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G F Koob

Publications and source records attributed to G F Koob.

At least 37 records · Page 2Linked to original sources
PubMed2001

Neurobiological processes in alcohol addiction.

This article represents the proceedings of a symposium at the ISBRA Meeting in Yokohama, Japan. The chairs were A. D. Lê and K. Kiianmaa. The presentations were (1) Alcohol reward and aversion, by C. L. Cunningham; (2) The role of sensitization of neuronal mechanisms in ethanol self-administration, by J. A. Engel, M. Ericson, and B. Söderpalm; (3) Alcohol self-administration in dependent animals: Neurobiological mechanisms, by G. F. Koob, A. J. Roberts, and F. Weiss; (4) Stress and relapse to alcohol, by A. D. Lê; (5) Alcohol-preferring AA and alcohol-avoiding ANA rats differ in locomotor activation induced by repeated morphine injections, by P. Hyytiä, S. Janhunen, J. Mikkola, P. Bäckström, and K. Kiianmaa; and (6) Initial sensitivity and acute functional tolerance to the hypnotic effects of ethanol in mice genetically selected for mild and severe ethanol withdrawal convulsions, by I. Ponomarev and J. C. Crabbe.

Alcoholism↗
PubMed2001

Increased ethanol self-administration in delta-opioid receptor knockout mice.

BACKGROUND: The role of the delta-opioid receptor in ethanol drinking has remained unclear despite the use of traditional pharmacological and correlational approaches. The results of several studies suggest that pharmacological blockade of these receptors results in decreases in ethanol drinking behavior, but an approximately equal number of reports have failed to observe an effect of delta-receptor antagonism on ethanol drinking. It is clear that alternative approaches to understanding opioid-receptor involvement in ethanol drinking are needed. METHODS: In this study, ethanol drinking was examined in delta-opioid receptor knockout (KO) mice by using first a two-bottle-choice test, then an operant self-administration paradigm and a second two-bottle-choice test, in that order. In addition, because KO mice were previously shown to display enhanced anxiety-like behavior relative to wild-type (WT) mice, the effect of ethanol self-administration on anxiety-like responses was determined. RESULTS: delta KO mice initially showed no evidence of a preference for ethanol in the first two-bottle-choice drinking test; however, after an experience of operant self-administration of ethanol, a preference for ethanol developed in the second two-bottle-choice test. KO mice also showed a preference for ethanol over water and self-administered more ethanol than WT mice in the operant self-administration paradigm. The ethanol self-administered in this procedure was sufficient to reverse the innate anxiety-like response observed in this strain. CONCLUSIONS: delta KO mice showed a greater preference for ethanol and consumed more ethanol than their WT counterparts, suggesting that a decrease in delta-receptor activity is associated with increased ethanol-drinking behavior. It is hypothesized that delta receptors may influence ethanol self-administration at least partly through an effect of these receptors on anxiety-like behavior.

Animals↗
PubMed2000

Quantification of neurosteroids in rat plasma and brain following swim stress and allopregnanolone administration using negative chemical ionization gas chromatography/mass spectrometry.

A simplified method for the quantitative analysis of neurosteroids in rat plasma and brain is described. The method uses negative chemical ionization gas chromatography/mass spectrometry and involves the synthesis of pentafluorobenzyloxime/trimethylsilyl ether derivatives with excellent chromatographic and electron-capturing properties. Deuterium-labeled analogs of the steroids of interest were synthesized and used as internal standards. The steroids (allopregnanolone, epiallopregnanolone, pregnenolone, testosterone, and dehydroepiandrosterone) were isolated from the plasma or brain matrix by a rapid and straightforward solid-phase extraction procedure. The mass spectrometer was operated in a selective ion monitoring mode, allowing for picograms of neurosteroids to be quantified from biological extracts. The method was linear (typical R(2) = 0.999) over the concentration range (100 to 8000 pg from 0.3 ml plasma and 250 to 8000 pg from 100 mg brain tissue) with good precision and accuracy. In experimental protocols, the procedure was suitable for measuring concentrations of endogenous neurosteroids in rat plasma and brain. Significant elevations (P < 0.001) were observed in the frontal cortex for allopregnanolone and pregnenolone following a swim stress and for allopregnanolone and epiallopregnanolone following allopregnanolone injection (8 mg/kg, sc). The present method allows accurate determination of neurosteroids and will be helpful in elucidating the role of neurosteroids in health and disease.

Animals↗
PubMed2000

Neurotrophic factor expression after CNS viral injury produces enhanced sensitivity to psychostimulants: potential mechanism for addiction vulnerability.

Hypothesized risk factors for psychostimulant, amphetamine, and cocaine abuse include dopamine (DA) receptor polymorphisms, HIV infection, schizophrenia, drug-induced paranoias, and movement disorders; however, the molecular, cellular, and biochemical mechanisms that predispose to drug sensitivity or drive the development of addiction are incompletely understood. Using the Borna disease rat, an animal model of viral-induced encephalopathy wherein sensitivity to the locomotor and stereotypic behavioral effects of d-amphetamine and cocaine is enhanced (Solbrig et al., 1994, 1998), we identify a specific neurotrophin expression pattern triggered by striatal viral injury that increases tyrosine hydroxylase activity, an early step in DA synthesis, to produce a phenotype of enhanced amphetamine sensitivity. The reactive neurotrophin pattern provides a molecular framework for understanding how CNS viral injury, as well as other CNS adaptations producing similar growth factor activation profiles, may influence psychostimulant sensitivity.

Animals↗
PubMed2000

CRF and urocortin decreased brain stimulation reward in the rat: reversal by a CRF receptor antagonist.

The present studies were designed to investigate the effects of corticotropin-releasing factor (CRF) receptor activation and antagonism on intracranial self-stimulation (ICSS) reward using a discrete-trial current-intensity threshold procedure. Bipolar electrodes were implanted in the lateral hypothalamus, and cannula guides were implanted above the lateral ventricle of male Wistar rats. Dose-effect functions were established for the effects on ICSS of the competitive CRF receptor agonist h/rCRF (0-5.0 microg, i.c.v. ), the CRF receptor agonist urocortin (0-5.0 microg, i.c.v.), and the CRF receptor antagonist [D-Phe(12), Nle(21,38), C(alpha) MeLeu(37)] h/rCRF(12-41) (0-5.0 microg, i.c.v.). Administration of h/rCRF or urocortin dose-dependently elevated ICSS thresholds without altering performance measures (latencies to respond to stimulation, extra and time-out responses). CRF was more potent than urocortin in terms of threshold dose-effects on ICSS thresholds compared to vehicle. Despite these apparent potency differences, percent effect sizes on ICSS thresholds were comparable at the highest doses of both peptides. In contrast to the significant threshold elevation effects of CRF and urocortin, the competitive CRF antagonist D-Phe CRF(12-41) had no effect on ICSS thresholds or performance measures. To determine the neuropharmacological specificity of the effect of CRF on brain stimulation reward, D-Phe CRF(12-41) was used to antagonize CRF-induced threshold elevations. Pretreatment with either the 5.0- or 10.0-microg doses of D-Phe CRF(12-41) effectively blocked CRF-induced reward threshold elevations (3.0 microg) without affecting other ICSS performance measures. These results indicate that CRF neurotransmission can modulate ICSS reward processes.

Animals↗
PubMed2000

Cocaine vaccines: antibody protection against relapse in a rat model.

The efficacy of active immunization with the cocaine immunogen GNC-keyhole limpet hemocyanin (KLH) in preventing cocaine self-administration reinstatement was assessed in rats. An animal model of relapse was used where rats were trained to self-administer cocaine, subjected to a period of extinction by substituting the drug for saline, vaccinated, and re-exposed to cocaine. Compared with controls, animals immunized with GNC-KLH did not reinstate cocaine self-administration behavior when given a noncontingent cocaine infusion on two consecutive days. Upon double and triple infusions, 38-62% of vaccinated animals failed to reinstate as compared with full reinstatement in all control animals. Exposure to ad libitum cocaine reinstated baseline values in control animals and resulted in double to triple the baseline values of self-infusions in vaccinated animals, suggesting a partial antibody-mediated blockade of cocaine access to the central nervous system. This compensating effect was blocked by passive immunization pretreatment with the monoclonal IgG GNC92H2 in both vaccinated and control groups. To further assess the surmountability potential of GNC-KLH-induced antibody titers by cocaine self-administration, and the capacity of these titers to block the reinforcing effects of the drug, rats were tested at various doses of cocaine (0.015-0.5 mg/infusion). Active immunization with GNC-KLH produced approximately an 8-fold rightward shift of the dose-effect function for cocaine. The results reported suggest that immunopharmacotherapy may offer a promising means to treat cocaine abuse by aiding in the prevention of relapse.

Animals↗
PubMed2000

Microinjections of an opiate receptor antagonist into the bed nucleus of the stria terminalis suppress heroin self-administration in dependent rats.

Recent anatomical evidence suggests that the shell of the nucleus accumbens, the bed nucleus of the stria terminalis, and the central nucleus of the amygdala, together referred to as the extended amygdala, may play a role in opiate dependence. The bed nucleus of the stria terminalis and the shell of the nucleus accumbens have a moderately high density of opiate receptors, which allows for manipulation of opiate neurotransmission with receptor antagonists. The goal of this study was to determine the role these regions play in opiate reinforcement, and whether dependence alters the reinforcing effects of opiates by examining the effect of local administration of the opiate receptor antagonist methylnaloxonium on heroin self-administration in dependent and nondependent rats. Previous studies revealed that blockade of the reinforcing effects of opiates with systemic administration of opiate receptor antagonists results in an increase in heroin self-administration in nondependent rats, and a greater increase in dependent rats. In the present study, methylnaloxonium dose-dependently suppressed heroin intake when injected into the bed nucleus of the stria terminalis and shell of the nucleus accumbens of dependent rats, and had no effect in nondependent rats. These results demonstrate that opiate receptors in parts of the extended amygdala may be responsible for the reinforcing effects of opiates in dependent animals and suggest that activity in this system may be recruited during the development of dependence.

Animals↗
PubMed2000

Genetic differences in response to novelty and spatial memory using a two-trial recognition task in mice.

A two-trial memory task, based on a free-choice exploration paradigm in a Y-maze, was previously developed to study recognition processes in Sprague-Dawley rats. Because this paradigm avoids the use of electric shock or deprivation that may have nonspecific effects and does not require learning of a rule, it may be particularly useful for studying memory in mice. Four inbred strains (Balb/cByJ, DBA/2J, C57BL/6J, and SJL/J), an F1 hybrid (C57BL/6 x SJL/J), and one outbred strain (CD1) were used to validate this task in mice and to characterize a strain distribution in response to novelty and working memory. Exploration was measured with a short (2 min) intertrial interval (ITI) between acquisition and retrieval, while memory was examined with longer intervals (30 min, 1 h, and 2 h). A study of the time course of the response to novelty revealed varying degrees of preference and/or habituation to novelty among the different strains, with CD1 exhibiting a very high response to novelty and others showing lower (C57 x SJL hybrids) to complete absence (SJL) of exploration of novelty. Memory span, assessed with increasing ITIs, varied widely among strains from 30 min (C57 x SJL hybrids) to at least 2 h (C57 and BALB). Such demonstrated sensitivity to a wide range of behavioral phenotypes supports the use of this spatial memory task as an effective tool for the study of genetic influences on the response to novelty and recognition processes in mice.

Animals↗
PubMed2000

Differential effects of dopamine receptor subtype blockade on performance of rats in a reaction-time paradigm.

RATIONALE: Pharmacological manipulation of the dopaminergic system with antipsychotic agents disrupts motor behavior. Although most antipsychotic drugs have high affinity for D2 receptors, they also interact with other dopamine receptor subtypes. Therefore, the role of each of these receptor subtypes on motor performance is unclear. OBJECTIVE: The present study sought to investigate the relative importance of D1, D2, and D3 receptors on performance in a conditioned reaction-time task known to be extremely sensitive to dysfunction of the dopaminergic nigrostriatal pathway. METHODS: Rats were trained to release a lever in response to a visual cue within a reaction-time limit to receive a reinforcer (45mg food pellet). After the behavior of the rats had stabilized, the effects of a D1 (A69024), D2 (eticlopride), and D3 (nafadotride) receptor antagonists were assessed. RESULTS: A-69024 had no effect on performance at any dose tested (0.3, 0.6, and 1.3 mg/kg s.c.). Nafadotride (0.1, 0.3, and 1 mg/kg s.c.) produced only a mild deficit in performance at the highest dose. This deficit was characterized by an increase in the number of delayed responses with a non-significant decrease in the number of premature responses indicative of non-specific sedative effects. In contrast, the D2 receptor antagonist eticlopride (0.005, 0.01, and 0.02 mg/kg s.c.) produced profound deficits in performance as evidenced by a dose-dependent decrease in the number of correct responses. This decrease was accompanied by an increase in the number of delayed responses and a lengthening of the reaction time at the highest doses. CONCLUSIONS: These results provide further evidence that the execution of the reaction-time task is dependent preferentially upon the activation of D2 receptors, but not D1 or D3 receptors.

Animals↗
PubMed2000

Opiate withdrawal-induced place aversion lasts for up to 16 weeks.

RATIONALE: Administration of low doses of opiate antagonists to morphine-dependent rats produces an aversive response as measured by a conditioned place aversion, but the time course of such a learned aversion is largely unknown. OBJECTIVES: The purpose of this experiment was to examine the time course for the expression of a place aversion to opiate withdrawal. METHODS: Morphine-dependent rats were tested in a three-chamber place-aversion apparatus. The conditioning phase consisted of three pairings of either naloxone (15 microg/kg s.c.) or vehicle with two compartments, with the most similar time allotments during the preconditioning test. During the testing phase, rats were again allowed to explore the entire apparatus. Different groups were tested at 24 h, 1 week, 2 weeks, 4 weeks, 8 weeks, and 16 weeks post-conditioning (morphine-free tests). RESULTS: A robust place aversion was recorded at every time point tested, including at 16 weeks. In previously published work, placebo-pelleted rats tested with naloxone at the same dose failed to show a place aversion and nondependent rats showed a stable lack of aversion at tests up to 56 days. Dependent animals without naloxone also failed to show a place aversion at any of those time points. CONCLUSIONS: In the absence of any active intervention, the place aversion produced by opiate withdrawal is very long lasting and provides a model for protracted abstinence that may be useful for delineating the neurobiological substrate for vulnerability to relapse.

Animals↗
PubMed2000

Time-dependent alterations in ICSS thresholds associated with repeated amphetamine administrations.

The time interval between successive injections of psychostimulant drugs, such as amphetamine, plays an important role in the development of neuroadaptive responses to these drugs. Changes in reward function were quantified using a discrete-trial current-intensity paradigm to determine thresholds for lateral hypothalamic electrical self-stimulation after experimenter-administered amphetamine injections (4 mg/kg, IP) at 1- and 5-day intervals. Repeated administration of amphetamine produced progressive changes in ICSS behavior that were dependent on the time interval between injections. The acute effects of amphetamine on ICSS thresholds were potentiated, and threshold elevations associated with withdrawal from the drug diminished after repeated drug challenges at 5-day intervals. By contrast, daily injections of the same dose of amphetamine did not alter the acute threshold-lowering effect of the drug, but resulted in progressive increments in thresholds at later time points. Notably, the decreases in response latency produce by acute amphetamine administration were potentiated by both exposure regimens, which indicates a dissociation of drug effects on motor performance and brain stimulation reward. Thus, the distinct components of changes in reward function associated with acute amphetamine administration and subsequent withdrawal were differentially altered by the two exposure regimens, suggesting that the pattern of exposure is an important determinant of neuroadaptive responses to the drug.

Amphetamine↗
PubMed2000

Heroin-specific stimuli reinstate operant heroin-seeking behavior in rats after prolonged extinction.

The clinical literature suggests that exposure to environmental stimuli previously associated with heroin availability may precipitate relapse. However, experimental studies elucidating the significance of learned associations between drug availability and reinstatement of heroin-seeking behavior in the rat are still scarce. To examine the role of environmental stimuli in reinstatement of heroin-seeking behavior, rats were trained to associate discriminative stimuli (DS+) with intravenous heroin availability vs. nonreward [i.e., availability of intravenous saline (DS-)]. The animals then were subjected to extinction training during which the discriminative stimuli were not presented, and lever pressing did not result in drug or saline infusion. The resistance to extinction varied greatly among animals (2.5-11.4 weeks). When the discriminative stimuli were reintroduced, the DS+ reinstated responding while the DS- did not. The average number of responses for heroin during the reinstatement trial (12.8) paralleled the average responding for heroin during discrimination training (12.6), suggesting that the associations between environmental stimuli and drug availability are long-lasting and powerful motivators of drug-seeking behavior.

Animals↗
PubMed2000

Neuropeptide Y blocks anxiogenic-like behavioral action of corticotropin-releasing factor in an operant conflict test and elevated plus maze.

Central administration of neuropeptide Y (NPY) produces anxiolytic-like behavioral effects in rat models of anxiety. Because previous evidence has suggested a relationship between NPY and corticotropin-releasing factor (CRF) in the brain, we have focused on the interaction of these neuropeptide systems in emotional responsiveness to stressful stimuli. Intracerebroventricular administration of CRF produced a marked response suppression in an operant incremental shock conflict paradigm. NPY [(1 microg, intracerebroventricularly (i.c.v.)] significantly antagonized the response-suppressing effects of CRF (0.75 microg, i.c.v.) on punished responding in the conflict test at doses that produced little or no behavioral effect when administered alone. Central administration of the CRF antagonist [D-Phe(12), Nle(21,38),C(alpha) MeLeu(37)]CRF (D-Phe CRF(12-41)) alone did not alter punished or unpunished responding in the conflict test. However, pretreatment with the CRF antagonist before a subthreshold dose of NPY (1 microg, i.c.v.) produced a significant potentiation of the release of punished responding relative to NPY alone and untreated controls. NPY also antagonized the "anxiogenic-like" behavioral effects of CRF in the elevated plus maze. These findings support the hypothesis that NPY and CRF may reciprocally modulate an animal's behavioral response to stressful stimuli.

Animals↗
PubMed2000

Conditioned place aversion to the "hangover" phase of acute ethanol administration in the rat.

The purpose of this study was to examine ethanol's delayed effects (termed hangover) using conditioned place testing. Four groups of rats received a single pairing of a distinctive environment (tactile and visual) 10 h after injection with ethanol (0, 2, 3, 4 g/kg, i.p. ) or saline in a counterbalanced design. Rats receiving 3 and 4 g/kg ethanol showed a conditioned place aversion to ethanol hangover. Conditioning 10 h after 0 or 2 g/kg ethanol did not produce a significant place preference or aversion. The results suggest that the hangover following an acute injection of high doses of ethanol (3-4 g/kg) produces a significant and dose-related conditioned place aversion in the rat.

Animals↗
PubMed2000

Behavioral effects of central administration of the novel CRF antagonist astressin in rats.

Astressin, a novel corticotropin releasing factor (CRF) antagonist, has been found to be particularly potent at inhibiting the hypothalamo-pituitary-adrenal axis. The aim of the present study was to determine the effects in rats of astressin in attenuating the anxiogenic-like response produced by social stress and intracerebroventricular (ICV) CRF administration on the elevated plus-maze, and ICV CRF-induced locomotor activation in the rat. Astressin significantly reversed the anxiogenic-like response induced by both social stress and ICV rat/humanCRF (r/hCRF) on the elevated plus-maze, but failed to block the effects of r/hCRF-induced locomotor activity in a familiar environment. When these results were compared to previous studies performed with the same paradigms using other CRF antagonists, astressin showed effects similar to those of D-PheCRF(12-41) on plus-maze performance. However, contrary to alpha-helicalCRF(9-41) and D-PheCRF(12-41), astressin had no effect on CRF-induced locomotor activity. These results suggest that astressin may have a unique anti-CRF profile compared to previously tested antagonists.

Aggression↗
PubMed2000

Persistent increase in the motivation to take heroin in rats with a history of drug escalation.

The transition from stable to escalated levels of cocaine self-administration has been shown to depend upon drug availability. The generality of this phenomenon is assessed here by studying the effects of availability on heroin self-administration. Two groups of rats were trained on a 1-h continuous schedule of self-administration, after which, access to heroin (40 microg/injection) was increased to 11 h in one group (long access or LgA rats) or kept to 1 h in the other group (short access or ShA rats). After 18 sessions on this regimen, both ShA and LgA rats were tested for extinction and stress-induced reinstatement of heroin-seeking behavior. In LgA rats, both total and first hour intake gradually escalated over time. After escalation, LgA rats were slower to extinguish heroin-seeking behavior and responded more to the reinstating effect of stress after extinction. These findings show that: (1) the escalation process in drug consumption is common to both opiate and stimulant self-administration; (2) escalation in heroin consumption is associated with a persistent increase in the motivation for taking heroin.

Animals↗
PubMed2000

Excessive ethanol drinking following a history of dependence: animal model of allostasis.

Alcohol withdrawal symptoms, particularly negative emotional states, can persist for months following the removal of alcohol. These protracted withdrawal symptoms have been implicated as an important trigger of relapse to excessive drinking in alcoholics and may represent a long lasting shift in affective tone as a result of chronic alcohol exposure. It was shown previously that ethanol-dependent rats increased their operant responding for ethanol when tested during the first 12 hr after withdrawal. The purpose of the present experiments was to determine the persistence of this finding by examining operant oral ethanol self-administration in rats with a history of physical dependence upon ethanol, detoxified and then allowed a two week period of protracted abstinence. The results of these experiments indicate that operant responding for ethanol was enhanced during protracted abstinence by 30-100% and remained elevated for 4-8 weeks post acute withdrawal. These results have important implications for understanding the characteristics and mechanisms underlying vulnerability to relapse.

Alcohol Drinking↗