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George F Koob

Publications and source records attributed to George F Koob.

At least 37 records · Page 2Linked to original sources
PubMed2006

The neurobiology of addiction: a neuroadaptational view relevant for diagnosis.

AIMS: The purpose of this review is to provide a synthesis of our knowledge of the neurobiological bases of addiction relevant for the diagnosis of addiction. METHODS: A heuristic framework of neuroadaptive changes within key brain neurocircuitry responsible for different stages of the addiction cycle is outlined and linked to human studies to provide important future translational links for diagnosis. RESULTS: Animal studies have revealed dysregulation of specific neurochemical mechanisms (dopamine, opioid peptides) in the brain reward systems and recruitment of brain stress systems (corticotropin-releasing factor) during the development of dependence that convey vulnerability to relapse. Animal studies have implicated the prefrontal cortex and basolateral amygdala in drug- and cue-induced relapse, respectively, and the brain stress systems in stress-induced relapse. Genetic studies suggest roles for the genes encoding the neurochemical elements involved in both the brain reward and stress systems in the vulnerability to addiction, and molecular studies have identified transduction and transcription factors that may mediate dependence-induced reward dysregulation. Human imaging studies reveal similar neurocircuits involved in acute intoxication, chronic drug dependence and vulnerability to relapse. CONCLUSIONS: Major neurobiological changes in substance abuse disorders common to human and animal studies relevant for diagnosis include a compromised reward system, overactivated brain stress systems and compromised orbitofrontal/prefrontal cortex function. No biological markers of substance abuse disorders currently exist, but there are many promising neurobiological features of substance abuse disorders that will eventually aid in the specific diagnoses of substance use, misuse and dependence.

Adaptation, Physiological↗
PubMed2006

Alcohol-related genes: contributions from studies with genetically engineered mice.

Since 1996, nearly 100 genes have been studied for their effects related to ethanol in mice using genetic modifications including gene deletion, gene overexpression, gene knock-in, and occasionally by studying existing mutants. Nearly all such studies have concentrated on genes expressed in brain, and the targeted genes range widely in their function, including most of the principal neurotransmitter systems, several neurohormones, and a number of signaling molecules. We review 141 published reports of effects (or lack thereof) of 93 genes on responses to ethanol. While most studies have focused on ethanol self-administration and reward, and/or sedative effects, other responses studied include locomotor stimulation, anxiolytic effects, and neuroadaptation (tolerance, sensitization, withdrawal). About 1/4 of the engineered mutations increase self-administration, 1/3 decrease it, and about 40% have no significant effect. In many cases, the effects on self-administration are rather modest and/or depend on the specific experimental procedures. In some cases, genes in the background strains on which the mutant is placed are important for results. Not surprisingly, review of the systems affected further supports roles for serotonin, gamma-aminobutyric acid, opioids and dopamine, all of which have long been foci of alcohol research. Novel modulatory effects of protein kinase C and G protein-activated inwardly rectifying K+ (GIRK) channels are also suggested. Some newer research with cannabinoid systems is promising, and has led to ongoing clinical trials.

Alcoholism↗
PubMed2006

Monoamine oxidase A rather than monoamine oxidase B inhibition increases nicotine reinforcement in rats.

Although nicotine is considered to be responsible for the addictive properties of tobacco, growing evidence underlines the importance of non-nicotine components in smoking reinforcement. It has been shown that tobacco smoke contains monoamine oxidase (MAO) A and B inhibitors and decreases MAO-A and MAO-B activity in smokers. Here, we investigated the effects of clorgyline hydrochloride (irreversible MAO-A inhibitor; 2 mg/kg/day), selegiline (irreversible MAO-B inhibitor; 4 mg/kg) and the beta-carboline norharmane hydrochloride (reversible MAO-B inhibitor; 5 mg/kg/day) treatments on nicotine self-administration (30 microg/kg/infusion, free base) in rats. Independent of the responsiveness to novelty and locomotor activity stimulation, only clorgyline hydrochloride treatment increased the intake of nicotine in a fixed-ratio schedule (FR5) of reinforcement. When a progressive-ratio schedule was implemented, both clorgyline hydrochloride and norharmane hydrochloride treatments potentiated the reinforcing effects of nicotine, whereas selegiline had no effect. Taken together, these results indicate that MAO-A inhibition interacts with nicotine to enhance its rewarding effects in rats and suggest that other compounds present in tobacco, such as beta-carboline, may also play an important role in sustaining smoking behavior in humans.

Analysis of Variance↗
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↗
PubMed2004

Metabotropic glutamate 5 receptor blockade may attenuate cocaine self-administration by decreasing brain reward function in rats.

RATIONALE: Evidence is accumulating that metabotropic glutamate 5 (mGlu5) receptors play an important role in regulating the reinforcing actions of drugs of abuse. OBJECTIVES: We examined the effects of the mGlu5 receptor antagonist MPEP on cocaine consumption and cocaine-enhanced brain reward function in rats. METHODS: Cocaine consumption was measured in rats with 1 h (short-access; ShA) or 6 h (long-access; LgA) daily access to intravenous cocaine (0.25 mg/infusion) self-administration. Cocaine-enhanced brain reward function was measured by cocaine-induced lowering of intracranial self-stimulation (ICSS) thresholds. RESULTS: Cocaine consumption remained stable and unaltered over successive self-administration sessions in ShA rats. In contrast, cocaine consumption progressively "escalated" in LgA rats. MPEP (1--9 mg/kg) dose-dependently decreased responding similarly in ShA and LgA rats. These data suggest that mGlu5 receptors regulate the reinforcing properties of cocaine, and that this action of mGlu5 receptors is independent of the escalation in consumption associated with extended access to cocaine self-administration. MPEP doses (1--9 mg/kg) that decreased cocaine self-administration elevated brain reward thresholds to a similar degree in cocaine- and vehicle-treated rats, indicating that MPEP induced a negative affective state. The additive effects of MPEP and cocaine on thresholds resulted in attenuation of the magnitude of cocaine-induced (10 mg/kg) lowering of ICSS thresholds. CONCLUSIONS: Overall, mGlu5 receptors appear to play an important role in regulating cocaine consumption, and also in regulating brain reward function. Further, it is likely that blockade of mGlu5 receptors may attenuate cocaine consumption, at least in part, by decreasing the baseline activity of brain reward circuitries.

Animals↗
PubMed2004

A role for GABA mechanisms in the motivational effects of alcohol.

Low doses of ethanol have been hypothesized to act directly via proteins that form ligand-gated receptor channels, such as the gamma-aminobutyric acid (GABA) receptor complex, to allosterically alter function, particularly in specific brain areas such as those hypothesized to be involved in ethanol reinforcement. At the pharmacological level, one can antagonize the effects of ethanol with GABA antagonists, particularly its sedative, anxiolytic-like and acute reinforcing actions. Brain sites involved in the GABAergic component of ethanol reinforcement include the ventral tegmental area, elements of the extended amygdala (including the central nucleus of the amygdala), and the globus pallidus. Chronic administration of ethanol sufficient to produce dependence and increased ethanol intake are associated with increased GABA release in the amygdala and increased sensitivity to GABA agonists. A hypothesis is proposed that GABAergic interactions with the brain stress neurotransmitter corticotropin-releasing factor in specific elements of the extended amygdala may be an important component for the motivation for excessive drinking associated with the transition from social drinking to addiction.

Alcoholism↗