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Biomedical subjects

G F Koob

Publications and source records attributed to G F Koob.

At least 253 records · Page 14Linked to original sources
PubMed1991

CRF antagonist reverses the "anxiogenic" response to ethanol withdrawal in the rat.

The role of the neuropeptide corticotropin-releasing factor (CRF) in mediating the behavioral effects of ethanol withdrawal in the rat was examined using the elevated plus-maze test. In Experiment 1, CRF (0.5 microgram ICV) reduced the percentage of time spent on the open arms of the elevated plus-maze, consistent with an "anxiogenic-like" effect. CRF also reduced the total number of arm entries, indicating a reduction in general activity. Low doses (5 and 25 micrograms ICV) of the CRF antagonist, alpha-helical CRF produced no behavioral effects in the elevated plus-maze, while a higher dose (50 micrograms ICV) elicited CRF-like activity. In experiment 2, rats were maintained for 2-3 weeks on a liquid diet containing ethanol (8.5-11.5% v/v) or sucrose. Eight hours after withdrawal from the ethanol diet rats displayed "anxiogenic-like" responses as well as a reduction in general activity in the elevated plus-maze compared with rats withdrawn from control diet. Alpha-helical CRF significantly antagonized the "anxiogenic-like" effects of ethanol withdrawal in the plus-maze. General activity and physical signs of ethanol withdrawal such as tail stiffness, body tremor and ventromedial distal flexion were unaffected by alpha-helical CRF. Blood Alcohol Levels (BALs) determined immediately after removal of the ethanol diet showed no group differences in ethanol consumption. These results suggest that increased activity of central CRF systems may mediate the anxiogenic effects of ethanol withdrawal.

Animals↗
PubMed1991

Both conditioned taste preference and aversion induced by corticotropin-releasing factor.

Postprandial administration in the rat of a wide variety of drugs, peptides and toxins suppresses future consumption of a meal of previously unfamiliar but otherwise attractive saccharin-flavored solution. Since the intensity of this conditioned flavor aversion in the rat is sensitive to plasma stress hormone levels, the present study examined the effects on flavor conditioning of corticotropin-releasing factor, a peptide known to be involved in behavioral and hormonal responses to stress. In two-bottle water vs. saccharin choice tests, CRF (0.5 microgram ICV) increased significantly the consumption of saccharin solution following a single saccharin/CRF pairing, while a tenfold larger dose of CRF (5 micrograms ICV) abolished saccharin intake following two saccharin/CRF pairings. Hence, exogenous CRF is capable of inducing both flavor preference and aversion in a dose- and situation-dependent manner. Further, direct neurotropic actions of CRF probably subserve its aversive effect since dexamethasone pretreatment weakened but did not prevent CRF-induced conditioned taste avoidance. These results suggest that at low doses CRF can produce arousal actions that result in taste preference and at higher doses produces aversive effects that are reflected in taste avoidance.

Animals↗
PubMed1991

Nucleus accumbens NMDA antagonist decreases locomotor activity produced by cocaine, heroin or accumbens dopamine, but not caffeine.

Glutamatergic afferents to the nucleus accumbens (NAC) have been suggested to modulate psychostimulant-induced locomotor activation. The purpose of this study was 1) to determine the importance of nucleus accumbens N-methyl-D-aspartate (NMDA) glutamate receptors in the control of psychostimulant-induced locomotion, 2) to determine whether NMDA receptor modulation of psychostimulant-induced locomotion occurs presynaptic to or postsynaptic to NAC dopamine terminals, and 3) to determine whether NMDA receptors also modulate opiate- and caffeine-induced locomotor activation. For this purpose, rats treated with cocaine (10 mg/kg IP), dopamine (20 micrograms directly into the NAC), heroin (0.5 mg/kg SC), or caffeine (10 mg/kg SC) were challenged with intra-NAC microinfusion of 2-amino-5-phosphonovaleric acid (APV), a selective NMDA receptor antagonist. APV reduced locomotor activation induced by cocaine, heroin and intra-NAC dopamine, but not caffeine. These results suggest that NAC glutamate modulates psychomotor stimulation at the level of the NAC through an interaction with the integrated output of this region.

2-Amino-5-phosphonovalerate↗
PubMed1991

Differential effects of ethanol on punished responding in the P and NP rats.

The effects of ethanol administration (0, 0.25, 0.5, 0.75 and 1.0 g/kg intraperitoneal) were examined in a conflict test in 24 alcohol-preferring (P)-rats, 17 alcohol-nonpreferring (NP)-rats, and 24 heterogeneous Wistar rats. The conflict test was a modified Geller-Seifter procedure employing an unpunished random interval 30-sec component and an incremental shock conflict component. Heterogeneous Wistar rats displayed significant increases in punished responding with doses of 0.5, 0.75, and 1.0 g/kg of ethanol. P-rats did not show a significant increase in punished responding until 0.75 g/kg ethanol. NP rats displayed significant increases in punished responding with all doses tested (0.25, 0.5, and 0.75 g/kg). There were no group differences in the effects of ethanol on unpunished responding. Thus NP-rats were more sensitive and P-rats were less sensitive to the anticonflict effects of ethanol than heterogeneous Wistar rats. The results suggest that the P and NP rats may show a profile of sensitivity to the anticonflict effects of ethanol similar to the sensitivity to the intoxicating effects of ethanol observed in family history positive and family history negative human subjects.

Alcoholism↗
PubMed1991

Endocrine, immune, and neurochemical changes in rats during withdrawal from chronic amphetamine intoxication.

In humans who chronically abuse amphetamine (AMPH), sudden abstinence often precipitates an organic mood disorder that mimics many symptoms of major depression. We report that AMPH exposure and withdrawal in rats modifies hypothalamic-pituitary-adrenal axis endocrine responses, peripheral immune functions, and regional brain catecholamine levels. Compared to vehicle-treated animals, rats treated with AMPH for 10 days exhibit significantly decreased physostigmine-induced release of adrenocorticotropin hormone (ACTH). During AMPH withdrawal, these animals show a loss of the normal correlation between levels of plasma ACTH and corticosterone. Chronic AMPH treatment in rats causes a significant increase in natural killer cell activity. Brain dopamine levels in these animals are decreased in the caudate nucleus but are increased in the nucleus accumbens. AMPH withdrawal in rats may be a useful model for studying the physiologic and neural substrates of human AMPH withdrawal states.

Adrenocorticotropic Hormone↗
PubMed1991

Postcocaine anhedonia. An animal model of cocaine withdrawal.

Cocaine use frequently occurs in episodic, prolonged binges. Following such a cocaine binge, the user suffers from severe depressive symptoms mixed with irritability and anxiety ("crash"). The present study was an attempt to develop an animal model of postcocaine depression or anhedonia and to study the time course of this cocaine withdrawal symptom. Rats were allowed to self-administer cocaine intravenously for prolonged periods of time and their brain reward thresholds were then assessed using intracranial self-stimulation (ICSS) thresholds. ICSS thresholds were used operationally as a measure of the animals' "hedonic-anhedonic" state. It was found that during cocaine withdrawal ICSS thresholds were elevated compared to predrug baseline levels and to control animals' thresholds, reflecting an "anhedonic" state. The magnitude and duration of the "anhedonic" state was proportional to the amount of cocaine consumed during the binge. A measure of response latency provided evidence that this postcocaine elevation of thresholds is due to a desensitization of the reward pathways mediating ICSS reward and not to any nonspecific (e.g., performance) effects of the cocaine exposure.

Analysis of Variance↗
PubMed1990

Central administration of a CRF antagonist blocks the development of stress-induced behavioral sensitization.

This experiment examined the effects of intracerebroventricular (i.c.v.) administration of a corticotropin-releasing factor (CRF) antagonist on the development of stress-induced sensitization of the behavioral response to amphetamine. Restraint stress was found to enhance both the locomotor response to a s.c. injection of saline and the intensity of stereotypy induced by a s.c. injection of 3.0 mg/kg D-amphetamine. Both of these effects of restraint stress were severely attenuated in rats that had been injected with the CRF antagonist prior to restraint stress. This result is compatible with the hypothesis that CRF is critically involved in initiating behavioral and physiological responses to aversive stimuli.

Amphetamines↗
PubMed1990

The ventral pallidum plays a role in mediating cocaine and heroin self-administration in the rat.

The hypothesis that the ventral pallidum is an important site mediating psychomotor stimulant and opiate reinforcement was tested in rats trained to self-administer i.v. cocaine or heroin. Ibotenic acid lesions of the ventral pallidum produced significant decreases in cocaine and heroin self-administration behavior maintained on a fixed-ratio 5 schedule of reinforcement, suggesting an attenuation of the reinforcing value of cocaine and heroin. On a progressive-ratio schedule, ventral pallidal lesions produced significant decreases in the highest ratio obtained in rats self-administering cocaine. Similar results were observed with heroin in a progressive-ratio procedure modified to produce higher levels of responding; lesions of the ventral pallidum produced a significant decrease in the highest ratio obtained. Further, the i.v. co-administration of naloxone and heroin produced a decrease in progressive-ratio responding relative to heroin alone using the modified progressive-ratio schedule. These results suggest that the ventral pallidum is an important site mediating the reinforcing effects of cocaine and heroin and that the nucleus accumbens-ventral pallidum circuit may be a common pathway for both stimulant and opiate reinforcement.

Animals↗
PubMed1990

Ethanol effects on delayed spatial matching as modeled by a negative exponential forgetting function.

Performance on delayed matching-to-position as a function of ethanol was investigated in rats and dose effects assessed by fitting an exponential decay model of forgetting to signal detection sensitivity scores. Three ethanol doses (0.25, 0.50, and 0.75 g/kg) and one isovolume saline control were examined. For further comparison, one dose of chlordiazepoxide (CDP; 5 mg/kg) and its saline control were also given. Forgetting functions were reasonably well described by the decay model under all treatment conditions. In addition, the functions's decay constant (-b) proved to be differentially sensitive to both drug and dose effects. Reduced decay estimates were obtained following the two lowest ethanol doses, the reduction being statistically significant for the 0.25 g/kg dose. In contrast, the function estimate of initial sensitivity, the intercept parameter (SI0), was not significantly affected by ethanol. Consistent with the low-dose ethanol effects, CDP significantly decreased the value of the decay parameter while leaving the intercept parameter unaffected. But unlike ethanol, the variance accounted for by the model for the individual data was less following CDP administration. Drug effects were interpreted using the exponential decay model of forgetting, and the results suggest independent discriminative control over SI0 and b. The significant effect of the low-dose sedative-hypnotics upon b, with no attendant effects upon SI0, is suggested to result from enhanced, spontaneous, delay interval mediation.

Animals↗
PubMed1990

Free-choice responding for ethanol versus water in alcohol preferring (P) and unselected Wistar rats is differentially modified by naloxone, bromocriptine, and methysergide.

The role of opioids, dopamine and serotonin in ethanol (EtOH) reward and preference was investigated in non-deprived, Alcohol-Preferring (P), and genetically heterogenous Wistar rats. Operant responding for ethanol was initiated using sweet-solution substitution procedures. The rats were then trained in 30-min daily sessions to respond for ethanol (10% v/v) versus water under a two-lever, free-choice contingency. All testing was conducted in the absence of water and food deprivation or addition of sweeteners to the ethanol drinking solution. Rats of both strains developed stable preferences in responding for ethanol over water and consumed ethanol at quantities sufficient to produce pharmacologically relevant mean blood alcohol concentrations (P-Rats: 98 +/- 19.6 mg%; unselected Wistars: 41.7 +/- 8.5 mg%). In P-rats, systemic naloxone (NAL; 0.125, 0.25 and 0.5 mg/kg) pretreatments resulted in a dose-dependent suppression in responding for both ethanol and water, but did not alter ethanol preference (expressed as percent ethanol of total intake). In contrast, bromocriptine (BRO; 1.0, 2.0 and 4.0 mg/kg) produced a significant, dose-dependent shift in preference from ethanol toward water by inhibiting responding for ethanol while enhancing water consumption. In unselected Wistar rats, NAL and BRO treatments produced changes in ethanol preference patterns similar to those observed in P-rats. However, compared to P-rats, these changes were smaller and not consistently dose dependent. No changes in ethanol preference and water or ethanol intake were observed with methysergide (MET; 2.5, 5.0, 10.0 mg/kg) in either strain of rat. Together, the results suggest a possible involvement of dopaminergic mechanisms in the reinforcing properties of ethanol.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Drinking↗
PubMed1990

Amphetamine disruption of prepulse inhibition of acoustic startle is reversed by depletion of mesolimbic dopamine.

Previous studies have demonstrated that dopamine (DA) agonists disrupt sensorimotor gating as measured by prepulse inhibition (PPI) of the acoustic startle response (ASR) in rats; other reports suggest that this stimulant-induced disruption of PPI may reflect drug-induced increases in ASR amplitude rather than changes in sensorimotor gating. In the current study, 6-hydroxydopamine lesions that depleted dopamine from the nucleus accumbens, olfactory tubercles and anterior striatum reversed the disruption of PPI caused by amphetamine (AMPH), but did not disrupt AMPH potentiation of ASR baseline. These findings strongly suggest that increased mesolimbic DA activity is one substrate of the AMPH-induced disruption of PPI; in contrast, AMPH potentiation of baseline startle amplitude may be independent of mesolimbic DA activation.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Critical role of the hypothalamic pituitary adrenal axis in amphetamine-induced sensitization of behavior.

Behavioral sensitization can be observed with repeated administration of amphetamine where the intensity of motor stimulation increases over time. The process of sensitization has been well characterized, however, the neurochemical mechanisms that are critical for the development of sensitization are not known. In the present study, the role of the hypothalamic pituitary adrenal axis (HPA) in the development of behavioral sensitization to amphetamine was explored by pretreating rats with an intravenous administration of an antiserum to corticotropin-releasing factor in a volume that has been shown to block significantly stress- and cocaine-induced activation of the HPA. Four groups of eight rats were pretreated intravenously with either heparinized saline or CRF antiserum and subcutaneously with saline or d-amphetamine in a balanced design. The rats were then returned to their home cages and left undisturbed for seven days after which they were given three consecutive behavioral tests with saline SC, 0.75 mg/kg d-amphetamine SC, and 3.0 mg/kg d-amphetamine SC. The rats pretreated with intravenous CRF antiserum showed a significant attenuation of the development of d-amphetamine-induced sensitization but the antiserum did not alter the magnitude of the behavioral response to the initial, sensitizing dose of d-amphetamine. These results suggest that activation of the hypothalamic pituitary adrenal axis may be of critical importance to the development of behavioral sensitization to amphetamine.

Animals↗
PubMed1990

EEG effects of Ro 15-4513 and FG 7142 alone and in combination with ethanol.

The electrophysiological effects of Ro 15-4513 and FG 7142 alone and in combination with ethanol were investigated. Intraperitoneal administration of Ro 15-4513 (3, 6 mg/kg) was found to significantly increase power in the 6-16 Hz frequency range, an effect which was antagonized by ethanol (1 g/kg). FG 7142 administration (2, 5 mg/kg IP) was found to enhance spectral power in the 6-8 Hz range, an effect which was also blocked by coadministration of ethanol. Both drugs also produced dose-related abnormal EEG activity in the form of episodic bursts of EEG spiking. These ictal episodes, which lasted 5-40 seconds, were associated with an arrest of behavior but no overt behavioral convulsions. Coadministration of ethanol caused an elimination or significant reduction in these episodes. These studies suggest that Ro 15-4513 and FG 7142 have potent electrophysiological actions of their own which are partially antagonized by ethanol.

Animals↗
PubMed1990

Effects of two benzodiazepine inverse agonists, RO 15-4513 and FG 7142, on recovery from pentobarbital and halothane anesthesia in the rat.

A new class of drugs, the benzodiazepine inverse agonists, have recently been shown to antagonize some of the behavioral and sedative effects of benzodiazepines, barbiturates, and alcohol. Preliminary studies suggested that at least one of these drugs, RO 15-4513, may also be able to reverse the general anesthetic properties of volatile halogenated agents. Another inverse agonist, FG 7142, exhibits a similar ability to antagonize alcohol or benzodiazepines. However, FG 7142 is less potent than RO 15-4513 and has less affinity for the benzodiazepine receptor (BZR). The present studies were therefore undertaken to compare the analeptic effects and relative potencies of RO 15-4513 and FG 7142 on the anesthetic properties of pentobarbital compared with the general anesthetic agent halothane as measured by the time for recovery of the righting reflex in the rat. Three basic experimental paradigms were employed. Drug (FG or RO) or carrier was administered 5 minutes prior to the induction of pentobarbital anesthesia. Drug or carrier was administered to anesthetized animals 60 minutes after pentobarbital injection. Lastly, drug or carrier was administered 5 minutes prior to 15 minutes of halothane anesthesia. In addition, the selective benzodiazepine antagonist, flumazenil (RO 15-1788), was used to determine if the effects of the benzodiazepine inverse agonists on recovery from barbiturate or halothane anesthesia were due to activity at the BZR. The results revealed that RO was both more potent and more effective than FG at speeding recovery from barbiturate anesthesia in the rat. RO's effects appeared to be primarily due to BZR inverse agonist activity since it could be reversed by the BZR antagonist, flumazenil.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia Recovery Period↗
PubMed1990

Nucleus accumbens and amygdala are possible substrates for the aversive stimulus effects of opiate withdrawal.

Specific brain sites for the opiate abstinence syndrome syndrome have been elusive to delineate, and the classic overt signs of withdrawal such as wet dog shakes, ptosis and teeth chattering appear to be widely represented in the brain. Using a more general motivational test involving a disruption of operant behavior in dependent rats, the brain site most sensitive to the response disruptive effects of intracerebral administration of the opiate antagonist, methylnaloxonium, was the region of the nucleus accumbens, a site also implicated in the acute reinforcing properties of opiates. This disruption of operant responding was hypothesized to reflect the aversive properties of opiate withdrawal. The present study directly tested that hypothesis by exploring whether intercerebral administration of methylnaloxonium produced aversive stimulus effects as measured by the formation of place aversions. Rats implanted intracerebroventricularly or with bilateral cannulae aimed at the medial dorsal thalamus, periaqueductal gray, ventral tegmental area, amygdala or nucleus accumbens were made dependent on morphine by subcutaneous implantation of two 75-mg morphine pellets. The animals were then subjected to place aversion training by pairing of a distinct environment (one of three arms of a three-armed box with distinct texture, markings and smell) with a single injection of methylnaloxonium intracerebroventricularly or intracerebrally. Results showed that at high doses of methylnaloxonium (1000-2000 ng) all sites produced a place aversion. However, lower doses (250-500 ng) produced a significant brain site selectivity with the region of the nucleus accumbens the most sensitive. Observational measurements taken during the postinjection period with the high dose of methylnaloxonium showed that agitation was particularly observed following methylnaloxonium administration into the nucleus accumbens and periaqueductal gray.(ABSTRACT TRUNCATED AT 250 WORDS)

Amygdala↗
PubMed1990

Bromocriptine produces decreases in cocaine self-administration in the rat.

The effect of bromocriptine pretreatment was investigated in rats trained to self-administer intravenous cocaine on a fixed-ratio (FR) 5 schedule of reinforcement. Bromocriptine, a dopamine agonist, produced dose-dependent decreases in cocaine self-administration at doses of 4.0, 8.0, 16.0, and 32.0 mg/kg. In a separate group of rats trained on a DRL 20-second schedule of food reinforcement used to produce the same overall rate of responding for food as for cocaine on the FR 5 schedule, bromocriptine did not produce a significant effect on overall response rate, number of reinforced responses, or percent of responses that were reinforced. Given that bromocriptine produced a specific effect on cocaine-maintained responding, the present results suggest that bromocriptine is interacting with the neurochemical substrate mediating the reinforcing effects of cocaine. The potential effectiveness of bromocriptine as a pharmacotherapy for cocaine dependence is discussed.

Animals↗