Biomedical subjects

George F Koob

Publications and source records attributed to George F Koob.

At least 19 recordsLinked to original sources

PubMed2006

Effects of terguride, ropinirole, and acetyl-L-carnitine on methamphetamine withdrawal in the rat.

Withdrawal from psychostimulants, including methamphetamine, induces a depressive state associated with lethargy, dysphoria, hyperphagia and psychomotor retardation. Previous work with repeated administration of amphetamine in rats has shown that amphetamine withdrawal produces decreased motivation to work for a non-drug reward, and this withdrawal is reversed by administration of a dopamine partial agonist. The purpose of the present study was to examine decreased motivation to work for a non-drug reward during methamphetamine withdrawal and explore the effects of a dopamine agonist, dopamine partial agonist, and indirect monoamine agonist on methamphetamine withdrawal. During withdrawal from repeated methamphetamine administration, rats showed reduced responding for a sweet solution in a progressive-ratio schedule of reinforcement, and this effect was significantly more pronounced than previously observed with amphetamine. Repeated systemic treatment with the dopamine partial agonist terguride (0.2 and 0.4 mg/kg, i.p., twice daily), the full dopamine agonist ropinirole (1 mg/kg, i.p., twice daily), and acetyl-L-carnitine (60 and 100 mg/kg, i.p.), a compound with a potential antidepressant effect, during methamphetamine withdrawal restored responding for the sweet solution, suggesting that these drugs may represent potential therapeutic strategies for the treatment of methamphetamine addiction during the withdrawal phase.

Acetylcarnitine↗

PubMed2006

Toward understanding the genetics of alcohol drinking through transcriptome meta-analysis.

Much evidence from studies in humans and animals supports the hypothesis that alcohol addiction is a complex disease with both hereditary and environmental influences. Molecular determinants of excessive alcohol consumption are difficult to study in humans. However, several rodent models show a high or low degree of alcohol preference, which provides a unique opportunity to approach the molecular complexities underlying the genetic predisposition to drink alcohol. Microarray analyses of brain gene expression in three selected lines, and six isogenic strains of mice known to differ markedly in voluntary alcohol consumption provided >4.5 million data points for a meta-analysis. A total of 107 arrays were obtained and arranged into six experimental data sets, allowing the identification of 3,800 unique genes significantly and consistently changed between all models of high or low amounts of alcohol consumption. Several functional groups, including mitogen-activated protein kinase signaling and transcription regulation pathways, were found to be significantly overrepresented and may play an important role in establishing a high level of voluntary alcohol drinking in these mouse models. Data from the general meta-analysis was further filtered by a congenic strain microarray set, from which cis-regulated candidate genes for an alcohol preference quantitative trait locus on chromosome 9 were identified: Arhgef12, Carm1, Cryab, Cox5a, Dlat, Fxyd6, Limd1, Nicn1, Nmnat3, Pknox2, Rbp1, Sc5d, Scn4b, Tcf12, Vps11, and Zfp291 and four ESTs. The present study demonstrates the use of (i) a microarray meta-analysis to analyze a behavioral phenotype (in this case, alcohol preference) and (ii) a congenic strain for identification of cis regulation.

Alcohol Drinking↗

PubMed2006

Diminished nicotine withdrawal in adolescent rats: implications for vulnerability to addiction.

RATIONALE: Enhanced reinforcing effects of nicotine during adolescence appear to contribute to the rapid development of dependence in this age group. However, the contribution of nicotine withdrawal to dependence in adolescents is unclear. OBJECTIVE: We compared motivational and somatic signs of nicotine withdrawal in adolescent and adult rats. MATERIALS AND METHODS: In experiment 1, motivational signs of nicotine withdrawal were compared using intracranial self-stimulation procedures after administration of mecamylamine (1.5 mg/kg, i.p.) in adolescent and adult rats made dependent on nicotine (9 mg/kg/day). Somatic signs of withdrawal were compared in two experiments using various doses of nicotine (adolescent doses: 0, 1.6, 3.2, 4.7 mg/kg/day; adult doses: 0, 1, 2.1, 3.2 mg/kg/day, expressed as nicotine base) to produce dependence and one dose of mecamylamine (1.5 mg/kg, i.p.) to precipitate withdrawal (experiment 2) and in a subsequent experiment, using various doses of mecamylamine (0, 0.75, 1.5, 3.0 mg/kg, i.p.) to precipitate withdrawal and a dose of nicotine (adolescent dose: 4.7 mg/kg/day; adult dose: 3.2 mg/kg/day) that produced equivalent nicotine blood levels in these age groups (experiment 3). RESULTS: Adolescents did not display the decreases in brain reward function observed in adults experiencing withdrawal, and displayed fewer somatic signs of nicotine withdrawal relative to adults regardless of the dosing procedure used. CONCLUSION: The negative effects of nicotine withdrawal are lower during adolescence relative to later periods of development. Both the enhanced rewarding effects and the diminished nicotine withdrawal likely contribute to the rapid development of nicotine use during adolescence.

Age Factors↗

PubMed2006

Escalation of methamphetamine self-administration in rats: a dose-effect function.

RATIONALE: The transition from stable to escalated drug intake has been demonstrated in rats self-administrating cocaine and heroin using a single dose of drug. OBJECTIVES: To investigate the prolonged exposure to methamphetamine self-administration and the effect of various training doses of methamphetamine on the changes of methamphetamine intake over a 21-day period. METHODS: Two groups of rats were trained in 1-h daily sessions of methamphetamine self-administration [0.033 mg/infusion (inf); approximately 0.066 mg/kg/inf]. Methamphetamine access was increased to 6 h in one group [Long Access (LgA)] or maintained at 1 h in another [Short Access (ShA)]. The same procedure was repeated in rats exposed to different training doses of methamphetamine (0.05, 0.1, and 0.2 mg/kg/inf). RESULTS: In LgA rats, total and first hour intake of methamphetamine significantly increased compared to ShA rats at various methamphetamine doses. LgA animals, at all doses in the second study, escalated intake to 8-9 mg/kg per 6-h session, with the most rapid escalation occurring at 3-5 days at a methamphetamine dose of 0.1 mg/kg/inf. CONCLUSIONS: The escalation of drug intake observed with extended access is produced at multiple doses of methamphetamine. The rapidity of escalation depends on the dose. Ultimately, all doses in the dose-response study engendered self-administration of the same amount of total drug in a 6-h session in the extended-access group. Results suggest that the rapidity of escalation is dependent on dose and has an upper limit of intake over a period of 21 days.

Animals↗

PubMed2006

Unlimited access to heroin self-administration: independent motivational markers of opiate dependence.

The goal of the present study was to develop and validate an animal model of unlimited access to intravenous heroin self-administration combined with responding for food and water to characterize the transition to drug dependence. Male Wistar rats were allowed to lever press for heroin (60 microg/kg/0.1 ml infusion/s; fixed ratio 1; 20-s time out) and nosepoke for food and water in consecutive, daily 23-h sessions. Daily heroin intake increased over days, reaching significance by Day 14. Drug-taking increased across the circadian cycle, reflected as increases in both the nocturnal peak and diurnal nadir of heroin intake. Changes in the circadian pattern of food intake and meal patterning preceded and paralleled the changes in heroin intake. By Day 7, the circadian amplitude of feeding was blunted. Nocturnal intake decreased because rats consumed smaller and briefer meals. Diurnal intake increased due to increased meal frequency, whereas total daily food intake decreased. To control for time or experience in the self-administration boxes as a possible confound, rats with saline (no drug) tethers were tested and did not display significant changes in food intake pattern. Body weight gain slowed slightly in heroin rats relative to saline controls. Separate groups of rats revealed that significant physical dependence as measured by physical signs of opiate withdrawal following a naloxone injection (1.0 mg/kg, subcutaneous (s.c.)) was reached by Day 14. Significant increases in heroin intake could be produced using low doses of naloxone (0.003-0.03 mg/kg, s.c.) on days 28-31 of heroin access. After 6 weeks of heroin self-administration, rats injected with buprenorphine (0, 0.01, 0.04, and 0.2 mg/kg, s.c.) showed a dose-dependent reduction in heroin intake. Changes in the pattern of drug and food intake in the present unlimited heroin access model may serve as independent motivational markers for the transition to a drug-dependent state.

Analgesics, Opioid↗

PubMed2006

Kappa opioid control of seizures produced by a virus in an animal model.

Epilepsy remains a major medical problem of unknown aetiology. Potentially, viruses can be environmental triggers for development of seizures in genetically vulnerable individuals. An estimated half of encephalitis patients experience seizures and approximately 4% develop status epilepticus. Epilepsy vulnerability has been associated with a dynorphin promoter region polymorphism or low dynorphin expression genotype, in man. In animals, the dynorphin system in the hippocampus is known to regulate excitability. The present study was designed to test the hypothesis that reduced dynorphin expression in the dentate gyrus of hippocampus due to periadolescent virus exposure leads to epileptic responses. Encephalitis produced by the neurotropic Borna disease virus in the rat caused epileptic responses and dynorphin to disappear via dentate granule cell loss, failed neurogenesis and poor survival of new neurons. Kappa opioid (dynorphin) agonists prevented the behavioural and electroencephalographic seizures produced by convulsant compounds, and these effects were associated with an absence of dynorphin from the dentate gyrus granule cell layer and upregulation of enkephalin in CA1 interneurons, thus reproducing a neurochemical marker of epilepsy, namely low dynorphin tone. A key role for kappa opioids in anticonvulsant protection provides a framework for exploration of viral and other insults that increase seizure vulnerability and may provide insights into potential interventions for treatment of epilepsy.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed2006

Understanding and treating alcohol dependence.

This article represents the proceedings of a symposium presented at the 158th Annual Meeting of the American Psychiatric Association held in Atlanta, Georgia, on May 24, 2005. The organizer/chairman was Bankole A. Johnson, DSc, MD, PhD. The presentations included the following: (1) Neuropharmacological Basis of Alcohol Dependence, by George F. Koob, PhD; (2) Recent Developments in the Genetics of Alcohol Dependence, by Marc A. Schuckit, MD; (3) New Pharmacological Strategies for Treating Alcohol Dependence, by Barbara J. Mason, PhD; (4) New Medications: The Use of Anticonvulsants, Both Alone and in Combination, with Various Forms of Psychotherapy, by Bankole A. Johnson, DSc, MD, PhD; and (5) Differential Effects of Pharmacological Agents on Craving, by Nassima Ait-Daoud, MD.

Alcoholism↗

PubMed2005

Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior.

Hypocretin-1 and -2 (Hcrt-1 and Hcrt-2), also referred to as orexin-A and -B, are neuropeptides synthesized by a few thousand neurons in the lateral hypothalamus. Hypocretin-containing neurons project throughout the brain, with a prominent input to basal forebrain structures involved in motivation, reward, and stress. However, the role of hypocretins in addiction-related behaviors remains largely unexplored. Here we show that intracerebroventricular infusions of Hcrt-1 lead to a dose-related reinstatement of cocaine seeking without altering cocaine intake in rats. Hcrt-1 also dramatically elevates intracranial self-stimulation thresholds, indicating that, unlike treatments with reinforcing properties such as cocaine, Hcrt-1 negatively regulates the activity of brain reward circuitries. Hypocretin-induced reinstatement of cocaine seeking was prevented by blockade of noradrenergic and corticotropin-releasing factor systems, suggesting that Hcrt-1 reinstated drug seeking through induction of a stress-like state. Consistent with this interpretation, the selective Hcrt-1 receptor antagonist SB-334867 blocked footshock-induced reinstatement of previously extinguished cocaine-seeking behavior. These findings reveal a previously unidentified role for hypocretins in driving drug seeking through activation of stress pathways in the brain.

Analysis of Variance↗

PubMed2005

Delta9-tetrahydrocannabinol immunochemical studies: haptens, monoclonal antibodies, and a convenient synthesis of radiolabeled delta9-tetrahydrocannabinol.

Immunopharmacotherapy as an approach to combat drugs of abuse has become an active area of investigation. Marijuana is the most commonly used illicit drug in the U.S. The main active chemical in marijuana is delta9-tetrahydrocannabinol (delta9-THC); hence, monoclonal antibodies with high affinity and specificity for delta9-tetrahydrocannabinol could be valuable immunopharmacotherapeutic intervention and diagnostic tools. We have synthesized immunoconjugates that induce an effective immune response to delta9-THC and describe a convenient synthesis of radiolabeled delta9-THC. We demonstrate the value and use of this probe to select anti-delta9-THC antibodies that bind delta9-THC with good affinity. The synthetic route to radiolabeled delta9-THC has enabled the correct assessment of the affinity of these antibodies to their ligand and may facilitate future binding studies between delta9-THC and its analogues and the cannabinoid receptors.

Animals↗

PubMed2005

Monoamine oxidase inhibition dramatically increases the motivation to self-administer nicotine in rats.

Nicotine is the major neuroactive compound of tobacco, which has, by itself, weak reinforcing properties. It is known that levels of the enzymes monoamine oxidase A (MAO-A) and MAO-B are reduced in the platelets and brains of smokers and that substances, other than nicotine, present in tobacco smoke have MAO-inhibitory activities. Here, we report that inhibition of MAO dramatically and specifically increases the motivation to self-administer nicotine in rats. These effects were more prominent in rats selected for high responsiveness to novelty than in rats with low responsiveness to novelty. The results suggest that the inhibition of MAO activity by compounds present in tobacco smoke may combine with nicotine to produce the intense reinforcing properties of cigarette smoking that lead to addiction.

Animals↗

PubMed2005

Gene expression evidence for remodeling of lateral hypothalamic circuitry in cocaine addiction.

By using high-density oligonucleotide arrays, we profiled gene expression in reward-related brain regions of rats that developed escalated cocaine intake after extended access to cocaine (6 h per day). Rats allowed restricted daily access to cocaine (only 1 h) that displayed a stable level of cocaine intake and cocaine naive rats were used for controls. Four analysis methods were compared: Affymetrix microarray suite 4 and microarray suite 5, which use perfect-match-minus-mismatch models, and dchip and rma, which use perfect-match-only models to generate expression values. Results were validated by RT-PCR in individual animals from an independent replication of the experiment. A small number of genes was associated with escalated cocaine intake (ESC genes). Unexpectedly, of the brain regions examined [prefrontal cortex, nucleus accumbens, septum, lateral hypothalamus (LH), amygdala, and ventral tegmental area], the LH was the most transcriptionally responsive in escalation of cocaine intake. Most of the ESC genes identified are also expressed during synaptogenesis and synaptic plasticity and include genes that code for several presynaptic and postsynaptic proteins involved in neurotransmission. These results suggest that LH intrinsic circuitry undergoes a structural reorganization during escalation of cocaine use. This remodeling of LH circuitry could contribute to the chronic deficit in reward function that has been hypothesized to drive the transition to drug addiction. Results also support the value of using multiple analysis strategies to identify the most robust changes in gene expression and to compensate for the biases that affect each strategy.

Animals↗

PubMed2005

Transition to drug addiction: a negative reinforcement model based on an allostatic decrease in reward function.

RATIONALE: The transition from initial drug use to drug addiction has been proposed to result from an allostatic decrease in reward function driven by an overactivation of brain antireward processes. OBJECTIVES: How decreased reward function explains compulsive drug use is not entirely clear at present, and is still a subject for debate. METHODS: We present a quantitative model of cocaine self-administration that integrates pharmacokinetic, pharmacodynamic, and motivational factors to address this question. The model assumes that reward system responsivity is a homeostatically regulated process where the desired level of responsivity (called the reward set point) is initially different from the baseline level. The reduction or correction of this difference or error in reward function would drive cocaine self-administration. RESULTS: Theoretical data obtained by computer simulation fit the experimental data obtained in animals self-administering cocaine (i.e., the within-session pattern of self-injections, the shape and curvature of the dose-injection function, the nonlinear relationship between drug intake and regulated drug effects). Importantly, simulation of an allostatic decrease in reward system responsivity exacerbates the initial error that drives self-administration, thereby increasing both the intake of, and the motivation for, the drug. This allostatic change manifests as a vertical shift in the dose-injection function similar to that seen in animals with escalating cocaine self-administration. CONCLUSIONS: The present model provides a satisfactory explanation of escalated drug intake and suggests a novel negative reinforcement view of addiction based on an allostatic decrease in reward function.

Adaptation, Physiological↗

PubMed2005

Measuring meals: structure of prandial food and water intake of rats.

Attempts to understand ingestion have sought to understand the control of meals. The present study evaluated a meal definition that included prandial drinking (drinking-explicit meals). The spontaneous nocturnal intake of male Wistar rats was studied. The meal breakpoint was defined as the interval between feeding or drinking events providing the most stable estimate of meal structure. Alternative breakpoints derived from prevailing methodology, log-survivorship, or frequency histogram analysis of interfeeding intervals without respect to drinking were compared (drinking-naive meals). Threshold interfeeding intervals that accounted for drinking indirectly were evaluated as surrogate breakpoints (drinking-implicit meals). Definitions were compared by determining which criterion better conformed to predictions of satiety. Microstructural differences resulting from the definitions were also studied. Under the drinking-explicit definition, rats averaged nine or ten 13-min meals/night, during which they consumed food and water equally in duration (5-6 min) and quantity (2.3 g). Individual differences were observed in microstructure measures. Meals defined by drinking-informed, but not drinking-naive, methods were followed by the behavioral satiety sequence and by an initially low likelihood of resuming feeding that monotonically increased with time. The drinking-explicit definition uniquely revealed preprandial and postprandial correlations of similar magnitude. Under drinking-informed definitions, food restriction increased meal size, whereas drinking-naive definitions increased meal frequency. Drinking-implicit definitions provided workable approximations of meal frequency and size but inferior estimates of feeding duration, eating rate, and the preprandial correlation. Thus log-survivorship analysis is not appropriate for identifying meal breakpoints, and the consideration of drinking in meal definitions can provide a better estimate of meal structure.

Algorithms↗

PubMed2005

Impairment of dopaminergic system function after chronic treatment with corticotropin-releasing factor.

Mounting evidence suggests that chronic stress may have a detrimental effect on dopaminergic function and, in certain individuals, could contribute to the pathophysiology of central nervous system disorders like depression, schizophrenia, and Parkinson's disease. Therefore, the effects of chronic elevated brain levels of corticotropin-releasing factor (CRF), a crucial mediator of the behavioral stress response, on dopaminergic function were investigated. Rats treated intracerebroventricularly (i.c.v.) with 1 microg of CRF per day for 13 days displayed a decreased stereotyped response to D-amphetamine 1 day after chronic CRF and 1 month post-CRF. These rats also displayed an increased cataleptic response to eticlopride at 2 days post-CRF, consistent with decreased functional activity in the dopaminergic systems. CRF treatment induced a transient decrease of dopamine tissue levels in the prefrontal cortex at 1 day and 1 week post-CRF, an increase in the nucleus accumbens 1 week post-CRF and no change in the striatum. An increase of the dihydroxyphenylacetic acid/dopamine (DOPAC/DA) ratio, an indicator of dopamine turnover, also was seen in the prefrontal cortex and striatum in CRF-treated animals at 1 week post-CRF. The dopaminergic system is very sensitive to oxidative insults. Levels of malondialdehyde, a membrane lipid peroxidation marker, also were measured in the same brain areas. In the prefrontal cortex, we observed a decrease of malondialdehyde at 1 week after chronic CRF treatment. This result may indicate an activation of the antioxidant system in response to chronic stress. These results show that chronic hyperactivity of the CRF system leads to a transient dysfunction of the dopaminergic systems, possibly through oxidative mechanisms, and suggest that stress could be a cofactor in the pathogenesis and/or progression of disorders of the dopaminergic systems.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2005

Plasticity of reward neurocircuitry and the 'dark side' of drug addiction.

Drug seeking is associated with activation of reward neural circuitry. Here we argue that drug addiction also involves a 'dark side'--a decrease in the function of normal reward-related neurocircuitry and persistent recruitment of anti-reward systems. Understanding the neuroplasticity of the dark side of this circuitry is the key to understanding vulnerability to addiction.

Animals↗

PubMed2005

Buprenorphine and a CRF1 antagonist block the acquisition of opiate withdrawal-induced conditioned place aversion in rats.

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.

Acamprosate↗

PubMed2005

Stress enhancement of craving during sobriety: a risk for relapse.

This report of the proceedings of a symposium presented at the 2004 Research Society on Alcoholism Meeting provides evidence linking stress during sobriety to craving that increases the risk for relapse. The initial presentation by Rajita Sinha summarized clinical evidence for the hypothesis that there is an increased sensitivity to stress-induced craving in alcoholics. During early abstinence, alcoholics who were confronted with stressful circumstances showed increased susceptibility for relapse. George Breese presented data demonstrating that stress could substitute for repeated withdrawals from chronic ethanol to induce anxiety-like behavior. This persistent adaptive change induced by multiple withdrawals allowed stress to induce an anxiety-like response that was absent in animals that were not previously exposed to chronic ethanol. Subsequently, Amanda Roberts reviewed evidence that increased drinking induced by stress was dependent on corticotropin-releasing factor (CRF). In addition, rats that were stressed during protracted abstinence exhibited anxiety-like behavior that was also dependent on CRF. Christopher Dayas indicated that stress increases the reinstatement of an alcohol-related cue. Moreover, this effect was enhanced by previous alcohol dependence. These interactive effects between stress and alcohol-related environmental stimuli depended on concurrent activation of endogenous opioid and CRF systems. A.D. Lê covered information that indicated that stress facilitated reinstatement to alcohol responding and summarized the influence of multiple deprivations on this interaction. David Overstreet provided evidence that restraint stress during repeated alcohol deprivations increases voluntary drinking in alcohol-preferring (P) rats that results in withdrawal-induced anxiety that is not observed in the absence of stress. Testing of drugs on the stress-induced voluntary drinking implicated serotonin and CRF involvement in the sensitized response. Collectively, the presentations provided convincing support for an involvement of stress in the cause of relapse and continuing alcohol abuse and suggested novel pharmacological approaches for treating relapse induced by stress.

Animals↗

PubMed2005

Role of the endogenous opioid system on the neuropsychopharmacological effects of ethanol: new insights about an old question.

This article presents the proceedings of the symposium "Endogenous Opioids and Voluntary Ethanol Consumption: What Have We Learnt From Knock-out Mice?" presented at the meeting of the International Society for Biomedical Research on Alcoholism held in Heidelberg/Mannheim, Germany, in September/October 2004. The organizers and chairpersons were Michael S. Cowen and Carles Sanchis-Segura. The presentations were as follows: (1) Regulation of the Opioid System by Alcohol: Comparison of Alcohol-Preferring and -Nonpreferring Strains by Michael S. Cowen; (2) Endogenous Opioids and Alcohol: Lessons From Microdialysis and Knock-out Mice by M. Foster Olive; (3) From Neurochemistry to Neuroanatomy: The Hypothalamic Arcuate Nucleus as a Main Site for Ethanol-Opioids Interaction by Carles Sanchis-Segura; (4) Sensitivity to Ethanol Is Modulated by beta-Endorphin in Transgenic Mice by Judy E. Grisel, Amanda J. Roberts, and George F. Koob; and () The mu-Opioid Receptor Modulates Acute Ethanol Sensitivity and Ethanol Withdrawal Severity by Sandra Ghozland.

Alcohol Withdrawal Delirium↗