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Biomedical subjects

G F Koob

Publications and source records attributed to G F Koob.

At least 217 records · Page 12Linked to original sources
PubMed1993

Selective effects of low-dose D2 dopamine receptor antagonism in a reaction-time task in rats.

Operant responses involving a cued discrimination are sensitively disrupted by neuroleptic drugs that block dopamine (DA) receptors in the brain; however, it is not clear which DA receptor subtypes may be involved in these effects. The role of D1 or D2 DA receptor antagonists on the execution of a conditioned reaction-time (RT) motor task was investigated in the present study. Rats were trained to release a lever after the presentation of a visual cue within a RT limit to be reinforced by a food pellet. The D1 receptor antagonist SCH-23390, at doses that significantly decrease the behavioral effects of cocaine, did not impair performance at any dose (5, 10, or 20 micrograms/kg) injected subcutaneously. In contrast, a selective D2 receptor antagonist raclopride (50, 100, or 200 micrograms/kg) induced a dose-dependent increase in the number of incorrect responses (release of the lever over the RT limit) associated with an increase in the RT. The results suggest that the dopaminergic nigrostriatal system, which has previously been shown to be specifically involved in this RT task (Amalric and Koob 1987), appears to be a sensitive site for sensorimotor integration, and that the execution of the conditioned RT motor task may depend preferentially on the activation of the dopaminergic D2 receptors in this system.

Animals↗
PubMed1993

Lisuride reduces psychomotor retardation during withdrawal from chronic intravenous amphetamine self-administration in rats.

Withdrawal from chronic use of psychostimulant drugs in humans induces a clinical syndrome characterized by fatigue, psychomotor depression, anhedonia, and disturbances of sleep. Spontaneous locomotor activity and catalepsy were assessed in rats during withdrawal from a schedule of intravenous self-administration of high doses of amphetamine. At 2 and 4 days after cessation of amphetamine self-administration, rats showed a state of psychomotor retardation as measured by reduction of locomotor activity and increased catalepsy. In search of a possible pharmacologic means of intervention for such behavioral changes, the effect of repeated treatment with the nonaddictive ergot derivative lisuride during the withdrawal phase was evaluated. At a dose devoid of any effects on locomotor activity, lisuride completely prevented the reduction in locomotor activity and the increase in catalepsy produced by amphetamine withdrawal. These results suggest the need for further studies on lisuride as a possible novel treatment during withdrawal from psychostimulant drugs in humans.

Amphetamine↗
PubMed1993

Rapid induction of conditioned opiate withdrawal in the rat.

Previous studies of conditioned opiate withdrawal in animals either have suffered from a lack of readily quantifiable data (e.g., measurement of diarrhea and vocalization in rodents) or were very long and costly (e.g., disruption of operant responding in monkeys). In this study, an attempt was made to produce a rapid and quantifiable measure of conditioned opiate withdrawal in the rat. Rats were trained to lever-press for food reinforcement on a fixed-ratio-15 schedule. All rats were then implanted with two subcutaneous 75-mg morphine pellets and allocated into three groups. The paired group received four naloxone injections (0.025 mg/kg SC) in the operant chambers paired with a distinctive tone and smell. The unpaired group was also exposed to the tone and smell in the chambers on four occasions, but received the naloxone injections in the home cage. The saline control animals were never exposed to naloxone or the tone and smell. On the test day, all rats were exposed to the tone and smell and injected with saline. The paired group showed a significant reduction in operant responding in response to the tone and smell when compared either with the other two groups, or to their own response rates on the previous day. In a second experiment, the paired and unpaired groups were again challenged with the tone and smell and a saline injection 1 month after removal of the morphine pellets. Again, the paired group showed a significant disruption of response. These results suggest that the conditioned stimulus acquired significant behavior-disruptive properties manifest even in the absence of opiate receptor occupancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1993

Anxiolytic-like action of neuropeptide Y: mediation by Y1 receptors in amygdala, and dissociation from food intake effects.

Evidence from animal and human studies suggests that neuropeptide Y (NPY) may be a potent endogenous anxiolytic. The anatomic structures mediating this action of the peptide remain unknown. Furthermore, in addition to its anxiolytic-like effects, intracerebroventricular administration of NPY induces food intake through hypothalamic mechanisms, making the anxiolytic-like action of the peptide more difficult to interpret. The purpose of this study was to examine the anatomic substrate for the effects of NPY on anxiety, and to characterize the NPY receptors mediating these effects. Intracerebroventricular injection of NPY produced increased food intake in free-feeding animals, and dose-dependent anticonflict/anxiolytic-like effects in an established animal model of anxiety, the Geller-Seifter punished responding test. In contrast, microinjection of NPY into the central nucleus of the amygdala did not increase food intake in free-feeding animals, did not affect unpunished lever pressing for food, but did reproduce the anticonflict/anxiolytic-like effect with high potency. The selective NPY-Y1 agonist, p[Leu31,Pro34]NPY was approximately equipotent with native NPY in the conflict paradigm, and markedly more potent than the Y2 agonist, NPY13-36. Intrastriatal injections had no effect on conflict behavior. Thus, activation of Y1 receptors in the central nucleus of the amygdala produces effects similar to established anxiolytics without affecting food intake, suggesting that Y1-receptors in the amygdala may be a substrate for anxiolytic actions of NPY.

Amygdala↗
PubMed1993

GABA antagonist and benzodiazepine partial inverse agonist reduce motivated responding for ethanol.

Brain gamma-aminobutyric acid (GABA) systems have long been associated with the behavioral actions of ethanol. This study investigated the effects of GABAergic agents on ethanol reinforcement. Rats were trained to orally self-administer ethanol in a 30-min, free-choice operant task. Responses at one of two levers produced contingent access to ethanol (10% w/v) or water. Pretreatment with RO 15-4513, a benzodiazepine inverse agonist (0.375 to 3.0 mg/kg ip), selectively reduced responses for ethanol, and a higher dose of RO 15-4513 (6.0 mg/kg) reduced both ethanol and water responses. Self-administration of saccharin in a free-choice task with access to saccharin (0.05%) and water was unaffected by RO 15-4513, suggesting that the effects of RO 15-4513 on ethanol reinforcement may not necessarily generalize to other reinforcers. Isopropylbicyclophosphate (IPPO), a picrotoxin ligand (5 and 10 micrograms/kg ip), selectively reduced responses for ethanol in alcohol-preferring, nonpreferring and Wistar rats. However, the highest dose of IPPO (20 micrograms/kg) reduced both ethanol and water responses. Chlordiazepoxide, a benzodiazepine, did not reduce responses for ethanol in the selectively bred animals, suggesting that this drug does not substitute for the reinforcing properties associated with acute ethanol intake. Together, these results suggest that compounds that act at the benzodiazepine inverse agonist and picrotoxin sites of the GABA/benzodiazepine receptor complex may decrease motivated responding for ethanol.

Alcohol Drinking↗
PubMed1993

Oral alcohol self-administration stimulates dopamine release in the rat nucleus accumbens: genetic and motivational determinants.

Dopaminergic neurotransmission in the nucleus accumbens may be an important factor in ethanol reinforcement and genetically determined ethanol preference. This hypothesis was tested by measuring dopamine (DA) release by intracranial microdialysis during voluntary oral ethanol self-administration in alcohol-preferring (P) and genetically heterogeneous Wistar rats. The animals were trained to respond for ethanol (10% w/v) or water in a free-choice operant task. Extracellular DA levels in the nucleus accumbens were subsequently monitored during 30-min self-administration sessions and a 15-min "waiting period" before session onset. Ethanol self-administration in all animals was followed by a significant, dose-dependent rise in DA release with maximal effects at approximately 15 min after peak intake. Dose-effect functions revealed significantly steeper slopes for the DA-releasing effects of ethanol in P than in genetically heterogeneous Wistar rats. Over an identical range of ethanol doses and blood alcohol levels, increases in DA efflux ranged from 143% to 459% of basal levels in P rats but only from 142% to 212% in Wistar rats. To differentiate the pharmacological effects of ethanol from the effects of operant responding, additional groups of P and Wistar rats were tested during self-administration of saccharin (0.05% w/v). By contrast with ethanol, saccharin did not substantially elevate extracellular DA levels. A significant, transient increase in DA efflux was, however, observed in both strains of rats during the presession waiting period in the absence of ethanol or saccharin availability.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1993

Effect of antagonists selective for mu, delta and kappa opioid receptors on the reinforcing effects of heroin in rats.

Antagonists selective for mu, delta and kappa-opioid receptors were evaluated for their effects on responding maintained by i.v. injections of heroin (60.0 micrograms/kg/injection) in rats during daily 3-hr sessions. Under base-line conditions, rats self-administered 10 to 20 heroin injections during each session, and injections were separated by relatively constant interinjection intervals of about 10 to 20 min. The mu-selective antagonist beta-funaltrexamine (beta-FNA; 5.0-20.0 mg/kg, s.c.) produced a dose-dependent increase in responding for heroin, with some doses of beta-FNA producing an extinction-like pattern of responding. These results were qualitatively similar to the effect obtained by lowering the unit dose per injection of heroin. The mu 1-selective antagonist naloxonazine (NXZ; 7.5-30.0 mg/kg, i.v.) and the delta-selective antagonist naltrindole (1.0-17.0 mg/kg) also produced dose-dependent increases in heroin self-administration, but neither naloxonazine nor naltrindole produced extinction-like patterns of responding. The kappa-selective antagonist nor-binaltorphimine (nor-BNI; 5.0-10.0 mg/kg, s.c.) had no effect on heroin self-administration. These results indicate that mu receptors play an important role in mediating the reinforcing effects of heroin in the rat. Delta and mu 1 receptors, but not kappa receptors, may also be involved.

Animals↗
PubMed1993

Antagonist effects of beta-funaltrexamine and naloxonazine on alfentanil-induced antinociception and muscle rigidity in the rat.

Alfentanil is a potent and short-acting mu opioid agonist that produces both antinociceptive effects and muscle rigidity. In the present study, the susceptibility of alfentanil-induced antinociception and rigidity to antagonism by the selective mu antagonist beta-funaltrexamine and the selective mu-1 antagonist naloxonazine was examined. Alfentanil (37.7-150.0 micrograms/kg) produced a dose-dependent increase both in antinociception as measured by the warm-water tail-dip assay and in rigidity as measured by electromyographic recording of the gastrocnemius muscle. Both beta-funaltrexamine (10.0 and 20.0 mg/kg) and naloxonazine (7.5 and 15.0 mg/kg) produced dose-dependent and parallel rightward shifts in the alfentanil dose-effect curves for both antinociception and rigidity. Furthermore, the alfentanil dose-effect curves for antinociception and rigidity were shifted to the right to a similar degree by any given pretreatment. These results suggest that alfentanil-induced antinociception in the warm-water tail-dip test and rigidity are mediated by pharmacologically similar populations of opioid receptors. More specifically, these results suggest that mu-1 opioid receptors mediate both alfentanil-induced antinociception and rigidity.

Alfentanil↗
PubMed1992

Corticotropin-releasing factor induces a place aversion independent of its neuroendocrine role.

The purpose of the present experiment was to test the hypothesis that corticotropin-releasing factor (CRF), a polypeptide of 41 amino acids, when administered either intracerebroventricularly (i.c.v.) or subcutaneously (s.c.), has aversive properties in the conditioned place-preference paradigm. Five doses of CRF (0, 0.005, 0.05, 0.5, 5 micrograms) were tested. i.c.v. CRF induced a specific dose-dependent reduction of the amount of time spent in the environment previously paired with the administration of CRF. Furthermore, this CRF-induced place aversion was prevented by pretreatment with alpha-helical-CRF(9-41), a specific CRF antagonist, administered i.c.v. In order to test whether the aversive effects induced by i.c.v. CRF could result from the stimulation of the HPA axis accompanying i.c.v. CRF injection, the reinforcing properties of s.c. CRF were studied using the same dose range. Only the higher s.c. dose was effective in producing a place aversion suggesting that the aversive effects of CRF could not be due solely to the stimulation of the pituitary-adrenocortical system, measured by plasmatic levels of adrenocorticotropic hormone (ACTH) and corticosterone, because the lower doses consistently activate the pituitary-adrenocortical system without producing any behavioral changes. Altogether, these data indicate that the non-neurosecretory CRF neurons may mediate the aversive state occurring during stress.

Animals↗
PubMed1992

NMDA receptors in the nucleus accumbens modulate intravenous cocaine but not heroin self-administration in the rat.

The role of endogenous glutamate neurotransmission within the nucleus accumbens in the modulation of intravenous (i.v.) cocaine and heroin self-administration in rats was analyzed. APV (2-amino-5-phosphonovaleric acid), a blocker of glutamate receptors of the N-methyl-D-aspartate (NMDA) type, was microinfused within the nucleus accumbens of the ventral striatum of rats trained to lever press for i.v. cocaine or heroin self-administration. APV, at the dose of 1.5 and 3.0 micrograms/side, reduced the rewarding value of cocaine while it left heroin self-administration unaffected. These results suggest that integrity of NMDA receptor function within the nucleus accumbens may be of importance for the maintenance of i.v. cocaine, but not heroin self-administration in rats.

2-Amino-5-phosphonovalerate↗
PubMed1992

Basal extracellular dopamine levels in the nucleus accumbens are decreased during cocaine withdrawal after unlimited-access self-administration.

The effects of withdrawal from cocaine on extracellular dopamine (DA) levels in the nucleus accumbens (NAC) were examined by intracranial microdialysis in awake rats after periods (9.5-21.75 h) of unlimited-access, intravenous cocaine self-administration. Cocaine withdrawal was associated with significant reductions in basal DA overflow that persisted up to 12 h. Maximal inhibition of DA release (mean +/- S.E.M. 66.15 +/- 3.30 percent of basal levels) was observed between 4-6 h after cessation of cocaine intake and was positively correlated (r = 0.88) with the duration of the preceding self-administration episode. The results suggest that suppression of basal DA release in the NAC is an adaptive consequence of sustained cocaine exposure and may in part underlie the post-cocaine anhedonia observed in behavioral models of cocaine withdrawal.

Animals↗
PubMed1992

Neural mechanisms of drug reinforcement.

The brain substrates involved in the effect of cocaine on brain stimulation reward, in the psychomotor activation associated with cocaine, and in cocaine self-administration appear to be focused on the medial forebrain bundle and its connections with the basal forebrain, notably the nucleus accumbens. Chronic access to cocaine produces a withdrawal state as reflected in increases in brain stimulation reward thresholds, and this change in reward threshold appears to be opposite to the actions of the drug administered acutely. These effects are thought to reflect a change in the activity of reward elements in the medial forebrain bundle and may be responsible for the negative reinforcing state associated with the anhedonia of cocaine withdrawal. Opiate receptors particularly sensitive to the reinforcing effects of heroin also appear to be located in the region of the nucleus accumbens and the ventral tegmental area. There is good evidence for both dopamine-dependent and dopamine-independent opioid interactions in the ventral tegmental-nucleus accumbens connection. In addition, the opiate receptors in the region of the nucleus accumbens may become sensitized during the course of opiate withdrawal and thus become responsible for the aversive stimulus effects of opiate dependence. Reliable measures of the acute reinforcing effects of ethanol have been established in rat models, and substantial evidence exists to show that non-deprived rats will orally self-administer pharmacologically relevant amounts of ethanol in lever-press choice situations. Neuropharmacological studies of ethanol reinforcement in non-dependent rats suggest important roles for serotonin, GABA and dopamine. A role for opioid peptides in ethanol reinforcement may reflect more general actions of opioid peptides in consummatory behavior. Studies of ethanol dependence have implicated brain GABAergic and CRF systems in the more motivational aspects of withdrawal. Future studies will need to focus on the common neurobiologic changes associated with all these drugs, particularly regarding their hedonic and motivational properties.

Animals↗
PubMed1992

Corticotropin-releasing factor antagonist reduces emotionality in socially defeated rats via direct neurotropic action.

Introduction of a socially naive male rat into the home territory of a resident counterpart results in agonistic interactions, leading to the rapid social defeat of the intruder. Exposure to the aggressive resident produces a stress-response profile consisting of neuroendocrine activation and coping behaviors such as submission. The present studies examined the dependence of these adaptive responses on endogenous brain Corticotropin-Releasing Factor (CRF), a peptide hormone known to coordinate neuronally mediated- and pituitary-adrenal responses to stress. The Elevated Plus-Maze was employed as an animal model of emotionality in which stressors reduce subsequent exploration of open maze arms without walls in favor of enclosed maze arms. A CRF antagonist, alpha-hel CRF9-41, administered intracerebroventricularly (5 and 25 micrograms i.c.v.) immediately post-stress and 5 min prior to maze testing reversed the heightened emotionality produced by the resident exposure stressor. This action paralleled that of an anxiolytic dose of the short-acting benzodiazepine, midazolam (1.5 mg/kg i.p.). Intra-amygdaloid administration of lower doses of the CRF antagonist (125, 250 and 500 ng i.c.) also reversed, dose-dependently, the effect of exposure to an aggressive resident without altering the behavior of unstressed control animals. Further, the enhanced release of ACTH and corticosterone following social conflict was not modified over the short term by the intra-amygdaloid dose of CRF antagonist (250 ng i.c.) which was effective in reversing stress-induced hyper-emotionality. These results suggest that limbic system CRF substrates exert an anxiogenic effect on the exploratory behavior of socially defeated rats via a pituitary-adrenal-independent mechanism.

Adrenocorticotropic Hormone↗
PubMed1992

Neuropharmacology of cocaine and ethanol dependence.

Drug addiction includes two important characteristics, chronic compulsive or uncontrollable drug use and a withdrawal syndrome when use of the drug is stopped. Animal models for the motivational components of drug dependence have been developed allowing a systematic exploration of the neurobiological mechanisms of drug dependence. The reinforcing actions of acute cocaine as measured by intravenous cocaine self-administration appear to be mediated by the presynaptic release of dopamine in the region of the nucleus accumbens and may preferentially involve the dopamine D-1 receptor subtype. The nucleus accumbens circuitry involved in the reinforcing actions of cocaine may include the ventral pallidum and may be modulated by serotonin. Chronic cocaine produces increases in brain reward thresholds that may reflect the "dysphoria" and anhedonia associated with cocaine dependence and suggests a dysregulation of brain reward systems possibly involving dopamine. Reliable measures for the acute reinforcing effects of ethanol in nondependent animals have been established in the rat using a lever press operant and a taste habituation procedure. Important roles have been established for serotonin, GABA, dopamine, and opioids in the acute reinforcing properties of ethanol, perhaps acting on some of the same neural circuitry subsuming the reinforcing actions of other drugs of abuse. Studies of the motivational aspects of ethanol dependence have suggested a functional role for brain corticotropin-releasing factor. These results suggest that the neurobiology of drug dependence involves not only neurotransmitters that mediate the acute reinforcing properties of drugs, but also the aversive motivational and emotional aspects of drug withdrawal. Advances in our understanding of brain changes associated with the switch from acute effects to chronic actions may provide a key to our understanding of not only drug dependence, but also psychopathology such as, anxiety, and affective disorders.

Alcoholism↗