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Biomedical subjects

G F Koob

Publications and source records attributed to G F Koob.

At least 19 recordsLinked to original sources
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↗
PubMed1992

Differences in one-way active avoidance learning in mice of three inbred strains.

DBA/2J, C57BL/6J, and C3H/HeJ mice were given 10 one-way avoidance training trials per day, using an unconditioned stimulus intensity that provided equivalent motivation for learning to mice of all three strains, and were found to differ in their abilities to learn and retain the response. DBA/2J mice acquired the response in fewer days than did the mice of the other two strains, although C57BL/6J mice eventually reached a level of performance similar to that of DBA/2J mice. Both the rate of acquisition and the level at which avoidance performance stabilized were significantly lower in C3H/HeJ, than in DBA/2J or C57BL/6J, mice. In addition, DBA/2J mice showed a significantly greater task retention from one testing day to the next than did C57BL/6J or C3H/HeJ mice.

Animals↗
PubMed1992

Responding to acoustic startle during chronic ethanol intoxication and withdrawal.

Ethanol (EtOH) withdrawal is characterized by a hyperexcitable state that includes anxiety, tremor, muscle rigidity and seizures. The present three experiments examined the effects of EtOH dependence and withdrawal on the acoustic startle response, an easily quantifiable measure of behavioral reactivity to exteroceptive stimuli. Two intensities of startle stimuli, 105 and 120 dB pulses, were presented to rats during chronic EtOH exposure and during EtOH withdrawal. Prepulse inhibition, which is a sensitive measure of sensorimotor gating processes associated with filtering sensory stimulation, was also assessed during chronic EtOH exposure and withdrawal. Prepulse inhibition was induced by the presentation of a weak 80 dB acoustic stimulus 100 ms prior to a 120 dB stimulus pulse. After 14 days of EtOH liquid diet administration the magnitude of responses elicited by 105 and 120 dB startle stimuli was less in ethanol-treated subjects during continued EtOH access than in animals fed a control liquid diet. When EtOH liquid diet treatment was continued for an additional 3-day period and animals were tested 8 h after withdrawal from EtOH, withdrawn animals were more reactive to startle stimuli at both intensities than were animals maintained on the EtOH liquid diet. A time-course experiment with repeated startle testing at 4, 8, and 12 h post-EtOH exposure revealed significant increases in responding to the 105 dB startle intensity at 8 h post-EtOH exposure. The ability of animals to respond to a prepulse stimulus was not affected during chronic EtOH treatment, but was reduced during withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)

Acoustic Stimulation↗
PubMed1992

Oral ethanol self-administration in rats is reduced by the administration of dopamine and glutamate receptor antagonists into the nucleus accumbens.

The purpose of this study was to assess the role of endogenous dopamine and glutamate systems within the nucleus accumbens in modulating responses for oral ethanol reinforcements (10% w/v) in a free-choice operant task. Pretreatment with both systemic (100 micrograms/kg) and intra-nucleus accumbens microinjection of fluphenazine (2 and 4 micrograms), a dopamine receptor antagonist, significantly decreased responding for ethanol, without significantly affecting responses for water. Ethanol self-administration was also attenuated by microinjection into the nucleus accumbens of 2-amino-5-phosphopentanoic acid (AP-5, 3 and 6 micrograms), a competitive NMDA receptor antagonist. These results suggest that dopamine and glutamate neurotransmission in the nucleus accumbens may regulate ethanol self-administration and its reinforcing effects.

2-Amino-5-phosphonovalerate↗
PubMed1992

Corticotropin-releasing factor modulates dietary preference in nutritionally and physically stressed rats.

In order to evaluate the action of central nervous system Corticotropin-Releasing Factor (CRF) in the control of feeding behavior the present studies employed a dietary self-selection task sensitive both to overall appetite as well as preferential intake of familiar versus unfamiliar foods. Prior to the diet selection test, one group of nutritionally stressed animals was fed a protein deficient diet in order to increase the preference for unfamiliar foods relative to nutritionally replete subjects. Both CRF (0.05 and 0.5 micrograms ICV) and physical restraint (30 min) attenuated selectively the consumption of a novel food choice by deficient animals without affecting concurrent intake of familiar food. Further, CRF administration did not alter water intake or consumption of either diet by the replete control group suggesting that the peptide produced a stress dependent, enhanced response to novelty without a general effect on appetite. The CRF antagonist, alpha-helical CRF9-41 (1, 5 and 25 micrograms ICV), increased familiar diet consumption in nutritionally deficient subjects without affecting the self-selection pattern or replete controls. Chlordiazepoxide (5 mg/kg) also increased selectively the intake of familiar food suggesting that this action is the anxiolytic complement of the effect of stress in this paradigm. The CRF antagonist (5 and 25 micrograms) reversed the anorexia produced by CRF (0.5 micrograms) as well as that induced by restraint stress. These results favor a direct role for endogenous CRF systems in coordinating the behavioral responses to dietary stress.

Animals↗
PubMed1992

Desmethylimipramine attenuates cocaine withdrawal in rats.

Depression and anhedonia are two major symptoms of cocaine withdrawal in humans. Hence, pharmacological treatments effective in depression might also alleviate the symptoms of cocaine withdrawal. In the present study, the effects of acute and repeated administration of a tricyclic antidepressant, desmethylimipramine (DMI), were investigated in naive and cocaine-withdrawing rats. An animal model of cocaine withdrawal was used that employs the elevation in intracranial self-stimulation (ICSS) thresholds following the termination of prolonged periods of cocaine self-administration as a measure of an animal's "anhedonic" state. The influence of chronic DMI treatment on beta-adrenergic receptor binding and affinity was also correlated with the behavioral signs of cocaine withdrawal. Neither acute nor repeated DMI treatment influenced reward functions in rats that were not undergoing cocaine withdrawal. However, repeated DMI treatment significantly down-regulated beta-adrenergic receptors, and shortened the duration of the post-cocaine "anhedonia" (elevation in thresholds). Furthermore, the magnitude of the beta-adrenergic receptor down-regulation correlated significantly with the degree of effectiveness of DMI treatment in reversing the post-cocaine "anhedonia". However, chronic DMI treatment did reduce the amount of cocaine self-administered by the animals. The reversal of the post-cocaine anhedonia in this animal model of cocaine withdrawal by chronic DMI treatment demonstrates the potential usefulness of the model in identifying new pharmacotherapies for cocaine withdrawal. In addition, the results indicate that tricyclic antidepressants may be able to ameliorate some of the symptoms of cocaine withdrawal.

Analysis of Variance↗
PubMed1992

Precipitation of morphine withdrawal syndrome in rats by administration of mu-, delta- and kappa-selective opioid antagonists.

The acute effects of opioid drugs are generally hypothesized to be mediated by multiple receptors, for which three types of binding sites have been established. In order to evaluate the selective participation of each type of opioid receptor in opiate withdrawal, the opiate withdrawal syndrome, precipitated by the intraventricular acute administration of mu-, delta- and kappa-selective opioid antagonists was investigated. After implantation of the cannula into the lateral ventricle, rats were made physically dependent by subcutaneous insertion of two 75-mg pellets of morphine (base). D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) (5-5000 ng), a mu-selective opioid antagonist, naltrindole (62-2000 ng), a delta-selective antagonist or nor-binaltorphimine (nor-BNI) (600-20,000 ng), a kappa-selective antagonist, were administered 72 hr after implantation of the pellets. All three drugs elicited some signs of morphine withdrawal but they differed in both their potency and their efficacy. The most efficacious and the most potent was CTAP, eliciting 8 of the 14 withdrawal signs at doses of 5-5000 ng. Nor-BNI was less efficacious and less potent, eliciting a significant increase in 5 of the 14 withdrawal signs in a dose range of 600-20,000 ng. Naltrindole was the least potent and least efficacious of the three drugs, eliciting a significant increase of only 2 withdrawal signs after intraventricular administration of 2000 ng. In a second experiment, the withdrawal syndrome was precipitated by the combined administration of CTAP+naltrindole or CTAP+nor-BNI. The severity of withdrawal, obtained with these two combinations, was similar to that observed with CTAP alone. These results support the importance of the mu receptor in the expression of central opiate dependence and suggest a minor role for delta and kappa receptors.

Animals↗
PubMed1992

Construct validity of a self-stimulation threshold paradigm: effects of reward and performance manipulations.

A discrete-trial current-threshold intracranial self-stimulation (ICSS) paradigm has been used extensively to examine the effects of drugs on reward thresholds. However, there is little work to date validating that this specific procedure measures reward. The purpose of the present study was to establish the construct validity of this procedure by testing the procedure's ability to measure reward effects and to discriminate these reward effects from performance effects. The discrete-trial ICSS procedure provides four measures: current thresholds, response latency, extra responses and time-out responses. The effects of a performance manipulation (variations in the force required to operate the manipulandum) and of a reward manipulation (variations in the train duration of the electrical stimulation) were evaluated on the four measures. Reward effects were reflected primarily in changes in thresholds, with no effect on any of the other three measures. Conversely, performance effects were reflected primarily in changes in response latency, extra responses and time-out responses, with only a small effect on thresholds. Finally, the paradigm's potential as a useful tool in the elucidation of the neurobiological basis of reward was demonstrated by investigating the effects of two pharmacological agents, cocaine and curare, on the four measures derived from the discrete-trial current-threshold ICSS procedure. The results suggest that the discrete-trial current-threshold procedure can readily discriminate reward from performance treatments.

Animals↗
PubMed1992

Pregnane steroid alphaxalone attenuates anxiogenic behavioral effects of corticotropin releasing factor and stress.

The 3 alpha-hydroxy A-ring-reduced steroid alphaxalone was examined for its ability to block stress-induced behavioral effects. Alphaxalone (3 and 6 mg/kg, IP) significantly antagonized the response-suppressing effects of corticotropin releasing factor (CRF) (0.5 micrograms, ICV) on punished responding in a conflict paradigm. In the plus maze, alphaxalone (3 and 6 mg/kg, IP) blocked the anxiogenic behavioral effects produced by a prior ambient-temperature swim stress. These doses of alphaxalone produced no intrinsic effects on plasma ACTH levels, nor did they attenuate CRF-induced increases in plasma ACTH. These findings support the hypothesis that some pregnane steroids may be involved in the modulation of an animal's behavioral response to stress and suggest that these effects may occur independently of the hypothalamic-pituitary-adrenocortical axis.

Adrenocorticotropic Hormone↗