George F. Koob, Ph.D.

@article{pmid38413576,

title = {µ-Opioid receptor antagonism facilitates the anxiolytic-like effect of oxytocin in mice},

author = {Khalin E Nisbett and Leandro F Vendruscolo and George F Koob},

url = {https://pubmed.ncbi.nlm.nih.gov/38413576/},

doi = {10.1038/s41398-024-02830-1},

issn = {2158-3188},

year  = {2024},

date = {2024-02-01},

urldate = {2024-02-01},

journal = {Transl Psychiatry},

volume = {14},

number = {1},

pages = {125},

abstract = {Mood and anxiety disorders are leading causes of disability worldwide and are major contributors to the global burden of diseases. Neuropeptides, such as oxytocin and opioid peptides, are important for emotion regulation. Previous studies have demonstrated that oxytocin reduced depression- and anxiety-like behavior in male and female mice, and opioid receptor activation reduced depression-like behavior. However, it remains unclear whether the endogenous opioid system interacts with the oxytocin system to facilitate emotion regulation in male and female mice. We hypothesized that opioid receptor blockade would inhibit the anxiolytic- and antidepressant-like effects of oxytocin. In this study, we systemically administered naloxone, a preferential μ-opioid receptor antagonist, and then intracerebroventricularly administered oxytocin. We then tested mice on the elevated zero maze and the tail suspension tests, respective tests of anxiety- and depression-like behavior. Contrary to our initial hypothesis, naloxone potentiated the anxiolytic-like, but not the antidepressant-like, effect of oxytocin. Using a selective μ-opioid receptor antagonist, D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2, and a selective κ-opioid receptor antagonist, norbinaltorphimine, we demonstrate that μ-opioid receptor blockade potentiated the anxiolytic-like effect of oxytocin, whereas κ-opioid receptor blockade inhibited the oxytocin-induced anxiolytic-like effects. The present results suggest that endogenous opioids can regulate the oxytocin system to modulate anxiety-like behavior. Potential clinical implications of these findings are discussed.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36123420b,

title = {Spironolactone as a potential new pharmacotherapy for alcohol use disorder: convergent evidence from rodent and human studies},

author = {Mehdi Farokhnia and Christopher T Rentsch and Vicky Chuong and M Adrienne McGinn and Sophie K Elvig and Eliza A Douglass and Luis A Gonzalez and Jenna E Sanfilippo and Renata C N Marchette and Brendan J Tunstall and David A Fiellin and George F Koob and Amy C Justice and Lorenzo Leggio and Leandro F Vendruscolo},

url = {https://pubmed.ncbi.nlm.nih.gov/36123420/},

doi = {10.1038/s41380-022-01736-y},

issn = {1476-5578},

year  = {2022},

date = {2022-11-01},

urldate = {2022-11-01},

journal = {Mol Psychiatry},

volume = {27},

number = {11},

pages = {4642--4652},

abstract = {Evidence suggests that spironolactone, a nonselective mineralocorticoid receptor (MR) antagonist, modulates alcohol seeking and consumption. Therefore, spironolactone may represent a novel pharmacotherapy for alcohol use disorder (AUD). In this study, we tested the effects of spironolactone in a mouse model of alcohol drinking (drinking-in-the-dark) and in a rat model of alcohol dependence (vapor exposure). We also investigated the association between spironolactone receipt for at least 60 continuous days and change in self-reported alcohol consumption, using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), in a pharmacoepidemiologic cohort study in the largest integrated healthcare system in the US. Spironolactone dose-dependently reduced the intake of sweetened or unsweetened alcohol solutions in male and female mice. No effects of spironolactone were observed on drinking of a sweet solution without alcohol, food or water intake, motor coordination, alcohol-induced ataxia, or blood alcohol levels. Spironolactone dose-dependently reduced operant alcohol self-administration in dependent and nondependent male and female rats. In humans, a greater reduction in alcohol consumption was observed among those who received spironolactone, compared to propensity score-matched individuals who did not receive spironolactone. The largest effects were among those who reported hazardous/heavy episodic alcohol consumption at baseline (AUDIT-C ≥ 8) and those exposed to ≥ 50 mg/day of spironolactone. These convergent findings across rodent and human studies demonstrate that spironolactone reduces alcohol use and support the hypothesis that this medication may be further studied as a novel pharmacotherapy for AUD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35728954,

title = {Neuronal Correlates of Hyperalgesia and Somatic Signs of Heroin Withdrawal in Male and Female Mice},

author = {Yocasta Alvarez-Bagnarol and Renata C N Marchette and Chase Francis and Marisela M Morales and Leandro F Vendruscolo},

url = {https://pubmed.ncbi.nlm.nih.gov/35728954/},

doi = {10.1523/ENEURO.0106-22.2022},

issn = {2373-2822},

year  = {2022},

date = {2022-06-01},

urldate = {2022-06-01},

journal = {eNeuro},

volume = {9},

number = {4},

abstract = {Opioid withdrawal involves the manifestation of motivational and somatic symptoms. However, the brain structures that are involved in the expression of different opioid withdrawal signs remain unclear. We induced opioid dependence by repeatedly injecting escalating heroin doses in male and female C57BL/6J mice. We assessed hyperalgesia during spontaneous heroin withdrawal and somatic signs of withdrawal that was precipitated by the preferential µ-opioid receptor antagonist naloxone. Heroin-treated mice exhibited significantly higher hyperalgesia and somatic signs than saline-treated mice. Following behavioral assessment, we measured regional changes in brain activity by automated the counting of c-Fos expression (a marker of cellular activity). Using Principal Component Analysis, we determined the association between behavior (hyperalgesia and somatic signs of withdrawal) and c-Fos expression in different brain regions. Hyperalgesia was associated with c-Fos expression in the lateral hypothalamus, central nucleus of the amygdala, ventral tegmental area, parabrachial nucleus, dorsal raphe, and locus coeruleus. Somatic withdrawal was associated with c-Fos expression in the paraventricular nucleus of the thalamus, lateral habenula, dorsal raphe, and locus coeruleus. Thus, hyperalgesia and somatic withdrawal signs were each associated with c-Fos expression in unique sets of brain areas. The expression of c-Fos in the dorsal raphe and locus coeruleus was associated with both hyperalgesia and somatic withdrawal. Understanding common neurobiological mechanisms of acute and protracted opioid withdrawal may help identify new targets for treating this salient aspect of opioid use disorder.The public impact of the opioid crisis has prompted an effort to understand the neurobiological mechanisms of opioid use disorder (OUD). The need to avoid withdrawal symptoms is hypothesized to drive compulsive drug-taking and -seeking in OUD. Thus, understanding the mechanisms of acute and protracted opioid withdrawal may help identify new targets for treating this salient aspect of OUD. We reported brain structures that are associated with the expression of hyperalgesia and somatic signs of opioid withdrawal in male and female heroin-dependent mice. Hyperalgesia during spontaneous opioid withdrawal and somatic withdrawal resulted in c-Fos expression in autonomic and limbic brain regions. The expression of c-Fos in the dorsal raphe and locus coeruleus were associated with both hyperalgesia and somatic withdrawal.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35296810,

title = {Corticosteroid sensitization drives opioid addiction},

author = {Stephanie A Carmack and Janaina C M Vendruscolo and M Adrienne McGinn and Jorge Miranda-Barrientos and Vez Repunte-Canonigo and Gabriel D Bosse and Daniele Mercatelli and Federico M Giorgi and Yu Fu and Anthony J Hinrich and Francine M Jodelka and Karen Ling and Robert O Messing and Randall T Peterson and Frank Rigo and Scott Edwards and Pietro P Sanna and Marisela Morales and Michelle L Hastings and George F Koob and Leandro F Vendruscolo},

url = {https://pubmed.ncbi.nlm.nih.gov/35296810/},

doi = {10.1038/s41380-022-01501-1},

issn = {1476-5578},

year  = {2022},

date = {2022-03-01},

urldate = {2022-03-01},

journal = {Mol Psychiatry},

abstract = {The global crisis of opioid overdose fatalities has led to an urgent search to discover the neurobiological mechanisms of opioid use disorder (OUD). A driving force for OUD is the dysphoric and emotionally painful state (hyperkatifeia) that is produced during acute and protracted opioid withdrawal. Here, we explored a mechanistic role for extrahypothalamic stress systems in driving opioid addiction. We found that glucocorticoid receptor (GR) antagonism with mifepristone reduced opioid addiction-like behaviors in rats and zebrafish of both sexes and decreased the firing of corticotropin-releasing factor neurons in the rat amygdala (i.e., a marker of brain stress system activation). In support of the hypothesized role of glucocorticoid transcriptional regulation of extrahypothalamic GRs in addiction-like behavior, an intra-amygdala infusion of an antisense oligonucleotide that blocked GR transcriptional activity reduced addiction-like behaviors. Finally, we identified transcriptional adaptations of GR signaling in the amygdala of humans with OUD. Thus, GRs, their coregulators, and downstream systems may represent viable therapeutic targets to treat the "stress side" of OUD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33318153,

title = {Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development},

author = {George F Koob},

url = {https://pubmed.ncbi.nlm.nih.gov/33318153/},

doi = {10.1124/pharmrev.120.000083},

issn = {1521-0081},

year  = {2021},

date = {2021-01-01},

urldate = {2021-01-01},

journal = {Pharmacol Rev},

volume = {73},

number = {1},

pages = {163--201},

abstract = {Compulsive drug seeking that is associated with addiction is hypothesized to follow a heuristic framework that involves three stages (binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation) and three domains of dysfunction (incentive salience/pathologic habits, negative emotional states, and executive function, respectively) via changes in the basal ganglia, extended amygdala/habenula, and frontal cortex, respectively. This review focuses on neurochemical/neurocircuitry dysregulations that contribute to hyperkatifeia, defined as a greater intensity of negative emotional/motivational signs and symptoms during withdrawal from drugs of abuse in the withdrawal/negative affect stage of the addiction cycle. Hyperkatifeia provides an additional source of motivation for compulsive drug seeking via negative reinforcement. Negative reinforcement reflects an increase in the probability of a response to remove an aversive stimulus or drug seeking to remove hyperkatifeia that is augmented by genetic/epigenetic vulnerability, environmental trauma, and psychiatric comorbidity. Neurobiological targets for hyperkatifeia in addiction involve neurocircuitry of the extended amygdala and its connections via within-system neuroadaptations in dopamine, enkephalin/endorphin opioid peptide, and γ-aminobutyric acid/glutamate systems and between-system neuroadaptations in prostress corticotropin-releasing factor, norepinephrine, glucocorticoid, dynorphin, hypocretin, and neuroimmune systems and antistress neuropeptide Y, nociceptin, endocannabinoid, and oxytocin systems. Such neurochemical/neurocircuitry dysregulations are hypothesized to mediate a negative hedonic set point that gradually gains allostatic load and shifts from a homeostatic hedonic state to an allostatic hedonic state. Based on preclinical studies and translational studies to date, medications and behavioral therapies that reset brain stress, antistress, and emotional pain systems and return them to homeostasis would be promising new targets for medication development. SIGNIFICANCE STATEMENT: The focus of this review is on neurochemical/neurocircuitry dysregulations that contribute to hyperkatifeia, defined as a greater intensity of negative emotional/motivational signs and symptoms during withdrawal from drugs of abuse in the withdrawal/negative affect stage of the drug addiction cycle and a driving force for negative reinforcement in addiction. Medications and behavioral therapies that reverse hyperkatifeia by resetting brain stress, antistress, and emotional pain systems and returning them to homeostasis would be promising new targets for medication development.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31400808,

title = {Neurobiology of Opioid Addiction: Opponent Process, Hyperkatifeia, and Negative Reinforcement},

author = {George F Koob},

url = {https://pubmed.ncbi.nlm.nih.gov/31400808/},

doi = {10.1016/j.biopsych.2019.05.023},

issn = {1873-2402},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Biol Psychiatry},

volume = {87},

number = {1},

pages = {44--53},

abstract = {Opioids are powerful drugs that usurp and overpower the reward function of endogenous opioids and engage dramatic tolerance and withdrawal via molecular and neurocircuitry neuroadaptations within the same reward system. However, they also engage the brain systems for stress and pain (somatic and emotional) while producing hyperalgesia and hyperkatifeia, which drive pronounced drug-seeking behavior via processes of negative reinforcement. Hyperkatifeia (derived from the Greek "katifeia" for dejection or negative emotional state) is defined as an increase in intensity of the constellation of negative emotional or motivational signs and symptoms of withdrawal from drugs of abuse. In animal models, repeated extended access to drugs or opioids results in negative emotion-like states, reflected by the elevation of reward thresholds, lower pain thresholds, anxiety-like behavior, and dysphoric-like responses. Such negative emotional states that drive negative reinforcement are hypothesized to derive from the within-system dysregulation of key neurochemical circuits that mediate incentive-salience and/or reward systems (dopamine, opioid peptides) in the ventral striatum and from the between-system recruitment of brain stress systems (corticotropin-releasing factor, dynorphin, norepinephrine, hypocretin, vasopressin, glucocorticoids, and neuroimmune factors) in the extended amygdala. Hyperkatifeia can extend into protracted abstinence and interact with learning processes in the form of conditioned withdrawal to facilitate relapse to compulsive-like drug seeking. Compelling evidence indicates that plasticity in the brain pain emotional systems is triggered by acute excessive drug intake and becomes sensitized during the development of compulsive drug taking with repeated withdrawal. It then persists into protracted abstinence and contributes to the development and persistence of compulsive opioid-seeking behavior.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Carmack:2019aa,

title = {Heroin addiction engages negative emotional learning brain circuits in rats.},

author = {Stephanie A Carmack and Robin J Keeley and Janaina Cm Vendruscolo and Emily G Lowery-Gionta and Hanbing Lu and George F Koob and Elliot A Stein and Leandro F Vendruscolo},

url = {https://www.ncbi.nlm.nih.gov/pubmed/30913040},

doi = {10.1172/JCI125534},

issn = {1558-8238 (Electronic); 0021-9738 (Linking)},

year  = {2019},

date = {2019-03-26},

journal = {J Clin Invest},

volume = {130},

abstract = {Opioid use disorder (OUD) is associated with the emergence of persistent negative emotional states during drug abstinence that drive compulsive drug taking and seeking. Functional magnetic resonance imaging (fMRI) in rats identified neurocircuits that were activated by stimuli that were previously paired with heroin withdrawal. The activation of amygdala and hypothalamic circuits was related to the degree of heroin dependence, supporting the significance of conditioned negative affect in sustaining compulsive-like heroin seeking and taking and providing neurobiological insights into the drivers of the current opioid crisis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30886240,

title = {Inactivation of a CRF-dependent amygdalofugal pathway reverses addiction-like behaviors in alcohol-dependent rats},

author = {Giordano de Guglielmo and Marsida Kallupi and Matthew B Pomrenze and Elena Crawford and Sierra Simpson and Paul Schweitzer and George F Koob and Robert O Messing and Olivier George},

url = {https://pubmed.ncbi.nlm.nih.gov/30886240/},

doi = {10.1038/s41467-019-09183-0},

issn = {2041-1723},

year  = {2019},

date = {2019-01-01},

urldate = {2019-01-01},

journal = {Nat Commun},

volume = {10},

number = {1},

pages = {1238},

abstract = {The activation of a neuronal ensemble in the central nucleus of the amygdala (CeA) during alcohol withdrawal has been hypothesized to induce high levels of alcohol drinking in dependent rats. In the present study we describe that the CeA neuronal ensemble that is activated by withdrawal from chronic alcohol exposure contains ~80% corticotropin-releasing factor (CRF) neurons and that the optogenetic inactivation of these CeA CRF+ neurons prevents recruitment of the neuronal ensemble, decreases the escalation of alcohol drinking, and decreases the intensity of somatic signs of withdrawal. Optogenetic dissection of the downstream neuronal pathways demonstrates that the reversal of addiction-like behaviors is observed after the inhibition of CeA CRF projections to the bed nucleus of the stria terminalis (BNST) and that inhibition of the CRF pathway is mediated by inhibition of the CRF-CRF system and inhibition of BNST cell firing. These results suggest that the CRF pathway could be targeted for the treatment of excessive drinking in alcohol use disorder.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28812595,

title = {Compulsive-Like Sufentanil Vapor Self-Administration in Rats},

author = {Janaina C M Vendruscolo and Brendan J Tunstall and Stephanie A Carmack and Brooke E Schmeichel and Emily G Lowery-Gionta and Maury Cole and Olivier George and Sophia A Vandewater and Michael A Taffe and George F Koob and Leandro F Vendruscolo},

url = {https://pubmed.ncbi.nlm.nih.gov/28812595/},

doi = {10.1038/npp.2017.172},

issn = {1740-634X},

year  = {2018},

date = {2018-01-01},

urldate = {2018-01-01},

journal = {Neuropsychopharmacology},

volume = {43},

number = {4},

pages = {801--809},

abstract = {Opioid misuse is at historically high levels in the United States, with inhalation (ie, smoking and vaping) being one of the most common routes of consumption. We developed and validated a novel preclinical model of opioid self-administration by inhalation that does not require surgery and reliably produces somatic and motivational signs of dependence. Rats were trained to perform an operant response (nosepoke) to receive 10 s of vaporized sufentanil, a potent opioid, in 2 h daily sessions. Rats readily and concentration-dependently self-administered vaporized sufentanil. Rats exhibited a significant increase in responding for sufentanil when given the preferential μ-opioid receptor inverse agonist naloxone, suggesting the participation of μ-opioid receptors in the reinforcing properties of sufentanil vapor. Serum sufentanil concentrations significantly correlated with the number of sufentanil vapor deliveries. Rats that were given long access (LgA; 12 h/day) but not short access (ShA; 1 h/day) to vaporized sufentanil escalated their drug intake over time and exhibited both naloxone-precipitated somatic signs of opioid withdrawal and spontaneous withdrawal-induced mechanical hypersensitivity. After 6 months of forced drug abstinence, LgA rats returned to pre-escalation baseline levels of responding for sufentanil and mechanical sensitivity. Upon subsequent re-escalation (ie, after the return to extended access to sufentanil vapor), LgA rats again developed naloxone-precipitated somatic signs of withdrawal and spontaneous withdrawal-induced mechanical hypersensitivity. These findings demonstrate that the operant sufentanil vapor self-administration model has both face and construct validity and therefore will be useful for investigating the neurobiological basis of opioid addiction.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27567312,

title = {Hypocretin Neurotransmission Within the Central Amygdala Mediates Escalated Cocaine Self-administration and Stress-Induced Reinstatement in Rats},

author = {Brooke E Schmeichel and Melissa A Herman and Marisa Roberto and George F Koob},

url = {https://pubmed.ncbi.nlm.nih.gov/27567312/},

doi = {10.1016/j.biopsych.2016.06.010},

issn = {1873-2402},

year  = {2017},

date = {2017-01-01},

urldate = {2017-01-01},

journal = {Biol Psychiatry},

volume = {81},

number = {7},

pages = {606--615},

abstract = {BACKGROUND: Cocaine addiction is characterized by patterns of compulsive drug-taking, including preoccupation with obtaining cocaine and loss of control over drug intake. The lateral hypothalamic hypocretin/orexin (HCRT) system has been implicated in drug-taking and the reinstatement of drug-seeking. Evidence suggests that HCRT may drive drug-seeking through activation of specific brain regions implicated in stress system dysfunction, including the central amygdala (CeA). The role of HCRT in the persistence of compulsive-like cocaine-taking has yet to be fully elucidated.



METHODS: Systemic and intra-CeA microinfusions of the HCRT-receptor 1 antagonist, SB-334867, were administered to rats allowed either short (1 hour; ShA) or long (6 hours; LgA) access to cocaine self-administration. Animals were tested for fixed and progressive ratio responding for cocaine and stress-induced reinstatement of drug-seeking. In addition, using electrophysiological techniques on in vitro slices, we investigated gamma-aminobutyric acidergic (GABAergic) neurotransmission in the medial CeA and the sensitivity of GABAergic synapses to modulation of the HCRT system in ShA or LgA rats.



RESULTS: We found systemic administration of SB-334867 (0, 7.5, 15, 30 mg/kg) dose dependently decreased cocaine intake specifically in LgA rats but not in ShA rats. Microinjections of SB-334867 (20 nmol) bilaterally into the CeA significantly reduced cocaine intake in LgA rats. We also observed a significant attenuation of yohimbine-induced reinstatement of cocaine-seeking after intra-CeA SB-334867 (10 nmol) administration. Finally, electrophysiological data indicated enhanced GABAergic neurotransmission within the medial CeA in LgA rats, which was blocked with SB-334867 (10 μmol/L).



CONCLUSIONS: These findings suggest that HCRT neurotransmission within the CeA is implicated in compulsive-like cocaine-seeking.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27475769,

title = {Neurobiology of addiction: a neurocircuitry analysis},

author = {George F Koob and Nora D Volkow},

url = {https://pubmed.ncbi.nlm.nih.gov/27475769/},

doi = {10.1016/S2215-0366(16)00104-8},

issn = {2215-0374},

year  = {2016},

date = {2016-08-01},

urldate = {2016-08-01},

journal = {Lancet Psychiatry},

volume = {3},

number = {8},

pages = {760--773},

abstract = {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. The rewarding effects of drugs of abuse, development of incentive salience, and development of drug-seeking habits in the binge/intoxication stage involve changes in dopamine and opioid peptides in the basal ganglia. The increases in negative emotional states and dysphoric and stress-like responses in the withdrawal/negative affect stage involve decreases in the function of the dopamine component of the reward system and recruitment of brain stress neurotransmitters, such as corticotropin-releasing factor and dynorphin, in the neurocircuitry of the extended amygdala. The craving and deficits in executive function in the so-called preoccupation/anticipation stage involve the dysregulation of key afferent projections from the prefrontal cortex and insula, including glutamate, to the basal ganglia and extended amygdala. Molecular genetic studies have identified transduction and transcription factors that act in neurocircuitry associated with the development and maintenance of addiction that might mediate initial vulnerability, maintenance, and relapse associated with addiction. },

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25060491,

title = {Compulsive-like responding for opioid analgesics in rats with extended access},

author = {Carrie L Wade and Leandro F Vendruscolo and Joel E Schlosburg and Daniel O Hernandez and George F Koob},

url = {https://pubmed.ncbi.nlm.nih.gov/25060491/},

doi = {10.1038/npp.2014.188},

issn = {1740-634X},

year  = {2015},

date = {2015-01-01},

urldate = {2015-01-01},

journal = {Neuropsychopharmacology},

volume = {40},

number = {2},

pages = {421--428},

abstract = {The abuse of prescription opioids that are used for the treatment of chronic pain is a major public health concern, costing ∼$53.4 billion annually in lost wages, health-care costs, and criminal costs. Although opioids remain a first-line therapy for the treatment of severe chronic pain, practitioners remain cautious because of the potential for abuse and addiction. Opioids such as heroin are considered very rewarding and reinforcing, but direct and systematic comparisons of compulsive intake between commonly prescribed opioids and heroin in animal models have not yet been performed. In the present study, we evaluated the potential for compulsive-like drug seeking and taking, using intravenous self-administration of oxycodone, fentanyl, and buprenorphine in rats allowed long access sessions (12 h). We measured compulsive-like intake using an established escalation model and responding on a progressive ratio schedule of reinforcement. We compared the potential for compulsive-like self-administration of these prescription opioids and heroin, which has been previously established to induce increasing intake that models the transition to addiction in humans. We found that animals that self-administered oxycodone, fentanyl, or heroin, but not buprenorphine had similar profiles of escalation and increases in breakpoints. The use of extended access models of prescription opioid intake will help better understand the biological factors that underlie opioid dependence. },

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25402857,

title = {VTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation},

author = {Taryn E Grieder and Melissa A Herman and Candice Contet and Laura A Tan and Hector Vargas-Perez and Ami Cohen and Michal Chwalek and Geith Maal-Bared and John Freiling and Joel E Schlosburg and Laura Clarke and Elena Crawford and Pascale Koebel and Vez Repunte-Canonigo and Pietro P Sanna and Andrew R Tapper and Marisa Roberto and Brigitte L Kieffer and Paul E Sawchenko and George F Koob and Derek van der Kooy and Olivier George},

url = {https://pubmed.ncbi.nlm.nih.gov/25402857/},

doi = {10.1038/nn.3872},

issn = {1546-1726},

year  = {2014},

date = {2014-12-01},

urldate = {2014-12-01},

journal = {Nat Neurosci},

volume = {17},

number = {12},

pages = {1751--1758},

abstract = {Dopaminergic neurons in the ventral tegmental area (VTA) are well known for mediating the positive reinforcing effects of drugs of abuse. Here we identify in rodents and humans a population of VTA dopaminergic neurons expressing corticotropin-releasing factor (CRF). We provide further evidence in rodents that chronic nicotine exposure upregulates Crh mRNA (encoding CRF) in dopaminergic neurons of the posterior VTA, activates local CRF1 receptors and blocks nicotine-induced activation of transient GABAergic input to dopaminergic neurons. Local downregulation of Crh mRNA and specific pharmacological blockade of CRF1 receptors in the VTA reversed the effect of nicotine on GABAergic input to dopaminergic neurons, prevented the aversive effects of nicotine withdrawal and limited the escalation of nicotine intake. These results link the brain reward and stress systems in the same brain region to signaling of the negative motivational effects of nicotine withdrawal. },

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24121188,

title = {The development and maintenance of drug addiction},

author = {Roy A Wise and George F Koob},

url = {https://pubmed.ncbi.nlm.nih.gov/24121188/},

doi = {10.1038/npp.2013.261},

issn = {1740-634X},

year  = {2014},

date = {2014-01-01},

urldate = {2014-01-01},

journal = {Neuropsychopharmacology},

volume = {39},

number = {2},

pages = {254--262},

abstract = {What is the defining property of addiction? We dust off a several-decades-long debate about the relative importance of two forms of reinforcement—positive reinforcement, subjectively linked to drug-induced euphoria, and negative reinforcement, subjectively linked to the alleviation of pain—both of which figure importantly in addiction theory; each of these forms has dominated addiction theory in its time. We agree that addiction begins with the formation of habits through positive reinforcement and that drug-opposite physiological responses often establish the conditions for negative reinforcement to come into play at a time when tolerance, in the form of increasing reward thresholds, appears to develop into positive reinforcement. Wise’s work has tended to focus on positive-reinforcement mechanisms that are important for establishing drug-seeking habits and reinstating them quickly after periods of abstinence, whereas Koob’s work has tended to focus on the negative-reinforcement mechanisms that become most obvious in the late stages of sustained addiction. While we tend to agree with each other about the early and late stages of addiction, we hold different views as to (i) the point between early and late at which the diagnosis of ‘addiction’ should be invoked, (ii) the relative importance of positive and negative reinforcement leading up to this transition, and (iii) the degree to which the specifics of negative reinforcement can be generalized across the range of addictive agents.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24305833,

title = {Long-term antagonism of κ opioid receptors prevents escalation of and increased motivation for heroin intake},

author = {Joel E Schlosburg and Timothy W Whitfield and Paula E Park and Elena F Crawford and Olivier George and Leandro F Vendruscolo and George F Koob},

url = {https://pubmed.ncbi.nlm.nih.gov/24305833/},

doi = {10.1523/JNEUROSCI.1979-13.2013},

issn = {1529-2401},

year  = {2013},

date = {2013-12-01},

urldate = {2013-12-01},

journal = {J Neurosci},

volume = {33},

number = {49},

pages = {19384--19392},

abstract = {The abuse of opioid drugs, both illicit and prescription, is a persistent problem in the United States, accounting for >1.2 million users who require treatment each year. Current treatments rely on suppressing immediate withdrawal symptoms and replacing illicit drug use with long-acting opiate drugs. However, the mechanisms that lead to preventing opiate dependence are still poorly understood. We hypothesized that κ opioid receptor (KOR) activation during chronic opioid intake contributes to negative affective states associated with withdrawal and the motivation to take increasing amounts of heroin. Using a 12 h long-access model of heroin self-administration, rats showed escalation of heroin intake over several weeks. This was prevented by a single high dose (30 mg/kg) of the long-acting KOR antagonist norbinaltorphimine (nor-BNI), paralleled by reduced motivation to respond for heroin on a progressive-ratio schedule of reinforcement, a measure of compulsive-like responding. Systemic nor-BNI also significantly decreased heroin withdrawal-associated anxiety-like behavior. Immunohistochemical analysis showed prodynorphin content increased in the nucleus accumbens core in all heroin-exposed rats, but selectively increased in the nucleus accumbens shell in long-access rats. Local infusion of nor-BNI (4 μg/side) into accumbens core altered the initial intake of heroin but not the rate of escalation, while local injection into accumbens shell selectively suppressed increases in heroin intake over time without altering initial intake. These data suggest that dynorphin activity in the nucleus accumbens mediates the increasing motivation for heroin taking and compulsive-like responding for heroin, suggesting that KOR antagonists may be promising targets for the treatment of opioid addiction. },

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid22875830,

title = {A combination of buprenorphine and naltrexone blocks compulsive cocaine intake in rodents without producing dependence},

author = {Sunmee Wee and Leandro F Vendruscolo and Kaushik K Misra and Joel E Schlosburg and George F Koob},

url = {https://pubmed.ncbi.nlm.nih.gov/22875830/},

doi = {10.1126/scitranslmed.3003948},

issn = {1946-6242},

year  = {2012},

date = {2012-08-01},

urldate = {2012-08-01},

journal = {Sci Transl Med},

volume = {4},

number = {146},

pages = {146ra110},

abstract = {Buprenorphine, a synthetic opioid that acts at both μ and κ opioid receptors, can decrease cocaine use in individuals with opioid addiction. However, the potent agonist action of buprenorphine at μ opioid receptors raises its potential for creating opioid dependence in non-opioid-dependent cocaine abusers. Here, we tested the hypothesis that a combination of buprenorphine and naltrexone (a potent μ opioid antagonist with weaker δ and κ antagonist properties) could block compulsive cocaine self-administration without producing opioid dependence. The effects of buprenorphine and various doses of naltrexone on cocaine self-administration were assessed in rats that self-administered cocaine under conditions of either short access (noncompulsive cocaine seeking) or extended access (compulsive cocaine seeking). Buprenorphine alone reproducibly decreased cocaine self-administration. Although this buprenorphine-alone effect was blocked in a dose-dependent manner by naltrexone in both the short-access and the extended-access groups, the combination of the lowest dose of naltrexone with buprenorphine blocked cocaine self-administration in the extended-access group but not in the short-access group. Rats given this low dose of naltrexone with buprenorphine did not exhibit the physical opioid withdrawal syndrome seen in rats treated with buprenorphine alone, and naltrexone at this dose did not block κ agonist-induced analgesia. The results suggest that the combination of buprenorphine and naltrexone at an appropriate dosage decreases compulsive cocaine self-administration with minimal liability to produce opioid dependence and may be useful as a treatment for cocaine addiction.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid20545871,

title = {Opioids, pain, the brain, and hyperkatifeia: a framework for the rational use of opioids for pain},

author = {Joseph Shurman and George F Koob and Howard B Gutstein},

url = {https://pubmed.ncbi.nlm.nih.gov/20545871/},

doi = {10.1111/j.1526-4637.2010.00881.x},

issn = {1526-4637},

year  = {2010},

date = {2010-07-01},

urldate = {2010-07-01},

journal = {Pain Med},

volume = {11},

number = {7},

pages = {1092--1098},

abstract = {OBJECTIVE: Opioids have relieved more human suffering than any other medication, but their use is still fraught with significant concerns of misuse, abuse, and addiction. This theoretical article explores the hypothesis that opioid misuse in the context of pain management produces a hypersensitivity to emotional distress, termed hyperkatifeia.



RESULTS: In the misuse of opioids, neural substrates that mediate positive emotional states (brain reward systems) are compromised, and substrates mediating negative emotional states (brain stress systems) are enhanced. A reflection and early marker of such a nonhomeostatic state may be the development of opioid-induced hyperkatifeia, defined as the increased intensity of the constellation of negative emotional/motivational symptoms and signs observed during withdrawal from drugs of abuse (derived from the Greek "katifeia" for dejection or negative emotional state) and is most likely to occur in subjects in whom the opioid produces a break with homeostasis and less likely to occur when the opioid is restoring homeostasis, such as in effective pain treatment. When the opioid appropriately relieves pain, opponent processes are not engaged. However, if the opioid is administered in excess of need because of overdose, pharmacokinetic variables, or treating an individual without pain, then the body will react to that perturbation by engaging opponent processes in the domains of both pain (hyperalgesia) and negative emotional states (hyperkatifeia).



CONCLUSIONS: Repeated engagement of opponent processes without time for the brain's emotional systems to reestablish homeostasis will further drive changes in emotional processes that may produce opioid abuse or addiction, particularly in individuals with genetic or environmental vulnerability.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Koob2010,

title = {Neurocircuitry of addiction.},

author = {George F Koob and Nora D Volkow},

url = {https://www.ncbi.nlm.nih.gov/pubmed/19710631},

doi = {10.1038/npp.2009.110},

issn = {1740-634X (Electronic); 0893-133X (Linking)},

year  = {2010},

date = {2010-01-01},

journal = {Neuropsychopharmacology},

volume = {35},

number = {1},

pages = {217--238},

address = {Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, USA. gkoob@scripps.edu},

abstract = {Drug addiction is a chronically relapsing disorder that has been characterized by (1) compulsion to seek and take the drug, (2) loss of control in limiting intake, and (3) emergence of a negative emotional state (eg, dysphoria, anxiety, irritability) reflecting a motivational withdrawal syndrome when access to the drug is prevented. Drug addiction has been conceptualized as a disorder that involves elements of both impulsivity and compulsivity that yield a composite addiction cycle composed of three stages: 'binge/intoxication', 'withdrawal/negative affect', and 'preoccupation/anticipation' (craving). Animal and human imaging studies have revealed discrete circuits that mediate the three stages of the addiction cycle with key elements of the ventral tegmental area and ventral striatum as a focal point for the binge/intoxication stage, a key role for the extended amygdala in the withdrawal/negative affect stage, and a key role in the preoccupation/anticipation stage for a widely distributed network involving the orbitofrontal cortex-dorsal striatum, prefrontal cortex, basolateral amygdala, hippocampus, and insula involved in craving and the cingulate gyrus, dorsolateral prefrontal, and inferior frontal cortices in disrupted inhibitory control. The transition to addiction involves neuroplasticity in all of these structures that may begin with changes in the mesolimbic dopamine system and a cascade of neuroadaptations from the ventral striatum to dorsal striatum and orbitofrontal cortex and eventually dysregulation of the prefrontal cortex, cingulate gyrus, and extended amygdala. The delineation of the neurocircuitry of the evolving stages of the addiction syndrome forms a heuristic basis for the search for the molecular, genetic, and neuropharmacological neuroadaptations that are key to vulnerability for developing and maintaining addiction.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid19483710,

title = {Development of pharmacotherapies for drug addiction: a Rosetta stone approach},

author = {George F Koob and G Kenneth Lloyd and Barbara J Mason},

url = {https://pubmed.ncbi.nlm.nih.gov/19483710/},

doi = {10.1038/nrd2828},

issn = {1474-1784},

year  = {2009},

date = {2009-06-01},

urldate = {2009-06-01},

journal = {Nat Rev Drug Discov},

volume = {8},

number = {6},

pages = {500--515},

abstract = {Current pharmacotherapies for addiction represent opportunities for facilitating treatment and are forming a foundation for evaluating new medications. Furthermore, validated animal models of addiction and a surge in understanding of neurocircuitry and neuropharmacological mechanisms involved in the development and maintenance of addiction - such as the neuroadaptive changes that account for the transition to dependence and the vulnerability to relapse - have provided numerous potential therapeutic targets. Here, we emphasize a 'Rosetta Stone approach', whereby existing pharmacotherapies for addiction are used to validate and improve animal and human laboratory models to identify viable new treatment candidates. This approach will promote translational research and provide a heuristic framework for developing efficient and effective pharmacotherapies for addiction.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid18614026,

title = {A role for brain stress systems in addiction},

author = {George F Koob},

url = {https://pubmed.ncbi.nlm.nih.gov/18614026/},

doi = {10.1016/j.neuron.2008.06.012},

issn = {1097-4199},

year  = {2008},

date = {2008-07-01},

urldate = {2008-07-01},

journal = {Neuron},

volume = {59},

number = {1},

pages = {11--34},

abstract = {Drug addiction is a chronically relapsing disorder characterized by compulsion to seek and take drugs and has been linked to dysregulation of brain regions that mediate reward and stress. Activation of brain stress systems is hypothesized to be key to the negative emotional state produced by dependence that drives drug seeking through negative reinforcement mechanisms. This review explores the role of brain stress systems (corticotropin-releasing factor, norepinephrine, orexin [hypocretin], vasopressin, dynorphin) and brain antistress systems (neuropeptide Y, nociceptin [orphanin FQ]) in drug dependence, with emphasis on the neuropharmacological function of extrahypothalamic systems in the extended amygdala. The brain stress and antistress systems may play a key role in the transition to and maintenance of drug dependence once initiated. Understanding the role of brain stress and antistress systems in addiction provides novel targets for treatment and prevention of addiction and insights into the organization and function of basic brain emotional circuitry.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid17079660,

title = {Corticotropin-releasing factor within the central nucleus of the amygdala mediates enhanced ethanol self-administration in withdrawn, ethanol-dependent rats},

author = {Cindy K Funk and Laura E O'Dell and Elena F Crawford and George F Koob},

url = {https://pubmed.ncbi.nlm.nih.gov/17079660/},

doi = {10.1523/JNEUROSCI.3096-06.2006},

issn = {1529-2401},

year  = {2006},

date = {2006-11-01},

urldate = {2006-11-01},

journal = {J Neurosci},

volume = {26},

number = {44},

pages = {11324--11332},

abstract = {Alcohol dependence is characterized by excessive consumption, loss of control over intake, and the presence of a withdrawal syndrome, including both motivational and physical symptoms. The motivational symptoms, including anxiety, have been hypothesized to be important factors eliciting excessive drinking during abstinence. Previous work has shown that ethanol-dependent rats also display enhanced anxiety-like behaviors and enhanced ethanol self-administration during withdrawal, likely resulting from dysregulation of brain corticotropin-releasing factor (CRF) stress systems. The present study was designed to explore the brain sites within the extended amygdala [central nucleus of the amygdala (CeA), lateral bed nucleus of the stria terminalis (BNST), and nucleus accumbens shell (NAcSh)] that mediate the increased ethanol self-administration observed during withdrawal. Ethanol-dependent animals showed an increase in ethanol self-administration after acute withdrawal relative to nondependent controls. The CRF antagonist D-Phe-CRF(12-41) ([D-Phe(12),Nle(21,38),C alpha MeLeu(37)]-rCRF(12-41)) was administered into the CeA, lateral BNST, or NAcSh of acute-withdrawn dependent and nondependent rats. Administered into the CeA, the antagonist reduced ethanol self-administration in dependent animals, with no effect in nondependent animals. Administration of D-Phe-CRF(12-41) into the lateral BNST and NAcSh was without effect on ethanol self-administration in dependent and nondependent animals. At the same time point of withdrawal, there was a decrease in CRF immunoreactivity within the CeA, suggesting an increased extracellular release of CRF during withdrawal. There was no change in CRF immunoreactivity in the BNST or NAcSh. These results indicate that CRF, specifically within the CeA, plays a role in mediating excessive ethanol consumption in ethanol-dependent animals.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15138444,

title = {Buprenorphine and a CRF_{1} antagonist block the acquisition of opiate withdrawal-induced conditioned place aversion in rats},

author = {Luis Stinus and Martine Cador and Eric P Zorrilla and George F Koob},

url = {https://pubmed.ncbi.nlm.nih.gov/15138444/},

doi = {10.1038/sj.npp.1300487},

issn = {0893-133X},

year  = {2005},

date = {2005-01-01},

urldate = {2005-01-01},

journal = {Neuropsychopharmacology},

volume = {30},

number = {1},

pages = {90--98},

abstract = {Conditioned place aversion in rats has face validity as a measure of the aversive stimulus effects of opiate withdrawal that reflects an important motivational component of opiate dependence. The purpose of the present study was to validate conditioned place aversion as sensitive to medications that will alleviate the aversive stimulus effects of opiate withdrawal in humans, and to extend this model to the exploration of the neuropharmacological basis of the motivational effects of opiate withdrawal. Male Sprague-Dawley rats were implanted with two subcutaneous morphine pellets and 5 days later began place conditioning training following subcutaneous administration of a low dose of naloxone. Animals were subjected to three pairings of a low dose of naloxone (15 microg/kg, s.c.) to one arm of a three-chambered place conditioning apparatus. Buprenorphine administered prior to each pairing dose-dependently blocked the place aversion produced by precipitated opiate withdrawal. A corticotropin-releasing factor-1 (CRF1) receptor antagonist (antalarmin) also reversed the place aversion produced by precipitated opiate withdrawal. Antalarmin did not produce a place preference or place aversion by itself in morphine-dependent rats. No effect was observed with pretreatment of the dopamine partial agonist terguride or the selective serotonin reuptake inhibitor fluoxetine. Also, chronic pretreatment with acamprosate (a glutamate receptor modulator used to prevent relapse in alcohol dependence) did not alter naloxone-induced place aversion. Buprenorphine by itself in dependent rats produced a mild place preference at low doses and a mild place aversion at higher doses. These results suggest that buprenorphine blocks the aversive stimulus effects of precipitated opiate withdrawal in rats and provides some validity for the use of place conditioning as a measure that is sensitive to potential opiate-dependence medications. In addition, these results suggest that CRF1 antagonists can block the aversive stimulus effects of opiate withdrawal and may be potential therapeutic targets for opiate dependence.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11120394,

title = {Drug addiction, dysregulation of reward, and allostasis},

author = {G F Koob and M Le Moal},

url = {https://pubmed.ncbi.nlm.nih.gov/11120394/},

doi = {10.1016/S0893-133X(00)00195-0},

issn = {0893-133X},

year  = {2001},

date = {2001-02-01},

urldate = {2001-02-01},

journal = {Neuropsychopharmacology},

volume = {24},

number = {2},

pages = {97--129},

abstract = {This paper reviews recent developments in the neurocircuitry and neurobiology of addiction from a perspective of allostasis. A model is proposed for brain changes that occur during the development of addiction that explain the persistent vulnerability to relapse long after drug-taking has ceased. Addiction is presented as a cycle of spiralling dysregulation of brain reward systems that progressively increases, resulting in the compulsive use and loss of control over drug-taking. The development of addiction recruits different sources of reinforcement, different neuroadaptive mechanisms, and different neurochemical changes to dysregulate the brain reward system. Counteradaptive processes such as opponent-process that are part of normal homeostatic limitation of reward function fail to return within the normal homeostatic range and are hypothesized to form an allostatic state. Allostasis from the addiction perspective is defined as the process of maintaining apparent reward function stability by changes in brain reward mechanisms. The allostatic state represents a chronic deviation of reward set point and is fueled not only by dysregulation of reward circuits per se, but also by the activation of brain and hormonal stress responses. The manifestation of this allostatic state as compulsive drug-taking and loss of control over drug-taking is hypothesized to be expressed through activation of brain circuits involved in compulsive behavior such as the cortico-striatal-thalamic loop. The view that addiction is the pathology that results from an allostatic mechanism using the circuits established for natural rewards provides a realistic approach to identifying the neurobiological factors that produce vulnerability to addiction and relapse.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11120394b,

title = {Drug addiction, dysregulation of reward, and allostasis},

author = {G F Koob and M Le Moal},

url = {https://pubmed.ncbi.nlm.nih.gov/11120394/},

doi = {10.1016/S0893-133X(00)00195-0},

issn = {0893-133X},

year  = {2001},

date = {2001-02-01},

urldate = {2001-02-01},

journal = {Neuropsychopharmacology},

volume = {24},

number = {2},

pages = {97--129},

abstract = {This paper reviews recent developments in the neurocircuitry and neurobiology of addiction from a perspective of allostasis. A model is proposed for brain changes that occur during the development of addiction that explain the persistent vulnerability to relapse long after drug-taking has ceased. Addiction is presented as a cycle of spiralling dysregulation of brain reward systems that progressively increases, resulting in the compulsive use and loss of control over drug-taking. The development of addiction recruits different sources of reinforcement, different neuroadaptive mechanisms, and different neurochemical changes to dysregulate the brain reward system. Counteradaptive processes such as opponent-process that are part of normal homeostatic limitation of reward function fail to return within the normal homeostatic range and are hypothesized to form an allostatic state. Allostasis from the addiction perspective is defined as the process of maintaining apparent reward function stability by changes in brain reward mechanisms. The allostatic state represents a chronic deviation of reward set point and is fueled not only by dysregulation of reward circuits per se, but also by the activation of brain and hormonal stress responses. The manifestation of this allostatic state as compulsive drug-taking and loss of control over drug-taking is hypothesized to be expressed through activation of brain circuits involved in compulsive behavior such as the cortico-striatal-thalamic loop. The view that addiction is the pathology that results from an allostatic mechanism using the circuits established for natural rewards provides a realistic approach to identifying the neurobiological factors that produce vulnerability to addiction and relapse.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Ahmed1998,

title = {Transition from moderate to excessive drug intake: change in hedonic set point.},

author = {S H Ahmed and G F Koob},

url = {https://www.ncbi.nlm.nih.gov/pubmed/9765157},

issn = {0036-8075 (Print); 0036-8075 (Linking)},

year  = {1998},

date = {1998-10-09},

journal = {Science},

volume = {282},

number = {5387},

pages = {298--300},

address = {Division of Psychopharmacology, Department of Neuropharmacology, CVN-7, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. aserge@sage.scripps.edu},

abstract = {Differential access to cocaine self-administration produced two patterns of drug intake in rats. With 1 hour of access per session, drug intake remained low and stable. In contrast, with 6 hours of access, drug intake gradually escalated over days. After escalation, drug consumption was characterized by an increased early drug loading and an upward shift in the cocaine dose-response function, suggesting an increase in hedonic set point. After 1 month of abstinence, escalation of cocaine intake was reinstated to a higher level than before. These findings may provide an animal model for studying the development of excessive drug intake and the basis of addiction.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Koob1997,

title = {Drugs of abuse: anatomy, pharmacology and function of reward pathways.},

author = {G F Koob},

url = {https://www.ncbi.nlm.nih.gov/pubmed/9311926},

issn = {0165-6147 (Print); 0165-6147 (Linking)},

year  = {1997},

date = {1997-10-03},

journal = {Trends Pharmacol Sci},

volume = {13},

number = {5},

pages = {177--184},

address = {Department of Neuropharmacology, Scripps Research Institute, La Jolla, CA 92037.},

abstract = {Drugs of abuse are very powerful reinforcers, and even in conditions of limited access (where the organism is not dependent) these drugs will motivate high rates of operant responding. This presumed hedonic property and the drugs' neuropharmacological specificity provide a means of studying the neuropharmacology and neuroanatomy of brain reward. Three major brain systems appear to be involved in drug reward--dopamine, opioid and GABA. Evidence suggests a midbrain-forebrain-extrapyramidal circuit with its focus in the nucleus accumbens. Data implicating dopamine and opioid systems in indirect sympathomimetic and opiate reward include critical elements in both the nucleus accumbens and ventral tegmental areas. Ethanol reward appears to depend on an interaction with the GABAA receptor complex but may also involve common elements such as dopamine and opioid peptides in this midbrain-forebrain-extrapyramidal circuit. These results suggest that brain reward systems have a multidetermined neuropharmacological basis that may involve some common neuroanatomical elements.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Koob1997,

title = {Drug abuse: hedonic homeostatic dysregulation.},

author = {G F Koob and M Le Moal},

url = {https://www.ncbi.nlm.nih.gov/pubmed/9311926},

issn = {0036-8075 (Print); 0036-8075 (Linking)},

year  = {1997},

date = {1997-10-03},

journal = {Science},

volume = {278},

number = {5335},

pages = {52--58},

address = {The Scripps Research Institute, Department of Neuropharmacology CVN-7, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.},

abstract = {Understanding the neurobiological mechanisms of addiction requires an integration of basic neuroscience with social psychology, experimental psychology, and psychiatry. Addiction is presented as a cycle of spiralling dysregulation of brain reward systems that progressively increases, resulting in compulsive drug use and a loss of control over drug-taking. Sensitization and counteradaptation are hypothesized to contribute to this hedonic homeostatic dysregulation, and the neurobiological mechanisms involved, such as the mesolimbic dopamine system, opioid peptidergic systems, and brain and hormonal stress systems, are beginning to be characterized. This framework provides a realistic approach to identifying the neurobiological factors that produce vulnerability to addiction and to relapse in individuals with a history of addiction.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Koob1988,

title = {Cellular and molecular mechanisms of drug dependence.},

author = {G F Koob and F E Bloom},

url = {https://www.ncbi.nlm.nih.gov/pubmed/2903550},

issn = {0036-8075 (Print); 0036-8075 (Linking)},

year  = {1988},

date = {1988-11-04},

journal = {Science},

volume = {242},

number = {4879},

pages = {715--723},

address = {Research Institute of Scripps Clinic, La Jolla, CA 92037.},

abstract = {The molecular and cellular actions of three classes of abused drugs--opiates, psychostimulants, and ethanol--are reviewed in the context of behavioral studies of drug dependence. The immediate effects of drugs are compared to those observed after long-term exposure. A neurobiological basis for drug dependence is proposed from the linkage between the cellular and behavioral effects of these drugs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Sutton1982,

title = {Corticotropin releasing factor produces behavioural activation in rats.},

author = {R E Sutton and G F Koob and M Le Moal and J Rivier and W Vale},

url = {https://www.ncbi.nlm.nih.gov/pubmed/6978997},

issn = {0028-0836 (Print); 0028-0836 (Linking)},

year  = {1982},

date = {1982-05-27},

journal = {Nature},

volume = {297},

number = {5864},

pages = {331--333},

keywords = {},

pubstate = {published},

tppubtype = {article}

}