Neurobiology of addiction: a neurocircuitry analysis

In the paper

“By contrast, D2 receptors, which inhibit cAMP signalling, are stimulated by both phasic and tonic dopamine and are not deemed necessary for drug reward.”

What the sources say

• Partly supported

  The receptor-binding section describes dopamine agonist–mediated inhibition of cAMP accumulation, and the Discussion concludes that D2 receptors are not necessary for cocaine’s reinforcing effects in the mice studied (page numbers unavailable). The paper does not address stimulation by both phasic and tonic dopamine; it also reports that D2 receptors may be necessary for self-administration of some other drugs, so the broader claim about drug reward is not supported. (LLM, conf=0.88)

  cites [40] Caine, 2002, Role of dopamine D2-like receptors in cocaine self-administration: studies with D2 receptor mutant mice and novel D2 receptor antagonists, J Neurosci sourceExperimental — accuracy not yet measured
• Disputed

  The Introduction and Discussion distinguish D2 autoreceptors from D2 receptors generally. They report that mice lacking all D2 receptors have impaired or absent drug-reward responses, contrary to the claim that D2 receptors are not deemed necessary for drug reward; mice lacking only D2 autoreceptors instead show enhanced cocaine reward. The cited passages do not establish the cAMP or tonic-dopamine parts of the sentence. (LLM, conf=0.85)

  Checked by a reasoning model — may be wrong.

  cites [64] Bello, 2011, Cocaine supersensitivity and enhanced motivation for reward in mice lacking dopamine D2 autoreceptors, Nat Neurosci sourceExperimental — accuracy not yet measured

In the paper

“The blockade of metabotropic glutamate 1 receptors in the nucleus accumbens blocks cue-induced incubation reinstatement and cocaine-primed reinstatement; as a result, these receptors are potential therapeutic targets.145,146”

What the sources say

• Partly supported

  The Results and Discussion (pages unavailable) report that blocking mGluR1 in the accumbens core attenuated cocaine-primed reinstatement. They do not establish that it blocks cue-induced incubation reinstatement; the cue-related finding discussed concerns mGluR5. The claim also overstates attenuation as complete blockade and omits the core-specific qualification: the Introduction reports no effect of mGluR1 blockade in the accumbens shell. (LLM, conf=0.88)

  cites [145] Schmidt, 2015, Group I metabotropic glutamate receptor-mediated activation of PKC γ in the nucleus accumbens core promotes the reinstatement of cocaine seeking, Addict Biol sourceExperimental — accuracy not yet measured
• Disputed

  The Results section (‘The level of mGluR1 transmission regulates incubation’; page unavailable) says enhancing mGluR1 transmission prevented incubation, while mGluR1 antagonist treatment accelerated a synaptic change associated with it. The Discussion likewise proposes positive allosteric modulators—not blockade—to reduce incubated cue-induced craving. The cited paper does not report a cocaine-primed reinstatement result. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  cites [146] Loweth, 2014, Synaptic depression via mGluR1 positive allosteric modulation suppresses cue-induced cocaine craving, Nat Neurosci sourceExperimental — accuracy not yet measured

In the paper

“One particularly influential series of studies in non-human primates indicated that midbrain dopamine cells initially fired in response to a novel reward. After repeated exposure, the neurons stopped firing during predictable reward delivery and instead fired when they were exposed to stimuli that were predictive of the reward.”

What the sources say

• Supported

  The Information Encoded in Dopaminergic Activity section (p. 2) describes recordings from alert monkeys: before training, dopamine neurons respond to an unpredicted reward; after learning, the predicted reward no longer elicits a phasic response, while the reward-predicting light does. Here, “stop firing” is supported as the loss of the reward-evoked phasic response, not a cessation of all neuronal activity. (LLM, conf=0.93)

  cites [57] Schultz, 1997, A neural substrate of prediction and reward, Science source

In the paper

“Other observed changes include increases in μ opioid receptor responsivity during opioid withdrawal,71,72 and decreases in GABAergic and increases in NMDA glutamatergic transmission in the nucleus accumbens.”

What the sources say

• ?Not checked — no full text of the sourcecites [71] Stinus, 1990, Nucleus accumbens and amygdala are possible substrates for the aversive stimulus effects of opiate withdrawal, Neuroscience source
• ?Could not verify

  The citation is attached to the claim of increased μ-opioid receptor responsivity during opioid withdrawal, not the later GABAergic/NMDA clause. The Discussion (page unavailable) examines cocaine abstinence instead and reports fewer adverse effects from a μ-opioid receptor agonist in cocaine users than in controls. A search for opioid withdrawal and receptor responsivity found no passage addressing the cited claim. (LLM, conf=0.76)

  cites [72] Minkowski, 2012, Differential response to IV carfentanil in chronic cocaine users and healthy controls, Addict Biol sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [73] Davidson, 1995, Increased NMDA-induced excitability during ethanol withdrawal: a behavioural and histological study, Brain Res source

In the paper

“Such changes include decreases in dopaminergic and serotonergic transmission in the nucleus accumbens during drug withdrawal as measured by in-vivo microdialysis in rats69 and brain imaging studies in humans, in which amphetamine-induced or methylphenidate-induced striatal dopamine responses are 50% lower in detoxified abusers and 80% lower in active abusers, and accompanied by lower self-reports”

What the sources say

• ?Not checked — no full text of the sourcecites [25] Martinez, 2007, Amphetamine-induced dopamine release: markedly blunted in cocaine dependence and predictive of the choice to self-administer cocaine, Am J Psychiatry source
• Partly supported

  The Abstract reports methylphenidate-induced dopamine responses 70% lower in ventral striatum and 50% lower in putamen in detoxified alcoholics versus controls. The Behavioral responses to MP section reports lower self-rated drug liking and high in the alcoholic group. The paper does not report an 80% reduction in active abusers; the withdrawal-related dopamine and serotonin finding appears only in the title of a rat study listed in References, not as a finding of this study. (LLM, conf=0.88)

  cites [35] Volkow, 2007, Profound decreases in dopamine release in striatum in detoxified alcoholics: possible orbitofrontal involvement, J Neurosci sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [70] Volkow, 1997, Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects, Nature source

In the paper

“This hypothesis is also consistent with the finding that α5 nicotinic acetylcholine receptors in the habenula appear to modulate aversive responses to large doses of nicotine48 and, along with habenular α2 receptors, nicotine withdrawal (tables 1, 2, circuit 9).”

What the sources say

• Supported

  Citation 48 is attached to the claim about α5 receptors and aversive responses to high nicotine doses, not the subsequent withdrawal claim. The Abstract reports that α5 knockdown in the medial habenula abolished the inhibitory effects of higher nicotine doses on brain reward systems; the IPN activation section also reports that an aversive high dose activated the IPN in wildtype mice but not α5 knockout mice. The supplied passages have section labels but no page numbers. (LLM, conf=0.92)

  cites [48] Fowler, 2011, Habenular α5 nicotinic receptor subunit signalling controls nicotine intake, Nature source
• ?Not checked — no full text of the sourcecites [82] Salas, 2009, Nicotinic receptors in the habenulo-interpeduncular system are necessary for nicotine withdrawal in mice, J Neurosci source

In the paper

“Imaging studies have also revealed that cues associated with cocaine craving increase dopamine release in the striatum, amygdala, and prefrontal cortex (anterior cingulate and medial orbitofrontal cortex) and opioid peptides in the anterior cingulate and frontal cortex.9,31,106,107”

What the sources say

• Partly supported

  The Ventral Striatum/Dorsal Striatum/Thalamus section (page not provided) reports that drug-associated cues increase dopamine in the dorsal striatum and that the increase correlates with craving. It also links the amygdala and prefrontal cortex to cue-induced craving, but does not report cue-induced dopamine release in those regions. The cited passages do not support increased opioid peptides in the anterior cingulate or frontal cortex. (LLM, conf=0.88)

  cites [9] Koob, 2010, Neurocircuitry of addiction, Neuropsychopharmacology sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [31] Fotros, 2013, Cocaine cue-induced dopamine release in amygdala and hippocampus: a high-resolution PET [18F]fallypride study in cocaine dependent participants, Neuropsychopharmacology source
• ?Not checked — no full text of the sourcecites [106] Volkow, 2006, Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction, J Neurosci source
• Partly supported

  The Results and Discussion report cocaine cue-associated dopamine release in the striatum and prefrontal cortex, strongest in the medial orbitofrontal cortex, with a threshold response in the anterior cingulate. The paper does not report its own amygdala dopamine finding, though its References name a separate study on that region; a search for opioid peptides found no supporting passage. Thus it supports only part of the sentence attributed to it. (LLM, conf=0.88)

  cites [107] Milella, 2016, Cocaine cue-induced dopamine release in the human prefrontal cortex, J Psychiatry Neurosci sourceExperimental — accuracy not yet measured

In the paper

“In a study of patients with obsessive-compulsive disorder, patients showed enhanced avoidance habits compared with controls following overtraining on a shock avoidance task, providing support for a habit account of obsessive-compulsive disorder.”

What the sources say

• Supported

  The Methods describe a shock-avoidance task designed to induce habits through overtraining. The Results report that, following overtraining, patients with OCD showed greater avoidance habits than controls; the Discussion interprets their responses as habits rather than goal-directed avoidance, supporting a habit account. (LLM, conf=0.94)

  cites [83] Gillan, 2014, Enhanced avoidance habits in obsessive-compulsive disorder, Biol Psychiatry source

In the paper

“Decreases in the release of dopamine in the nucleus accumbens can also be driven by increases in the activity of the dynorphin-κ opioid receptor system in the ventral striatum and possibly increases in the activity of CRF in the ventral tegmental area, which contributes to the negative emotional state associated with withdrawal and protracted abstinence.”

What the sources say

• Partly supported

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

  cites [20] Koob, 2014, Addiction as a stress surfeit disorder, Neuropharmacology sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [21] Carlezon, 2000, Herpes simplex virus-mediated gene transfer as a tool for neuropsychiatric research, Crit Rev Neurobiol source

In the paper

“In rats, the prefrontal cortex (mainly prelimbic cortex, and some infralimbic cortex) sends glutamatergic projections directly to mesocortical dopamine neurons in the ventral tegmental area, thus exerting excitatory control over dopamine cell firing and dopamine release in the prefrontal cortex90”

What the sources say

• Partly supported

  Section 2.3 describes a predominantly glutamatergic projection from the prefrontal cortex to the VTA, concentrated in prelimbic cortex with a lesser contribution from infralimbic cortex, and says its axons synapse onto mesocortical dopamine neurons. The Introduction reports that activation of an excitatory prefrontal-to-VTA pathway induces dopamine-neuron burst firing. But the functional-anatomy discussion also emphasizes indirect pathways and inhibition of many dopamine neurons; our copy does not establish the claimed excitatory control of dopamine release specifically in the prefrontal cortex. (LLM, conf=0.88)

  cites [90] Geisler, 2008, Functional implications of glutamatergic projections to the ventral tegmental area, Rev Neurosci sourceExperimental — accuracy not yet measured

In the paper

“Indeed, Volkow and colleagues36 and Goldstein and Volkow14 have described a syndrome that is characterised by excessive salience to drug-paired cues, decreases in the responsiveness to non-drug rewards, and decreases in the ability to inhibit maladaptive behaviour.”

What the sources say

• Supported

  Figure 3 (p. 3) describes heightened salience of drugs and their associated cues alongside markedly reduced salience of other reinforcers. The Control circuit in addiction section (p. 6) describes disrupted self-control and inhibitory control, supporting the claim’s third component. (LLM, conf=0.93)

  cites [36] Volkow, 2003, The addicted human brain: insights from imaging studies, J Clin Invest source
• ?Not checked — no full text of the sourcecites [14] Goldstein, 2011, Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications, Nat Rev Neurosci source

In the paper

“alcohol use during adolescence might lead to epigenetic modifications that alter amygdalar gene expression and dendritic density, increasing susceptibility to anxiety-like behaviours and alcohol ingestion in adulthood.140”

What the sources say

• Supported

  The Discussion (page unavailable) reports that adolescent intermittent ethanol exposure produced persistent amygdalar histone changes, reduced BDNF and Arc expression and dendritic spines, and anxiety-like and alcohol-drinking behaviours in adult rats. This supports the claim’s hedged account; the study’s direct evidence is in rats. (LLM, conf=0.93)

  cites [140] Pandey, 2015, Potential role of adolescent alcohol exposure-induced amygdaloid histone modifications in anxiety and alcohol intake during adulthood, Neurobiol Dis source

In the paper

“Even more compelling, blockade of the mTORC1 pathway systemically blocked the reconsolidation of cocaine memories,150 and blockade of mTORC1 in the amygdala blocked the reconsolidation of alcohol memories;151 these results suggest a potential molecular target for the treatment of relapse.”

What the sources say

• Partly supported

  The Methods and Results report that systemic injection of the GSK3 inhibitor SB216763 after memory reactivation disrupted reconsolidation of cocaine reward memory. They do not report systemic blockade of mTORC1; the Discussion describes reduced mTORC1 phosphorylation after memory reactivation, not an mTORC1-blockade experiment. The alcohol-memory finding has a separate citation in the citing sentence and is not attributed to this paper. (LLM, conf=0.88)

  cites [150] Shi, 2014, Reactivation of cocaine reward memory engages the Akt/GSK3/mTOR signaling pathway and can be disrupted by GSK3 inhibition, Psychopharmacology (Berl) sourceExperimental — accuracy not yet measured
• Supported

  The Abstract reports that central amygdalar mTORC1 inhibition during reconsolidation disrupted alcohol-cue memories and produced long-lasting suppression of relapse. The Discussion identifies mTORC1-mediated disruption of reconsolidation as a potential strategy to prevent alcohol relapse. The cocaine finding is attached to a different citation, not this one. (LLM, conf=0.93)

  cites [151] Barak, 2013, Disruption of alcohol-related memories by mTORC1 inhibition prevents relapse, Nat Neurosci source

In the paper

“Consistent with this hypothesis, imaging studies have reported differential activation of the insula during craving, possibly reflecting interoceptive cues and hypothesised to involve CRF activation (table 2, circuit 18).54,117,118”

What the sources say

• Partly supported

  The Evidence for the role of the insula in addiction section reports imaging activation of the insula during drug urges, and the Proposed role section links those urges to interoceptive representations. The Anatomy and function section notes CRF receptors in the insula and a possible role in stress-related motivation to take drugs, but it does not link the reported imaging activation during craving to CRF activation. (LLM, conf=0.86)

  cites [54] Naqvi, 2009, The hidden island of addiction: the insula, Trends Neurosci sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [117] Sánchez, 1999, Autoradiographic and in situ hybridization localization of corticotropin-releasing factor 1 and 2 receptors in nonhuman primate brain, J Comp Neurol source
• Partly supported

  The Results (fMRI cue reactivity; page unavailable) report a positive association between gambling craving and left anterior insula activation, supporting the insula–craving portion of the claim. The passages do not link that activation to interoceptive cues or hypothesise CRF activation. (LLM, conf=0.86)

  cites [118] Goudriaan, 2010, Brain activation patterns associated with cue reactivity and craving in abstinent problem gamblers, heavy smokers and healthy controls: an fMRI study, Addict Biol sourceExperimental — accuracy not yet measured

In the paper

“Specifically, the infralimbic medial prefrontal cortex-to-nucleus accumbens shell circuit recruits calcium-permeable AMPA receptors,144 and the prelimbic medial prefrontal cortex-to-nucleus accumbens core circuit recruits non-calcium-permeable AMPA receptors.”

What the sources say

• Partly supported

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

  cites [144] Conrad, 2008, Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving, Nature sourceExperimental — accuracy not yet measured

In the paper

“The Go system could drive craving and engage habits via the basal ganglia.105,127”

What the sources say

• Supported

  Section 3.1 describes drug cues eliciting dopamine release and craving, and links the ventral striatum to the basal ganglia’s action output. Section 3.2 links dorsal-striatal circuits to the development and expression of drug-seeking habits. The paper does not use the term “Go system,” but it supports the mechanisms described in this paraphrase. (LLM, conf=0.86)

  cites [105] Jasinska, 2014, Factors modulating neural reactivity to drug cues in addiction: a survey of human neuroimaging studies, Neurosci Biobehav Rev source
• ?Could not verify

  The Discussion (page unavailable) reports caudate and putamen activation in executive-function tasks, but does not connect those regions to a Go system, craving, or habits. Searches for those terms and for basal-ganglia, striatal, reward, and motivational mechanisms found no passage addressing the claim. (LLM, conf=0.76)

  cites [127] Niendam, 2012, Meta-analytic evidence for a superordinate cognitive control network subserving diverse executive functions, Cogn Affect Behav Neurosci sourceExperimental — accuracy not yet measured

In the paper

“Methamphetamine-dependent individuals with striatal D2 receptor availability within the normal range had better treatment outcomes, potentially reflecting a greater ability to acquire new reward-related behaviours and the pursuit of healthy goals.126”

What the sources say

• Supported

  The Abstract reports that participants who completed detoxification did not differ from healthy controls in striatal D2 receptor availability, whereas those who relapsed had lower availability. The Discussion proposes that dopamine-depleted participants may have more difficulty shifting reward-directed behavior toward natural reinforcers, consistent with the claim’s tentative explanation. The source does not report directly measuring the acquisition of healthy behaviors. (LLM, conf=0.88)

  cites [126] Wang, 2012, Decreased dopamine activity predicts relapse in methamphetamine abusers, Mol Psychiatry source

In the paper

“The Stop system could control assessment of the incentive value of choices and suppression of affective responses to negative emotional signals.130–132”

What the sources say

• ?Not checked — no full text of the sourcecites [130] Damasio, 1996, The somatic marker hypothesis and the possible functions of the prefrontal cortex, Philos Trans R Soc Lond B Biol Sci source
• ?Not checked — no full text of the sourcecites [131] Bechara, 1999, Different contributions of the human amygdala and ventromedial prefrontal cortex to decision-making, J Neurosci source
• Partly supported

  The Introduction and Materials and Methods (page unavailable) describe top-down regulation and attempts to suppress emotional responses to negative pictures. The paper does not address a “Stop system” assessing the incentive value of choices, so that part of the claim is unsupported. (LLM, conf=0.85)

  cites [132] Johnstone, 2007, Failure to regulate: counterproductive recruitment of top-down prefrontal-subcortical circuitry in major depression, J Neurosci sourceExperimental — accuracy not yet measured

In the paper

“Tobacco smokers with damage to the insula (but not control smokers with extra non-insular lesions) were able to stop smoking easily and without experiencing cravings or relapse.114”

What the sources say

• Partly supported

  The paper’s results (section labelled Abstract; page unavailable) report that 12 of 13 smokers who quit after insula damage met criteria including easy quitting, no relapse, and no subsequent urges, compared with 4 of 19 quitters with non-insular lesions. The contrast is supported, but “not control smokers” is too absolute: four controls also met those criteria, and not every smoker with insula damage quit. (LLM, conf=0.90)

  cites [114] Naqvi, 2007, Damage to the insula disrupts addiction to cigarette smoking, Science sourceExperimental — accuracy not yet measured

In the paper

“These low levels of striatal D2 receptors have been associated with decreases in baseline glucose metabolism (ie, a marker of brain function) in the prefrontal cortex (including dorsolateral prefrontal cortex, anterior cingulate gyrus, and medial orbitofrontal cortex),35,123,124 impulsivity in methamphetamine abusers,125 and compulsive cocaine administration in rodents.15”

What the sources say

• Partly supported

  The Results section reports that baseline striatal D2/D3 receptor availability correlated with glucose metabolism in the cingulate gyrus and dorsolateral prefrontal cortex in detoxified alcoholics, but not controls. It does not report a baseline-receptor correlation with medial orbitofrontal metabolism; its orbitofrontal finding concerns methylphenidate-induced dopamine changes. The later impulsivity and rodent clauses have separate citations and are not attributed to this source. (LLM, conf=0.86)

  cites [35] Volkow, 2007, Profound decreases in dopamine release in striatum in detoxified alcoholics: possible orbitofrontal involvement, J Neurosci sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [123] Volkow, 1993, Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers, Synapse source
• ?Not checked — no full text of the sourcecites [124] Volkow, 2001, Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex, Am J Psychiatry source
• Supported

  The Discussion reports a significant negative relationship between striatal D2/D3 receptor availability and impulsiveness in methamphetamine-dependent subjects. In the citing sentence, this paper is citation 125, attached to the impulsivity finding; the glucose-metabolism and rodent findings have other citations. (LLM, conf=0.94)

  cites [125] Lee, 2009, Striatal dopamine d2/d3 receptor availability is reduced in methamphetamine dependence and is linked to impulsivity, J Neurosci source
• ?Not checked — no full text of the sourcecites [15] Everitt, 2008, Review. Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction, Philos Trans R Soc Lond B Biol Sci source

In the paper

“Notably, in animal models, dopamine D1 receptor knockout rats will not self-administer cocaine37 and μ opioid receptor knockout mice will not show the rewarding effects of opioids.153”

What the sources say

• Partly supported

  The Abstract and Discussion report that dopamine D1 receptor knock-out mice did not reliably self-administer cocaine. The citing sentence says rats, but this study tested mice. The separate claim about μ opioid receptor knock-out mice is attached to a different citation and is not assessed here. (LLM, conf=0.90)

  cites [37] Caine, 2007, Lack of self-administration of cocaine in dopamine D1 receptor knock-out mice, J Neurosci sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [153] Matthes, 1996, Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the μ-opioid-receptor gene, Nature source

In the paper

“As such, mTORC1 plays a major role in the molecular mechanisms associated with learning and memory147 and is involved in several brain disorders, including epilepsy, Parkinson’s disease, Alzheimer’s disease, and addiction.148,149”

What the sources say

• Supported

  The section ‘The mTOR Signaling Pathway Is Important for Synaptic Plasticity’ (p. 5) says proper control of mTORC1 signaling is crucial for long-lasting synaptic plasticity and memory consolidation. Citation 147 is attached to the learning-and-memory clause; the brain-disorder list is attached to citations 148 and 149 and is not attributed to this source. (LLM, conf=0.93)

  cites [147] Costa-Mattioli, 2009, Translational control of long-lasting synaptic plasticity and memory, Neuron source
• ?Not checked — no full text of the sourcecites [148] Costa-Mattioli, 2013, mTOR complexes in neurodevelopmental and neuropsychiatric disorders, Nat Neurosci source
• Supported

  The Introduction states that mTORC1 plays a major role in learning and memory and appears dysregulated in epilepsy, Parkinson’s disease, and Alzheimer’s disease. The “mTORC1 in the central nervous system” section also identifies addiction as a disorder involving malfunction of this pathway. Page numbers were not provided in our copy. (LLM, conf=0.94)

  cites [149] Neasta, 2014, mTOR complex 1: a key player in neuroadaptations induced by drugs of abuse, J Neurochem source

In the paper

“Positron emission tomography studies have uncovered substantial reductions of D2 receptor availability in the striatum in individuals with addiction that persist for months after protracted detoxification, which have also been observed in preclinical studies in rodents and non-human primates with repeated drug exposure.122”

What the sources say

• Partly supported

  Split into 2 atoms — 1 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

  cites [122] Volkow, 2009, Imaging dopamine's role in drug abuse and addiction, Neuropharmacology sourceExperimental — accuracy not yet measured

In the paper

“Our contention is that the field of the neurobiology of addiction has excellent and validated animal models and well developed clinical models that, combined with the neurocircuitry analysis herein, will provide a unique approach to medication development that emphasises excessive incentive salience, the loss of brain reward function, and the gain of stress function that drive negative reinfor”

What the sources say

• ?Not checked — no full text of the sourcecites [13] Koob, 2016, Existing and future drugs for the treatment of the dark side of addiction, Annu Rev Pharmacol Toxicol source
• Partly supported

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

  cites [185] Koob, 2009, Development of pharmacotherapies for drug addiction: a Rosetta stone approach, Nat Rev Drug Discov sourceExperimental — accuracy not yet measured

In the paper

“Drug exposure during adolescence is associated with more chronic and intensive use and greater risk of a substance use disorder than is initiation at older ages.167,169–172”

What the sources say

• Partly supported

  In “Broad implications of recent research for adolescent policy and programs” (page unavailable), the paper says adolescent responses to rewards may encourage continued and escalating drug use and lead to problematic involvement. It does not establish that people first exposed during adolescence have more chronic or intensive use, or a greater risk of substance use disorder, than people who initiate at older ages. (LLM, conf=0.82)

  cites [167] Spear, 2013, Adolescent neurodevelopment, J Adolesc Health sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [169] Grant, 2001, Age at onset of alcohol use and DSM-IV alcohol abuse and dependence: a 12-year follow-up study, J Subst Abuse source
• ?Not matched

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

  cites [170] Volkow, 2006, Altered pathways: drug abuse and age of onset, Addict Professional
• ?Not checked — no full text of the sourcecites [171] Hingson, 2006, Age of alcohol-dependence onset: associations with severity of dependence and seeking treatment, Pediatrics source
• ?Not checked — no full text of the sourcecites [172] King, 2007, A prospective study of the effects of age of initiation of alcohol and drug use on young adult substance dependence, J Stud Alcohol Drugs source

In the paper

“Advances in diagnosis that reflect such an endophenotype or research domain criterion approach will synergistically combine with advances in neurobiology to promote novel pharmacotherapeutic, brain stimulation (ie, transcranial magnetic stimulation and direct electrical stimulation), and behavioural treatments.186”

What the sources say

• Partly supported

  The Introduction’s “Changes in Nosology” section says that a mechanistically informed approach to diagnosis may identify improved treatments and better match patients to them; it discusses both medications and behavioural treatments. It does not support the more definite prediction that diagnostic and neurobiological advances will synergistically produce novel treatments, and the passages found do not address brain stimulation. Page numbers are unavailable in our copy. (LLM, conf=0.84)

  cites [186] Kwako, 2015, Addictions neuroclinical assessment: a neuroscience-based framework for addictive disorders, Biol Psychiatry sourceExperimental — accuracy not yet measured

In the paper

“From the perspective of the preoccupation/anticipation stage, a genetic knock-in mouse that bio logically recapitulates a common human mutation in the gene for fatty acid amide hydrolase (C385A [Pro129Thr], rs324420) presented a reduction of fatty acid amide hydrolase expression associated with the variant allele that selectively enhanced fronto-amygdala connectivity and fear extinction learning”

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 [165] Dincheva, 2015, FAAH genetic variation enhances fronto-amygdala function in mouse and human, Nat Commun source

In the paper

“Experimentation, as well as the process of addiction, most often starts in adolescence,166 a period during which the brain undergoes important developmental changes.167”

What the sources say

• ?Not checked — no full text of the sourcecites [166] Wagner, 2002, From first drug use to drug dependence; developmental periods of risk for dependence upon marijuana, cocaine, and alcohol, Neuropsychopharmacology source
• Supported

  Citation 167 is attached to the statement that the brain undergoes important developmental changes during adolescence; the preceding claim about when experimentation and addiction start has citation 166. The paper’s “Synaptic pruning and myelination” section describes substantial adolescent changes in synaptic connections and myelination. (LLM, conf=0.93)

  cites [167] Spear, 2013, Adolescent neurodevelopment, J Adolesc Health source

In the paper

“Normal adolescent-specific behaviours (eg, risk-taking, novelty-seeking, and high sensitivity to peer pressure) increase the propensity to experiment with legal and illegal drugs,167 which might reflect the incomplete development of brain regions (eg, myelination of frontal lobe regions) that are involved in the processes of executive control and motivation.168”

What the sources say

• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [167] Spear, 2013, Adolescent neurodevelopment, J Adolesc Health sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [168] Giedd, 1999, Brain development during childhood and adolescence: a longitudinal MRI study, Nat Neurosci source

In the paper

“The mechanisms that are responsible for stress-induced increases in vulnerability to drug use and relapse in those who are addicted are not yet well understood, but evidence suggests that the stress-responsive neuropeptide CRF is involved through its effects in the amygdala and hypothalamic-pituitary-adrenal axis.20”

What the sources say

• Supported

  The paper’s Abstract describes CRF activity in the extended amygdala and links the hypothalamic-pituitary-adrenal axis to dysregulation of CRF stress systems. It also proposes that a sensitized stress state makes acute stressors more likely to elicit drug seeking during vulnerability to relapse. No page numbers are available in our copy. (LLM, conf=0.88)

  cites [20] Koob, 2014, Addiction as a stress surfeit disorder, Neuropharmacology source

In the paper

“For example, genome-wide association studies have implicated two acetylcholine receptors, the α4 nicotinic receptor subunit157 and α5 nicotinic receptor subunit,158 in the vulnerability to nicotine dependence and a single-nucleotide polymorphism associated with regulating the trafficking and gating properties of AMPA-selective glutamate receptors (CNIH3) in opioid dependence.159”

What the sources say

• Supported

  Citation 157 is attached to the α4 nicotinic receptor subunit, not the separately cited α5 and CNIH3 claims. The Introduction reports that the GWAS meta-analysis identified CHRNA4, which encodes the α4 subunit, as a genome-wide significant locus for nicotine dependence; the Results report the association in European-ancestry ever smokers. (LLM, conf=0.93)

  cites [157] Hancock, 2015, Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence, Transl Psychiatr source
• Supported

  Citation 158 is attached to the α5 subunit claim, not the separate α4 or CNIH3 claims. The Introduction (page unavailable) reports that a common CHRNA5 variant is associated with nicotine dependence, and the Results (page unavailable) report increased risk in European and African Americans. (LLM, conf=0.92)

  cites [158] Olfson, 2016, Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans, Mol Psychiatry source
• Partly supported

  The Results (Confirmation of association findings) report genome-wide significant associations between CNIH3 SNPs and opioid dependence, while the Discussion describes CNIH3 as an AMPA-receptor auxiliary protein that affects receptor deactivation and desensitization. The paper does not establish that an associated SNP itself regulates AMPA-receptor trafficking or gating. Citation 159 is attached to the opioid-dependence clause, not the separate nicotine-dependence claims. (LLM, conf=0.83)

  cites [159] Nelson, 2016, Evidence of CNIH3 involvement in opioid dependence, Mol Psychiatry sourceExperimental — accuracy not yet measured

In the paper

“D3 receptors, which are high-affinity dopamine receptors and co-localise in the nucleus accumbens with D1 receptors, are also associated with drug-seeking behaviour.”

What the sources say

• ?Not checked — no full text of the sourcecites [65] Vorel, 2002, Dopamine D3 receptor antagonism inhibits cocaine-seeking and cocaine-enhanced brain reward in rats, J Neurosci source

In the paper

“However, impulsivity and compulsivity can coexist, and frequently do so in the different stages of the addiction cycle.”

What the sources say

• ?Not checked — no full text of the sourcecites [8] Berlin, 2014, Compulsivity, impulsivity, and the DSM-5 process, CNS Spectr source

In the paper

“Although no animal model of addiction fully emulates the human condition, they permit investigations of specific signs or symptoms that are associated with the psychopathological condition.”

In the paper

“Differential regional changes in nicotinic receptor function in the nucleus accumbens and ventral tegmental area in nicotine, alcohol, and other addictions have also been reported, implicating α4β2 nicotinic receptor subtypes.”

What the sources say

• ?Not checked — no full text of the sourcecites [19] Dani, 1996, Molecular and cellular aspects of nicotine abuse, Neuron source
• ?Not checked — no full text of the sourcecites [44] Tolu, 2013, Co-activation of VTA DA and GABA neurons mediates nicotine reinforcement, Mol Psychiatry source

In the paper

“Addiction can be conceptualised as a three-stage, recurring cycle—binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation (craving)—that worsens over time and involves neuroplastic changes in the brain reward, stress, and executive function systems.”

What the sources say

• ?Not checked — no full text of the sourcecites [4] Koob, 1997, Drug abuse: hedonic homeostatic dysregulation, Science source
• ?Not checked — no full text of the sourcecites [5] Goldstein, 2002, Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex, Am J Psychiatry source
• ?Not matched

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

  cites [6] Baumeister, 1994

In the paper

“Drug addiction represents a dramatic dysregulation of motivational circuits that is caused by a combination of exaggerated incentive salience and habit formation, reward deficits and stress surfeits, and compromised executive function in three stages.”

In the paper

“Activation of the ventral striatum leads to the recruitment of striatal-globus pallidalthalamocortical loops that engage the dorsal striatum, resulting in habit formation45 and triggering what is hypothesised to underlie compulsive responding for drugs (table 2, circuits 3 and 4).”

What the sources say

• ?Not checked — no full text of the sourcecites [45] Belin, 2009, Parallel and interactive learning processes within the basal ganglia: relevance for the understanding of addiction, Behav Brain Res source
• ?Not checked — no full text of the sourcecites [59] Belin, 2008, Cocaine seeking habits depend upon dopamine-dependent serial connectivity linking the ventral with the dorsal striatum, Neuron source

In the paper

“This mechanism implicates lower-affi nity D1 receptors, which stimulate cyclic adenosine monophosphate (cAMP) signalling, as being involved in both acute drug reward and conditioning, because both induce spikes in dopamine release.”

In the paper

“The specific circuitry that is associated with drug reward has been broadened to include many neural inputs and outputs that interact with the basal forebrain.”

In the paper

“A new reward—and subsequently the cues associated with the reward—triggered phasic dopamine cell firing and activation of dopamine D1 receptors, which are necessary for conditioning to occur (table 2, circuits 1–4).”

What the sources say

• ?Not checked — no full text of the sourcecites [58] Ungless, 2001, Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons, Nature source

In the paper

“Balanced circuits result in proper inhibitory control and decision making and normal functioning of reward, motivation, stress, and memory circuits.”

In the paper

“Both conditioned reinforcement and incentive salience provide constructs for what underlies cue-induced drug seeking, self-administration behaviours, and, conceivably, the transition to habit-like compulsive drug seeking.”

In the paper

“The ability of conditioned cues to recruit these circuits augments progression through the addiction cycle and helps explain intense desire for the drug (ie, craving) and compulsive use when individuals with addiction are exposed to drug cues or stressful environments that are linked with negative emotional states.”

In the paper

“In this context, individuals move from impulsivity to compulsivity, and the drive for drug-taking behaviour is paralleled by shifts from positive to negative reinforcement (figure 1).”

In the paper

“This process allows previously neutral stimuli to become endowed with incentive salience and strengthens the learned association with repeated exposure to the cues, which creates strong motivation to seek a reward.”

In the paper

“As a result, the concept of anti-reward was developed,2 based on the proposal that opponent processes that are a general feature of biological systems also act to limit reward.”

What the sources say

• ?Not checked — no full text of the sourcecites [2] Koob, 2008, Addiction and the brain antireward system, Annu Rev Psychol source
• ?Not checked — no full text of the sourcecites [4] Koob, 1997, Drug abuse: hedonic homeostatic dysregulation, Science source

In the paper

“Thus, the within-system and between-system construct could be equally valid for the preoccupation/anticipation stage.”

In the paper

“craving in itself has been diffi cult to measure in human clinical studies and does not always correlate with relapse.89”

What the sources say

• ?Not checked — no full text of the sourcecites [89] Tiffany, 2000, Challenges in the manipulation, assessment and interpretation of craving relevant variables, Addiction source

In the paper

“These aversive states are manifest when the drug is removed during acute withdrawal but also during protracted abstinence.”

What the sources say

• ?Not checked — no full text of the sourcecites [2] Koob, 2008, Addiction and the brain antireward system, Annu Rev Psychol source

In the paper

“Indeed, imaging studies have revealed baseline decreases in orbitofrontal (medial and lateral) and anterior cingulate (ventral and dorsal) function and dopamine function during dependence, but reactivation of dopamine and reward system function during acute craving episodes.108”

What the sources say

• ?Not checked — no full text of the sourcecites [108] Volkow, 1999, Association of methylphenidate-induced craving with changes in right striato-orbitofrontal metabolism in cocaine abusers: implications in addiction, Am J Psychiatry source

In the paper

“Decreases in reward can be driven by overactivation of the habenula or overactivation of the dynorphin system in the ventral striatum, both of which can decrease dopamine neuron firing.”

In the paper

“Anti-reward circuits are engaged as neuroadaptations during the development of addiction, producing aversive or stress-like states.”

What the sources say

• ?Not checked — no full text of the sourcecites [2] Koob, 2008, Addiction and the brain antireward system, Annu Rev Psychol source

In the paper

“Cue-induced reinstatement also involves a glutamatergic projection from the prelimbic prefrontal cortex, basolateral amygdala, and ventral subiculum to the nucleus accumbens, and dopamine modulation in the basolateral amygdala and dorsal striatum (tables 1, 2, circuits 14 and 15).51,52,95”

What the sources say

• ?Not checked — no full text of the sourcecites [51] Vorel, 2001, Relapse to cocaine-seeking after hippocampal theta burst stimulation, Science source
• ?Not checked — no full text of the sourcecites [52] Everitt, 2002, Psychomotor stimulant addiction: a neural systems perspective, J Neurosci source
• ?Not checked — no full text of the sourcecites [95] Vanderschuren, 2005, Involvement of the dorsal striatum in cue-controlled cocaine seeking, J Neurosci source

In the paper

“For example, in post-traumatic stress disorder there is substantial evidence of hypoactivity in the ventromedial prefrontal cortex and hyperactivity in the central nucleus of the amygdala that reflects an inhibitory connection between the ventromedial prefrontal cortex and central nucleus of the amygdala.133,134”

What the sources say

• ?Not checked — no full text of the sourcecites [133] Pitman, 2012, Biological studies of post-traumatic stress disorder, Nat Rev Neurosci source
• ?Not checked — no full text of the sourcecites [134] Mcdonald, 1996, Projections of the medial and lateral prefrontal cortices to the amygdala: a Phaseolus vulgaris leucoagglutinin study in the rat, Neuroscience source

In the paper

“Activation of the dorsal anterior cingulate is also associated with fear conditioning in post-traumatic stress disorder.129”

What the sources say

• ?Not checked — no full text of the sourcecites [129] Bryant, 2005, Neural networks of information processing in posttraumatic stress disorder: a functional magnetic resonance imaging study, Biol Psychiatry source

In the paper

“The neuroplastic changes outlined previously are triggered and sustained by molecular and cellular adaptations that can presumably also interact with genetic and environmental vulnerability to addiction.”

In the paper

“The kinase mammalian (mechanistic) target of rapamycin complex 1 (mTORC1) belongs to the phosphoinositide 3-kinase (PI3K)-related kinase (PIKK) family and plays a key role in the dendritic translation of synaptic proteins.”

In the paper

“Under this framework, a Stop system would inhibit the Go craving system and stress system.”

In the paper

“Introduction of cAMP response element binding protein in the nucleus accumbens decreases the reinforcing value of natural and drug rewards, and this change plausibly contributes to withdrawal/negative affect stage-related decreases in reward pathway function, which leave a drug-abstinent individual in an amotivational, dysphoric, or depressed-like state.138,139”

What the sources say

• ?Not checked — no full text of the sourcecites [138] Carlezon, 1998, Regulation of cocaine reward by CREB, Science source
• ?Not checked — no full text of the sourcecites [139] Nestler, 2004, Molecular mechanisms of drug addiction, Neuropharmacology source

In the paper

“For example, repeated substance use activates accumulating levels of ΔFosB, and animals with elevated ΔFosB exhibit exaggerated sensitivity to the rewarding effects of drugs of abuse, leading to the hypothesis that ΔFosB might be a sustained molecular trigger or switch that helps initiate and maintain a state of addiction.141,142”

What the sources say

• ?Not checked — no full text of the sourcecites [141] Nestler, 2005, Is there a common molecular pathway for addiction?, Nat Neurosci source
• ?Not checked — no full text of the sourcecites [142] Kelz, 1999, Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine, Nature source

In the paper

“In humans, only a few specific genes have been identified with polymorphisms (alleles) that either predispose an individual to or protect an individual from drug addiction,156 but the number is growing.”

What the sources say

• ?Not checked — no full text of the sourcecites [156] Uhl, 2004, The burden of complex genetics in brain disorders, Arch Gen Psychiatry source

In the paper

“Heritability of addictions is 40–60%, much of which is caused by genetic variations that affect underlying neurobiological mechanisms, and thus is consistent with there being common pathways to different addictions.152”

What the sources say

• ?Not checked — no full text of the sourcecites [152] Lerman, 2003, Elucidating the role of genetic factors in smoking behavior and nicotine dependence, Am J Med Genet B Neuropsychiatr Genet source

In the paper

“For example, chronic exposure to a wide variety of abused drugs upregulates cAMP formation, cAMP-dependent protein kinase A (PKA) activity, and PKA-dependent protein phosphorylation in the nucleus accumbens.”

In the paper

“A well characterised example is that chronic exposure to various drugs of abuse increases the activation of cAMP response element binding protein in the nucleus accumbens and deactivates it in the central nucleus of the amygdala.”

In the paper

“GABA co-release is modulated by binge-like doses of alcohol administered to mice, and diminished ALDH1a1 leads to enhanced alcohol consumption and preference.”

In the paper

“Although such approaches do not guarantee that these genes convey vulnerability in the human population, they provide viable candidates for exploring the genetic basis of endophenotypes that are associated with addiction.”

In the paper

“Identification of these molecular and neurochemical loads on the circuitry provides key information about vulnerability, resilience, treatment, and recovery from addiction, as well as information on how different drugs of abuse enter the overall addiction cycle.”

In the paper

“Beginning in preadolescence and continuing into the mid-20s, cortical grey matter volumes reduce, which reflects a normal pruning process;168 white matter volume increases over the course of adolescence, reflecting increases in connectivity, including axonal extension and myelination.168”

What the sources say

• ?Not checked — no full text of the sourcecites [168] Giedd, 1999, Brain development during childhood and adolescence: a longitudinal MRI study, Nat Neurosci source

In the paper

“Non-drug addictions elaborate self-regulation failures similarly to drug addictions, with transitions from impulsivity to compulsivity and a chronic relapsing trajectory.”

In the paper

“Non-drug addictions, such as pathological gambling, have a similar behavioural phenotype that fits into the three-stage cycle.”

In the paper

“Environmental factors that have been consistently associated with the propensity to self-administer drugs include structural factors (eg, low socioeconomic status and associated lack of social support systems), proximal factors (eg, parental drug use and dependence, as per the DSM-IV, poor quality of parenting, parental depression, and sibling and peer influences), and more distal factors (eg, dru”

What the sources say

• ?Not checked — no full text of the sourcecites [177] Hawkins, 1992, Risk and protective factors for alcohol and other drug problems in adolescence and early adulthood: implications for substance abuse prevention, Psychol Bull source
• ?Not checked — no full text of the sourcecites [178] Sloboda, 2012, Revisiting the concepts of risk and protective factors for understanding the etiology and development of substance use and substance use disorders: implications for prevention, Subst Use Misuse source

In the paper

“We elaborate here a heuristic framework based on the behavioural and imaging phenotypes of addiction as three stages linked by three functional domains that are mediated by three major neurobiological circuits (basal ganglia, extended amygdala, and prefrontal cortex) and numerous microcircuits of neuroplasticity.”