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

In the paper

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

What the sources say

• Disputed

  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.

  cites Kuzmin et al., 2009 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Lawton and Simpson, 2009 source
• Disputed

  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.

  cites Edlund et al., 2013 sourceExperimental — accuracy not yet measured

In the paper

“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)).”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Moore et al., 2017 source
• ?Not checked — no full text of the sourcecites Moore et al., 2019 source

In the paper

“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).”

What the sources say

• Partly 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)

  cites Shurman et al., 2010 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Koob, 2019 source

In the paper

“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).”

What the sources say

• Partly 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)

  cites Kwako et al., 2016 sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Supported

  The Results and Discussion report that direct statistical comparison of control and Oprm1−/− mice found connectivity changes concentrated in pain- and aversion-related nodes, leading to a conclusion of predominant reshaping of networks that process negative-valence information. The same section says the hub analysis reached a similar conclusion. (LLM, conf=0.95)

  cites Mechling et al., 2016 source

In the paper

“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).”

What the sources say

• Partly 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)

  cites Kwako et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Partly 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)

  cites Mechling et al., 2016 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Mechling et al., 2016 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Diana et al., 1993 source
• Supported

  The Ethanol withdrawal results report a progressive decline in accumbal dopamine during the eight hours after ethanol was removed from dependent rats exposed to a chronic ethanol diet. The Discussion likewise describes a withdrawal-associated fall in dopamine release. Page numbers are unavailable in our copy. (LLM, conf=0.93)

  cites Weiss et al., 1996 source

In the paper

“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).”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Cahill et al., 2016 source

In the paper

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

What the sources say

• Partly 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)

  cites Stamatakis and Stuber, 2012 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Partly 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)

  cites Hikosaka, 2010 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Partly 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)

  cites Hwa et al., 2017 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Boileau et al., 2003 source
• Supported

  The Discussion reports alcohol-induced dopamine release measured in vivo in young adults and estimates increases in extracellular dopamine after the alcohol challenge. The paper identifies the measurement as a [11C]raclopride PET study of oral alcohol in non-alcoholic participants. (LLM, conf=0.93)

  cites Urban et al., 2010 source

In the paper

“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).”

What the sources say

• Partly 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)

  cites Hikosaka, 2010 sourceExperimental — accuracy not yet measured
• Supported

  The Abstract describes habenular signaling that inhibits dopamine neurons in the VTA through the RMTg and links this pathway to reward and drug abuse. “Habenular Control of Dopamine, Serotonin, and Norepinephrine” says LHb signals affect the VTA and likely modulate dopamine release; “The Medial and the Lateral Habenula” suggests a role for the LHb in addiction. Page numbers were not provided. (LLM, conf=0.92)

  cites Velasquez et al., 2014 source
• Partly 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)

  cites Boulos et al., 2017 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Wang et al., 1997 source
• Partly 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)

  cites Ashok et al., 2017 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Partly 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)

  cites Koob and Volkow, 2010 sourceExperimental — accuracy not yet measured
• Supported

  The Abstract reports reduced dopamine-neuron activity in alcohol-, opiate-, and other drug-dependent rats, and decreased nucleus accumbens dopamine release in virtually all drug-dependent rodents. The section “Dopamine as a Possible Therapeutic Target” also describes mesolimbic dopamine hypofunction in addiction, including findings for alcohol- and morphine-dependent rats. No page numbers are provided in our copy. (LLM, conf=0.91)

  cites Diana, 2011 source

In the paper

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

What the sources say

• Supported

  Section 8 reports that a CRF antagonist injected into the central nucleus of the amygdala reversed conditioned place aversion caused by opioid withdrawal in rats. The paper identifies this as an aversive stimulus effect of withdrawal and discusses the extended amygdala as the proposed site of action. (LLM, conf=0.88)

  cites Koob, 2015 source

In the paper

“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)).”

What the sources say

• Partly 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)

  cites de Guglielmo et al., 2016 sourceExperimental — accuracy not yet measured
• Supported

  The Introduction reports that withdrawal activates CeA CRF neurons and that the effect on dependence-induced drinking requires their terminals in the BNST. The Discussion states that activation of the CeA–BNST CRF pathway is required for escalated drinking in dependent rats. (LLM, conf=0.94)

  cites de Guglielmo et al., 2019 source

In the paper

“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).”

What the sources say

• Partly 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)

  cites Knapp et al., 2004 sourceExperimental — accuracy not yet measured
• ?Not matched

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

  cites Overstreet et al., 2004a
• ?Not checked — no full text of the sourcecites Funk et al., 2007 source

In the paper

“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).”

What the sources say

• Supported

  The Drug treatments section describes intraperitoneal administration of CRA1000, a systemic treatment. The Discussion reports that this selective CRF1 receptor antagonist dose-dependently blocked withdrawal-induced social-interaction deficits, the study’s measure of anxiety-like behavior in rats. (LLM, conf=0.93)

  cites Knapp et al., 2004 source
• ?Not matched

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

  cites Overstreet et al., 2004b
• Supported

  The Drug Testing section describes intraperitoneal administration of the CRF1-receptor antagonist CP154,526, establishing systemic delivery. The Discussion reports that a CRF1-receptor antagonist administered during repeated ethanol withdrawals prevented withdrawal-induced anxiety-like behavior; the paper’s own experiments also found reduced stress-induced anxiety during abstinence after withdrawal. (LLM, conf=0.88)

  cites Breese et al., 2005 source

In the paper

“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).”

What the sources say

• Supported

  The Methods (Experimental design; page unavailable) describe rats made dependent through chronic intermittent alcohol-vapor exposure. The Results (Experiment 2; page unavailable) report lower corticosterone responses to an alcohol challenge in dependent rats than in low-responding non-dependent rats, supporting the citing sentence’s paraphrase. (LLM, conf=0.90)

  cites Richardson et al., 2008 source

In the paper

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

What the sources say

• Partly 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)

  cites Nealey et al., 2011 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Hölter et al., 2000 source
• Partly 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)

  cites Walker and Koob, 2008 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Nestler, 2004 source
• ?Not matched

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

  cites Koob, 2008
• Supported

  The section “Ethanol exposure in adulthood” states that voluntary ethanol consumption increases dynorphin expression or the mRNA encoding it, supporting the alcohol self-administration portion attributed to this source. The psychostimulant and opioid portion is attached to other citations, not this one. (LLM, conf=0.88)

  cites Karkhanis and Al-Hasani, 2020 source

In the paper

“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).”

What the sources say

• Supported

  The Results report increased CRF-like immunoreactivity in amygdala dialysate during ethanol withdrawal. Probe placement included the lateral central amygdala and the medial border of the basolateral amygdala, and the Discussion identifies central-amygdala CRF neurons as a possible source. This citation is attached to the CeA claim; the BNST claim has a separate citation. (LLM, conf=0.88)

  cites Merlo-Pich et al., 1995 source
• Supported

  The citation to Olive et al. (2002) supports the BNST portion of the sentence; the CeA portion is attributed to a different study. In the Discussion (section 4), Olive et al. report increased extracellular CRF levels in the BNST during acute ethanol withdrawal. (LLM, conf=0.95)

  cites Olive et al., 2002 source

In the paper

“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).”

What the sources say

• Supported

  The Study Sample section reports that 150 participants were randomized, and Study Design describes a 12-week, multisite, placebo-controlled trial. Secondary Efficacy Outcomes reports a significantly greater percentage of days abstinent with ABT-436 than placebo. The effect was analyzed in a smaller group than the 150 randomized participants, but the claim does not say all 150 were analyzed. (LLM, conf=0.94)

  cites Ryan et al., 2017 source

In the paper

“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).”

What the sources say

• Supported

  The Results (Fig. 5B; page not provided) report that intra-CeA nociceptin selectively reduced oxycodone self-administration in high-addiction (HA) rats. Materials and Methods states that injections began after escalation was established and identifies oxycodone self-administration as intravenous; the Discussion identifies the rats as outbred heterogeneous-stock rats. (LLM, conf=0.91)

  cites Kallupi et al., 2020 source

In the paper

“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).”

What the sources say

• Supported

  The “Liver-gut axis in alcoholic liver disease” section says alcohol can impair the gut barrier and that microbial products entering the liver activate Kupffer cells and other immune cells. The Abstract identifies gut-derived lipopolysaccharide (LPS) as a trigger of Kupffer-cell activation and describes inflammatory activation in alcoholic liver disease. (LLM, conf=0.94)

  cites Szabo et al., 2011 source

In the paper

“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).”

What the sources say

• Supported

  The Results section, “Oxytocin blocks alcohol’s effects on GABA release in dependent rats,” reports that oxytocin blocked the alcohol-induced increase in GABA release only in CeA neurons from alcohol-dependent rats. The Discussion specifies that this finding concerns spontaneous, action-potential–dependent GABA release; oxytocin also blunted alcohol’s effect on evoked GABAergic responses in both groups. (LLM, conf=0.93)

  cites Tunstall et al., 2019 source

In the paper

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

What the sources say

• Supported

  The Discussion reports that intranasal and intracerebroventricular oxytocin blocked the enhanced motivation for alcohol drinking in alcohol-dependent rats. It also states that both routes reduced their increased alcohol consumption. (LLM, conf=0.94)

  cites Tunstall et al., 2019 source

In the paper

“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).”

What the sources say

• Supported

  The Abstract explicitly concludes that proinflammatory cytokines expressed in PAG astrocytes may play an important role in morphine withdrawal. The Discussion supports this with findings that withdrawal induces astrocytic TNFα release in the PAG and that blocking TNFα signaling reduces withdrawal responses. (LLM, conf=0.95)

  cites Hao et al., 2011 source

In the paper

“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).”

What the sources say

• Partly 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)

  cites Crews et al., 2017 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Supported

  The Results report that intraventricular Hcrt-1 elevated ICSS thresholds in rats and produced a long-lasting reward deficit. The Discussion likewise interprets the higher thresholds as reduced activity in brain reward systems, supporting the citing sentence’s hedged inference of an aversive effect. Page numbers were not available in our copy. (LLM, conf=0.90)

  cites Boutrel et al., 2005 source

In the paper

“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).”

What the sources say

• Supported

  Section 3 reports increased orexin/hypocretin mRNA in the rat lateral hypothalamus during acute withdrawal from chronic intermittent escalating-dose morphine. This directly supports the claimed procedure, location, and withdrawal state; the provided passage does not specify a page. (LLM, conf=0.94)

  cites Zhou et al., 2010 source

In the paper

“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).”

What the sources say

• ?Could 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)

  cites Qin et al., 2007 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Partly 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)

  cites Koob and Volkow, 2010 sourceExperimental — accuracy not yet measured
• Partly 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)

  cites Crews and Vetreno, 2016 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Eriksson and Pikkarainen, 1968 source
• Supported

  The Animal Models section (page unavailable) reports greater alcohol intake in female rats of various strains and greater consumption in female mice across adolescence and adulthood. It also notes exceptions, so the claim is supported as a general pattern, not a universal rule. (LLM, conf=0.88)

  cites Becker and Koob, 2016 source

In the paper

“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).”

What the sources say

• Partly 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)

  cites Célèrier et al., 2001 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Simonnet and Rivat, 2003 source

In the paper

“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)).”

What the sources say

• Supported

  In “Opioid Receptors Modulate Pain and Reward,” the review says chronic pain produces anxiety and dysphoria, suggesting engagement of the dynorphin/kappa opioid system. Its abstract also says the system may contribute to the negative emotional states associated with chronic pain. The citing sentence’s “may” preserves that uncertainty. (LLM, conf=0.93)

  cites Cahill et al., 2014 source
• Supported

  The Introduction says the dynorphin/kappa opioid receptor system is highly involved in chronic pain processing and describes pain as a negative affective state. The section “Dopamine and kappa opioid system in chronic pain and stress disorders” also describes evidence for KOR involvement in chronic-pain-induced changes and a possible sustained dysphoric state during pain. The citing sentence's cautious “may” is consistent with this account. (LLM, conf=0.93)

  cites Massaly et al., 2016 source
• Partly 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)

  cites Massaly et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Supported

  The review’s Withdrawal/Negative Affect section describes only a few animal studies of sex differences in opioid withdrawal. Its “What We Do Not Know” section says there were no studies of opioid withdrawal or relapse across the reproductive cycle in rodents. Together, these passages support the claim that preclinical work on sex differences in opioid-related negative affect and reinforcement was limited. (LLM, conf=0.86)

  cites Becker and Koob, 2016 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Ho and Dole, 1979 source
• Supported

  The Discussion reports that people with opiate addiction who had been abstinent for four months showed shorter pain-tolerance times and greater pain-related distress than healthy controls, which the authors describe as a hyperalgesic state. The Introduction also reports hyperalgesia among people with a history of long-term opiate use. The study found similar pain-intensity ratings between groups, so its finding concerns tolerance and distress rather than every measure of pain perception. (LLM, conf=0.91)

  cites Ren et al., 2009 source

In the paper

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

What the sources say

• Supported

  The Results report no statistically significant difference in total oxazepam dose between the oxytocin and placebo groups. The Discussion identifies this as the principal finding for the three-day alcohol withdrawal treatment, although the mean dose was numerically lower with oxytocin. (LLM, conf=0.94)

  cites Melby et al., 2019 source

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Li and Lumeng, 1984 source
• ?Could 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)

  cites Moore and Lynch, 2015 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Tilson et al., 1973 source
• Partly 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)

  cites Angst and Clark, 2006 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• ?Not matched

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

  cites Edwards et al., 2012b
• Supported

  The Methods (Drugs; page unavailable) describe systemic administration of the CRF1 antagonist MPZP. In the extended-access heroin experiment, the Results report higher paw-withdrawal thresholds after chronic MPZP treatment, and the Discussion describes this as an absence of hyperalgesia. The treatment was given repeatedly before self-administration sessions, rather than as a single dose during withdrawal. (LLM, conf=0.90)

  cites Park et al., 2015 source

In the paper

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

What the sources say

• Supported

  The Discussion reports that female mice were less sensitive to morphine withdrawal than males when the withdrawal-sign scores were compared. The Behavioral studies results also report a significant sex difference between the withdrawal groups. The study concerned prepubertal mice undergoing naloxone-precipitated withdrawal. (LLM, conf=0.90)

  cites Diaz et al., 2005 source

In the paper

“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).”

What the sources say

• Supported

  The Introduction identifies the post-mortem comparison as males with AUD versus non-dependent males. The Discussion reports a significant increase in prefrontal-cortex OXT peptide mRNA in the AUD group compared with controls. (LLM, conf=0.95)

  cites Lee et al., 2017 source

In the paper

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

What the sources say

• Partly 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)

  cites Zale et al., 2015 sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• Supported

  The Discussion reports that participants in the experimental pain condition had greater urge to drink and intention to consume alcohol than those without pain induction. It also states that pain-induced negative affect mediated both effects. (LLM, conf=0.95)

  cites Moskal et al., 2018 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Gatch et al., 1999 source
• ?Not checked — no full text of the sourcecites Gatch, 2009 source
• Supported

  Section 2.2 reports reduced nociceptive thresholds in ethanol-dependent rats and describes ethanol withdrawal-induced hyperalgesia. Section 4.3 explicitly refers to hyperalgesia during alcohol withdrawal in animal pain assays, supporting the claim about abstinence after chronic exposure. (LLM, conf=0.92)

  cites Egli et al., 2012 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Gatch et al., 1999 source
• ?Not checked — no full text of the sourcecites Gatch, 2009 source
• Supported

  Section 2.2 reports reduced nociceptive thresholds in ethanol-dependent rats, and Section 6 reports heightened sensitivity to mechanical stimulation after repeated withdrawals. The Introduction also describes hyperalgesia after alcohol withdrawal, while the References identify a rat study of withdrawal and thermal nociception. Together, these passages support the claim that rodent withdrawal models show hyperalgesia across more than one type of pain measure. (LLM, conf=0.86)

  cites Egli et al., 2012 source

In the paper

“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).”

What the sources say

• Partly 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)

  cites Kwako et al., 2016 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Larson et al., 2007 source
• Partly 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)

  cites Caldeiro et al., 2008 sourceExperimental — accuracy not yet measured
• Partly 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)

  cites Witkiewitz et al., 2015 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Supported

  The Results section on ketoprofen, morphine, and norBNI states that norBNI did not alter lactic acid-induced depression of either nucleus accumbens dopamine or intracranial self-stimulation (ICSS). The Results section on lactic acid describes a rightward shift in the ICSS frequency–rate curve, consistent with the citing sentence’s description of elevated brain reward thresholds. Page numbers are unavailable in our copy. (LLM, conf=0.91)

  cites Leitl et al., 2014 source

In the paper

“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).”

What the sources say

• Supported

  The Discussion explicitly states that pharmacological, optogenetic, and chemogenetic approaches showed both dynorphin-containing neurons and KOR activity in the NAc shell to be necessary and sufficient for pain-induced negative affective states. No page number is supplied for the passage. (LLM, conf=0.95)

  cites Massaly et al., 2019 source

In the paper

“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).”

What the sources say

• Supported

  The Results (§3.4; page unavailable) report that JDTic failed to reduce acetic acid-induced conditioned place aversion in mice. The Methods (§2.2; page unavailable) state that test drugs were injected subcutaneously, a systemic route, and the Discussion identifies the acetic acid stimulus as visceral pain. (LLM, conf=0.93)

  cites Bagdas et al., 2016 source

In the paper

“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).”

What the sources say

• Supported

  The Discussion (p. 21) says the meta-analysis examined 18 controlled studies of healthy individuals and found effects supporting alcohol analgesia. The Abstract (p. 3) specifies alcohol-versus-no-alcohol comparisons and reports increased pain thresholds and reduced pain intensity. (LLM, conf=0.95)

  cites Thompson et al., 2017 source

In the paper

“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).”

What the sources say

• Supported

  The Results subsection on systemic KOR blockade reports that nor-BNI significantly prevented stress-induced loss of the DNIC response in morphine-primed rats, measured in both hindpaws. The supplied passage does not specify a page number. (LLM, conf=0.95)

  cites Nation et al., 2018 source

In the paper

“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).”

What the sources say

• Supported

  The Introduction (page unavailable) states that alcohol use disorder is highly comorbid with anxiety and depression, and identifies extended-amygdala circuits as regulators of mood and affect involved in the negative emotional state of withdrawal. It also describes heightened anxiety, irritability, and dysphoria during withdrawal and abstinence, supporting the claim’s reference to hyperkatifeia without using that term. (LLM, conf=0.84)

  cites Centanni et al., 2019 source

In the paper

“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.”

What the sources say

• Supported

  The Results report a significant association between OPRK1 haplotypes and opiate addiction, including a haplotype found only in Hispanic cases and not controls. The Discussion likewise identifies a significant association in Hispanics. This citation supports the kappa-opioid-receptor portion of the sentence; the prodynorphin portion is attributed to a different citation. (LLM, conf=0.90)

  cites Yuferov et al., 2004 source
• ?Not checked — no full text of the sourcecites Gerra et al., 2007 source
• Supported

  The Results report that the PDYN variant rs1022563 was associated with higher odds of opioid addiction in European Americans (OR 1.31), with a stronger association in women (OR 1.51). The citation to Clarke et al. supports the prodynorphin part of the sentence; the kappa-opioid receptor gene is attributed to other citations. The paper found no significant PDYN association in African Americans. (LLM, conf=0.90)

  cites Clarke et al., 2012 source

In the paper

“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).”

What the sources say

• Supported

  The “Effects of Opioid Exposure and Withdrawal on Heroin Choice” section says that heroin-versus-food choice results in rhesus monkeys support the hypothesis that opioid exposure and withdrawal can increase heroin’s reinforcing strength, consistent with negative reinforcement. The citing sentence preserves that interpretation as support for a hypothesis. (LLM, conf=0.94)

  cites Negus and Banks, 2018 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Grant et al., 2001 source
• Partly 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)

  cites Englund et al., 2008 sourceExperimental — accuracy not yet measured
• Partly 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)

  cites Enoch, 2011 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• ?Not matched

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

  cites Baker et al., 1987
• ?Not checked — no full text of the sourcecites Baker et al., 2004 source
• Partly 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)

  cites Diana, 2011 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Supported

  The Introduction asks whether the neural mechanisms of hyperkatifeia and opioid-induced hyperalgesia are linked and says stress-system neuroadaptations associated with addiction may overlap with neural substrates of emotional pain processing. It also hypothesizes that excessive opioid use disrupts emotional regulation and engages processes associated with both conditions. The claim retains the paper’s hypothetical framing; page numbers were not supplied. (LLM, conf=0.89)

  cites Shurman et al., 2010 source
• ?Not checked — no full text of the sourcecites Koob, 2019 source

In the paper

“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).”

What the sources say

• Supported

  The Discussion states that the study found a cumulative effect of childhood trauma: each additional type of violent crime or abuse experience nearly doubled the odds of dependence on alcohol, cocaine, and/or opioids. The Methods define the count as ranging from zero to three types of experience. (LLM, conf=0.95)

  cites Douglas et al., 2010 source

In the paper

“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).”

What the sources say

• Supported

  The Results section (‘Optogenetic inhibition of CeA CRF neurons’) reports that inhibition did not affect drinking in nondependent rats, whereas laser activation selectively reduced alcohol self-administration after the rats became dependent. The Discussion likewise describes a reversible decrease in drinking in dependent rats. (LLM, conf=0.94)

  cites de Guglielmo et al., 2019 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Griebel and Holsboer, 2012 source
• Partly 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)

  cites Dunlop et al., 2017 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Partly 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)

  cites Schmeichel et al., 2015 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Partly 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)

  cites Mason et al., 2014 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Supported

  The Discussion section reports that the OX-1/Hcrt-1 receptor antagonist SB334867 attenuated yohimbine-induced reinstatement of ethanol seeking in rats. Its Methodological considerations section also calls the effect a blockade of yohimbine-induced reinstatement. Page numbers were not available in our copy. (LLM, conf=0.93)

  cites Richards et al., 2008 source

In the paper

“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).”

What the sources say

• Supported

  The Results section reports that systemic NBI-80713 significantly reduced heroin self-administration in long-access rats but did not alter it in short-access rats. Figure 1 lists the tested doses, and the paper’s Abstract describes the reduction as dose-dependent. (LLM, conf=0.94)

  cites Schmeichel et al., 2015 source

In the paper

“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.”

What the sources say

• Partly 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)

  cites Perney et al., 2012 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Partly 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)

  cites Lopez et al., 2016 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Supported

  The Methods (Mifepristone treatment; page unavailable) describe subcutaneous pellets releasing mifepristone chronically, implanted before alcohol vapor exposure began. The Results (Antagonism of GRs; page unavailable) report that treatment selectively blocked escalation of alcohol intake in vapor-exposed rats, and the Discussion identifies this as escalation during acute withdrawal. (LLM, conf=0.93)

  cites Vendruscolo et al., 2012 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Koob et al., 2019 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Ballantyne et al., 2019 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Koob and Le Moal, 1997 source

In the paper

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

In the paper

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

In the paper

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

In the paper

“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 the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Ahmed and Koob, 2005 source

In the paper

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

In the paper

“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).”

In the paper

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

In the paper

“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.”

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Colpaert, 1996 source
• ?Not checked — no full text of the sourcecites Laulin et al., 1999 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Solomon and Corbit, 1973 source
• ?Not checked — no full text of the sourcecites Solomon and Corbit, 1974 source
• ?Not checked — no full text of the sourcecites Koob and Bloom, 1988 source

In the paper

“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.”

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Koob and Le Moal, 1997 source

In the paper

“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.”

In the paper

“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 the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Koob et al., 2019 source

In the paper

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

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Solomon and Corbit, 1974 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Kieffer and Gaveriaux-Ruff, 2002 source

In the paper

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

In the paper

“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.”

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Carlezon et al., 2000 source
• ?Not checked — no full text of the sourcecites Chavkin and Koob, 2016 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Altarifi et al., 2017 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Koob and Le Moal, 2005 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Bonci and Williams, 1997 source

In the paper

“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.”

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Heimer and Alheid, 1991 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Volkow et al., 1996 source
• ?Not checked — no full text of the sourcecites Kuikka et al., 2000 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Koob and Bloom, 1988 source

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Matsumoto and Hikosaka, 2007 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Koob and Bloom, 1988 source
• ?Not checked — no full text of the sourcecites Koob and Le Moal, 2008 source
• ?Not checked — no full text of the sourcecites Koob, 2019 source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites Schulteis et al., 1995 source
• ?Not checked — no full text of the sourcecites Ahmed et al., 2002 source
• ?Not matched

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

  cites Jang et al., 2013a

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Breiter et al., 1997 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Heimer and Alheid, 1991 source

In the paper

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

In the paper

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

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Maldonado, 1997 source
• ?Not checked — no full text of the sourcecites Gold et al., 1978 source
• ?Not checked — no full text of the sourcecites Harris and Gewirtz, 2005 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Kosten, 1994 source
• ?Not checked — no full text of the sourcecites Nader and Van der Kooy, 1996 source

In the paper

“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.”

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Zhou et al., 2008 source

In the paper

“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).”

What the sources say

• ?Not matched

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

  cites Greenwell et al., 2009a

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Weiss et al., 2001 source

In the paper

“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).”

What the sources say

• ?Not matched

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

  cites Carmack et al., unpublished results

In the paper

“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).”

What the sources say

• ?Not matched

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

  cites Greenwell et al., 2009b

In the paper

“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).”

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Hawley et al., 1981 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Koob and Bloom, 1988 source
• ?Not checked — no full text of the sourcecites Koob, 2019 source

In the paper

“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).”

In the paper

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

In the paper

“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.”

In the paper

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

In the paper

“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.”

In the paper

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

In the paper

“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.”

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Robinson and Thiele, 2017 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Brady and Randall, 1999 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Khantzian, 1985 source

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Compton et al., 2001 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Narita et al., 2006 source

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Laulin et al., 1998 source

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Célèrier et al., 2004 source

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Varlinskaya and Spear, 2004 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Célèrier et al., 1999 source
• ?Not checked — no full text of the sourcecites Laulin et al., 2002 source

In the paper

“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.”

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Doverty et al., 2001 source

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Devaud and Chadda, 2001 source

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Célèrier et al., 2000 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Compton et al., 2003 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Zuo et al., 2019 source

In the paper

“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.”

In the paper

“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).”

What the sources say

• ?Not matched

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

  cites Ji et al., 2007
• ?Not checked — no full text of the sourcecites Fu and Neugebauer, 2008 source

In the paper

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

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Demyttenaere et al., 2007 source

In the paper

“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.”

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Holahan et al., 2001 source
• ?Not checked — no full text of the sourcecites Brennan et al., 2005 source
• ?Not checked — no full text of the sourcecites Aira et al., 2008 source

In the paper

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

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Shumilla et al., 2005 source
• ?Not checked — no full text of the sourcecites Dina et al., 2006 source