlein et al., 2006).”

• cites Treutlein et al., 2006 sourceNot checked — no full text of the source

Acute alcohol exposure in rodents produces an anxiolytic-like response mediated by HDAC inhibition, histone acetylation, and chromatin opening.

“Acute alcohol exposure in rodents produces an anxiolytic-like response that is mediated at least partially by the inhibition of histone deacetylase, an increase in histone acetylation, and an increase in the opening of chromatin (Pandey et al., 2008a).”

• cites Pandey et al., 2008aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Knowledge of neuroadaptations within the hyperkatifeia construct provides fertile ground for developing new treatments for AUD, OUD, and other addictions.

“The thesis outlined herein is that the knowledge of neuroadaptations that occur within the framework of the hyperkatifeia construct of the addiction cycle withdrawal/negative affect stage provides fertile ground for developing new treatments for AUD and OUD and, by extrapolation, other drugs of addiction.”

Chromatin opening increases synaptic plasticity-related genes (BDNF, Arc, NPY) in the CeA.

“Such an opening of chromatin results in an increase in synaptic plasticity-related genes, such as BDNF, and an increase in activityrelated cytoskeleton-associated protein and NPY in the CeA (Pandey et al., 2008a,b).”

• cites Pandey et al., 2008aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Pandey et al., 2008bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Other negative results for the hyperkatifeia hypothesis have been reported based on behavioral procedures that reflect elements of compulsive-like responding for drugs.

“Other negative results for the hyperkatifeia hypothesis have been reported based on behavioral procedures that reflect elements of compulsive-like responding for drugs.”

CRF in the extended amygdala may play an important role in hyperkatifeia driving compulsive-like drug seeking for opioids and alcohol via negative reinforcement.

“Thus, CRF in the extended amygdala may play an important role in the development of hyperkatifeia that drives compulsive-like drug seeking that is associated with opioids and alcohol via a negative-reinforcement process (Koob, 2019).”

• cites Koob, 2019Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

There are limited data on effects of CRF1 receptor antagonists on addiction in humans.

“Despite the overwhelming evidence that CRF 1 receptor antagonists block hyperkatifeia-like responses in rodents, there are limited data on the effects of CRF 1 receptor antagonists on addiction in humans.”

A validation of the present thesis may be derived from construct validity, in which treatments for hyperkatifeia in animal models are effective in OUD and AUD in the clinical setting.

“A validation of the present thesis may be derived not only from such observations as a compromised dopamine system or sensitized HPA system in animal models and humans but also from construct validity, in which the observations that treatments for hyperkatifeia in animal models are effective in OUD and AUD in the clinical setting.”

Methadone and levo-alpha-acetylmethadol substitute for morphine self-administration.

“Several studies have shown that methadone and levo-a-acetylmethadol substitute for morphine self-administration (Jones and Prada, 1977;Moreton et al., 1976;Young et al., 1978).”

• cites Jones and Prada, 1977 sourceNot checked — no full text of the source
• cites Moreton et al., 1976 sourceNot checked — no full text of the source
• cites Young et al., 1978 sourceNot checked — no full text of the source

AUD and OUD move to compulsive drug seeking via negative-reinforcement mechanisms because drug use transiently prevents or relieves negative emotional symptoms or hyperkatifeia.

“As discussed above, AUD and OUD are hypothesized to move to compulsive drug seeking via negativereinforcement mechanisms because the use of these drugs transiently prevents or relieves negative emotional symptoms or hyperkatifeia.”

Full agonist treatment is expected to be transient because each subsequent treatment contributes to future hyperkatifeia, driving further tolerance and drug seeking.

“However, one would expect a full agonist treatment to be transient because each subsequent treatment would contribute to future hyperkatifeia, which would consequently drive further tolerance and drug seeking (Masten et al., 1978).”

• cites Masten et al., 1978 sourceNot checked — no full text of the source

Methadone-maintained individuals reestablish a homeostatic-like level of HPA activity.

“Moreover, in the domain of stress dysregulation, the pioneering work of Kreek and colleagues showed that methadonemaintained individuals reestablish a homeostatic-like level of HPA activity (Kreek, 1973;Kreek and Koob, 1998).”

• cites Kreek, 1973 sourceNot checked — no full text of the source
• cites Kreek and Koob, 1998 sourceNot checked — no full text of the source

Escape from and avoidance of negative affect are powerful motives for compulsive drug use.

“Here, as hypothesized by opponent process and allostatic theories, escape from and the avoidance of negative affect are powerful motives for compulsive drug use (Solomon, 1980;Koob and Le Moal, 2001;Baker et al., 2004;Evans and Cahill, 2016).”

• cites Solomon, 1980 sourceNot checked — no full text of the source
• cites Koob and Le Moal, 2001Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Baker et al., 2004 sourceNot checked — no full text of the source