Biomedical subjects

G F Koob

Publications and source records attributed to G F Koob.

At least 343 records · Page 19Linked to original sources

PubMed1984

The neural substrates of apomorphine-stimulated locomotor activity following denervation of the nucleus accumbens.

Efferent fibers from the nucleus accumbens (N.Acc.) to the substantia innominata and lateral preoptic region (SI/LPO) are believed to be essential for the supersensitive locomotor response to apomorphine in rats following 60HDA-induced denervation of the N.Acc., since destruction of cells within the SI/LPO eliminates this supersensitive response. In the present study, the neurochemical properties of this efferent projection were investigated. Injection of muscimol, a GABA agonist, directly into the SI/LPO produced a dose-dependent decrease in supersensitive locomotor activity at doses that did not alter baseline locomotion. Higher doses of muscimol actually produced a prolonged locomotor activation in all animals. These results suggest that the locomotor activation following stimulation of supersensitive dopamine receptors within the N.Acc. may involve a decrease in GABAergic activity at the level of the SI/LPO.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1984

Microinjections of nanogram amounts of sulfated cholecystokinin octapeptide into the rat nucleus accumbens attenuates brain stimulation reward.

Microinjections of nanogram amounts of sulfated cholecystokinin octapeptide (CCK-8S) into the nucleus accumbens were examined for effects on intracranial self-stimulation (ICSS) derived from the ventral tegmental area (VTA). The results showed that CCK-8S dose-dependently antagonized VTA intracranial self-stimulation (ICSS) without affecting maximum response rates. CCK-8S also increased the current threshold required for ICSS. These findings were interpreted to suggest that CCK-8S attenuates brain stimulation reward derived from the VTA.

Animals↗

PubMed1984

Antagonism of effects of vasopressin (AVP) on inhibitory avoidance by a vasopressin antagonist peptide [dPtyr(Me)AVP].

After training in two different passive avoidance tasks, the platform box of Ader and De Wied (1972) and the Jarvik box of Jarvik and Kopp (1967), rats injected with vasopressin immediately following the training trial showed a significant enhancement of retention 24 hours later. This vasopressin effect was reversed by high doses of the vasopressor antagonist, dPtyr(Me) AVP. These results support the hypothesis that the visceral afferent signals may be involved in the apparent memory-enhancing effects of AVP, but the high doses of antagonist required suggest that factors other than a simple reversal of the pressor effects of AVP may be important.

Animals↗

PubMed1984

Substantia innominata: critical link in the behavioral expression of mesolimbic dopamine stimulation in the rat.

The 'supersensitive' locomotor response to apomorphine resulting from 6-hydroxydopamine (6-OHDA)-induced denervation of the nucleus accumbens (N.Acc.) was studied in animals following selective damage to cell bodies within the substantia innominata (SI) and lateral preoptic region (LPO). Ibotenic acid-induced lesions of the SI and LPO dramatically attenuated the locomotor response to apomorphine in 6-OHDA-infused animals. Thus, the locomotor response that follows dopaminergic stimulation within the N.Acc. depends to a great degree on the integrity of cells within the SI and LPO region.

Animals↗

PubMed1984

Electrolytic lesions of the substantia innominata and lateral preoptic area attenuate the 'supersensitive' locomotor response to apomorphine resulting from denervation of the nucleus accumbens.

Apomorphine-stimulated locomotion in the rat is greatly enhanced following destruction of dopamine terminals in the nucleus accumbens (NA) with 6-hydroxydopamine (6-OHDA). While this augmented response is ascribed to the action of the dopamine stimulant apomorphine on supersensitive receptors within the NA, little is known regarding the mechanisms by which increased receptor stimulation within the NA influences lower motor circuitry to produce changes in locomotion. In this study, we examined apomorphine-stimulated locomotion in 6-OHDA-infused rats following electrolytic damage to the terminal region of first-order NA efferent fibers within the substantia innominata and lateral preoptic area. This damage greatly diminished the locomotor response to apomorphine in 6-OHDA-infused animals, but did not diminish locomotion in vehicle-infused animals. Destruction of dopamine terminals within the NA has also been reported to enhance the place-preference response to apomorphine in rats. Damage to the substantia innominata and lateral preoptic area significantly decreased the place-preference for apomorphine-paired environments in 6-OHDA-infused animals, but did not alter place-preference responses in vehicle-infused animals. Our results indicate that the efferent pathway from the NA to the substantia innominata and lateral preoptic area serves as an important output of mesolimbic activity into motor circuitry involved in the expression of apomorphine-stimulated locomotion and place-preference.

Animals↗

PubMed1984

Neuroleptic-like disruption of the conditioned avoidance response requires destruction of both the mesolimbic and nigrostriatal dopamine systems.

An examination of the ability to learn an active avoidance response was made in rats subjected to 6-hydroxydopamine (6-OHDA) lesions of the individual terminal areas of the midbrain dopamine (DA) system or a lesion to all these terminal regions in one group. Lesions were made by infusing 8 micrograms (base) of 6-OHDA in 2 microliter of vehicle into the following forebrain regions (each region representing a separate group of rats); frontal cortex, nucleus accumbens, corpus striatum and a double lesion of nucleus accumbens and corpus striatum. A separate group of rats received a smaller 6-OHDA lesion of the ventral substantia nigra. Only those rats with the combined double lesion of both the nucleus accumbens and corpus striatum (90% total depletion of dopamine) showed a severe deficit in acquisition of active avoidance. However, the rats with the separate 6-OHDA lesions to the mesolimbic or nigrostriatal DA systems did show the appropriate blockade of the amphetamine-induced locomotion or stereotyped behavior, respectively. In contrast, the rats with the double lesion showed no response to a low or high dose of amphetamine, remained cataleptic for the duration of the experiment but rapidly recovered from transient aphagia and adipsia (less than 10 days post lesion). Results suggest that a severe deficit in acquisition of an active avoidance response, similar to that observed with high doses of neuroleptics, requires destruction of all of the dopamine innervation of nucleus accumbens and corpus striatum. Results also suggest that both the mesolimbic and nigrostriatal dopamine systems act in concert to produce response enabling to important environmental events, and that the severe response enabling deficits observed in Parkinson's disease involves not only degeneration of the nigrostriatal dopamine system, but of the mesolimbic dopamine system as well.

Animals↗

PubMed1984

Dorsal noradrenergic bundle lesions fail to alter opiate withdrawal or suppression of opiate withdrawal by clonidine.

Previous work has shown that clonidine effectively suppresses many of the signs of opiate withdrawal. The present study was designed to test the hypothesis that the suppression of opiate withdrawal by clonidine is mediated by forebrain noradrenergic projections of the locus coeruleus. Two groups of 24 rats each were subjected to either a 6-hydroxydopamine lesion of the dorsal noradrenergic bundle (Lesion group) or a sham, vehicle injection (Sham group). All rats were made dependent on morphine by subcutaneous implantation of one 75 mg silastic morphine pellet for three days followed by 3 more days with two additional 75 mg pellets. Following removal of the morphine pellet, withdrawal was precipitated in all rats by subcutaneous injection of 4 mg/kg of naloxone. Pretreatment 10 min. before withdrawal with clonidine (0.1 or 0.2 mg/kg) produced a significant attenuation of withdrawal signs as compared to saline injected rats; this effect was equally significant in both sham and lesion groups. Lesions of the locus coeruleus had no effect on withdrawal, nor did they affect the ameliorating action of clonidine. These results substantiate the observation that clonidine can effectively attenuate signs of opiate withdrawal in the rat, but fail to support the hypothesis that these effects are mediated by the forebrain projections of the locus coeruleus.

Animals↗

PubMed1984

Restrained rats learn amphetamine-conditioned locomotion, but not place preference.

The relationship between the motor-activating and positive-reinforcing properties of d-amphetamine was examined in the place-preference paradigm. Two groups of animals were trained to associate one environment with amphetamine, and another environment with saline. Animals that were allowed to locomote in both environments during training later demonstrated a preference for the amphetamine-paired environment; animals in which hyperactivity was limited in both environments later failed to show any preference. However, both groups of animals demonstrated a conditioned locomotor activation to the amphetamine-associated environments. Our results suggest that a place-preference demonstrated for an amphetamine-paired environment depends on the ability of the drug to increase locomotor behavior.

Animals↗

PubMed1984

Destruction of dopamine in the nucleus accumbens selectively attenuates cocaine but not heroin self-administration in rats.

The hypothesis that separate neural systems mediate the reinforcing properties of opioid and psychomotor stimulant drugs was tested by examining the role of mesolimbic dopamine (DA) neurons in maintaining intravenous heroin and cocaine self-administration. After local destruction of the DA terminals in the nucleus accumbens (NAcc) with 6-hydroxydopamine (6-OHDA), rats trained to self-administer cocaine and heroin on alternate days were observed for changes in their drug-seeking behaviors. Postlesion responding for cocaine showed a time-dependent decrease or extinction, whereas heroin self-administration showed a time-dependent recovery. By the fifth trial postlesion, heroin self-administration had recovered to 76% of prelesion baseline levels, but cocaine self-administration had dropped to 30% of prelesion baseline rates. Thus, selective lesions of the DA terminals in the nucleus accumbens significantly attenuate cocaine but not heroin self-administration. These data support the hypothesis that independent neural substrates are responsible for the reinforcing actions of these two drugs.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1984

Cocaine antagonizes anxiolytic effects of ethanol.

A Geller-Seifter paradigm for discerning anxiolytic and ataxic effects of drugs was used to study the interactions between low doses of ethanol and cocaine. Ethanol produced significant anxiolytic and ataxic effects at a dose of 1 g/kg. Cocaine at a dose as low as 10 mg/kg markedly antagonized the anxiolytic effect of ethanol, but simultaneously augmented ethanol's ataxic effects, as measured by response rates during a random-interval schedule. These results indicate that ethanol may interact to a significant degree with brain aminergic systems and that, contrary to popular dogma, stimulants may reverse some components of ethanol intoxication, but increase ethanol's debilitating motor effects.

Animals↗

PubMed1984

Different effects of cholecystokinin and satiety on lateral hypothalamic self-stimulation.

The effects of cholecystokinin (CCK) and satiety were compared in animals lever-pressing for rewarding electrical stimulation of the lateral hypothalamus. For some rats, conditions of food deprivation and satiation, respectively, increased or decreased responding whereas the self-stimulation behavior of other rats was unresponsive to these feeding manipulations. CCK, at doses thought to signal satiety, reduced the responding of all rats independent of whether they were, or were not, responsive to real satiety. This same result was obtained with the aversive agent lithium chloride. These data suggest that the reduced feeding observed following CCK administration is due to aversive consequences and not satiety.

Analysis of Variance↗

PubMed1984

Brain norepinephrine depleting lesions selectively enhance behavioral responsiveness to novelty.

The noradrenergic innervation of the forebrain by cells from the locus coeruleus (LC) was interrupted by either electrolytic lesions of the LC or 6-hydroxydopamine (6-OHDA) lesions of the dorsal noradrenergic bundle (DB). Animals so treated were then tested in a modified open field test designed to measure responsiveness to environmental novelty and also tested for food consumption in their home cages. In addition, DB lesioned animals were tested in photocell activity cages for both their initial locomotor response to the novel cages as well as their activity level after habituation. The DB lesioned animals were also tested for rates of acquisition and extinction of an operant response. The DB lesion produced no deficits in either the acquisition or the extinction of a food rewarded operant response. The DB lesion did reduce the initial amount of locomotor activity in response to introduction to the activity cages but did not alter the rate of habituation of the locomotor response nor the "basal" level of activity at the end of two hr of exposure. Neither lesion affected the amount of food eaten by 24 hr-fasted animals in their home cages during the first 15 min. When fasted prior to being given access to food in a novel open field, however, both lesions resulted in decreased food consumption and decreased amounts eaten per approach to the food pedestal. The DB lesion, but not the LC lesion, resulted in decreased rearing and grooming in this setting.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1984

Destruction of the locus coeruleus or the dorsal NE bundle does not alter the release of punished responding by ethanol and chlordiazepoxide.

The hypothetical involvement of central noradrenergic projections in the manifestation of "anxiety" and the "anti-anxiety" effects of alcohol and benzodiazepines was tested in an operant conflict situation by examining the effects of destruction of this noradrenergic system on response rates. Rats were trained on a Geller-Seifter conflict test [9] modified for incremental shock [21], in which two food-reinforced lever press components were separated by a time-out. Responses during the "food-alone" component (RI) were reinforced on a random interval schedule-30 sec; responses during the "time-out" component were never reinforced; and responses during the conflict component (CONFLICT) were continuously reinforced with both food and shock. This shock strength increased incrementally with each successive shock during the conflict period. Each session consisted of two cycles of a 5 min RI period, a two min time out, and a two min CONFLICT period presented in succession. Both ethanol (0.5 to 1.0 g/kg) and chlordiazepoxide (5 and 10 mg/kg) produced a significant increase in punished responding during the CONFLICT component. Ethanol, but not chlordiazepoxide (CDP) also significantly decreased responding during the RI component. Virtual total destruction of the dorsal noradrenergic projection with 6-hydroxydopamine (6-OHDA), or destruction of the locus coeruleus itself, failed to significantly alter baseline responding or the release of punished responding to ethanol or CDP. These results do not support the hypothesis that the locus coeruleus projections have an essential role in "anxiety" or in the "anxiety-reducing" properties of ethanol or the benzodiazepines.

Animals↗

PubMed1984

Behavioral effects of peripheral administration of arginine vasopressin: a review of our search for a mode of action and a hypothesis.

In this review we present data summarizing our studies concerning the mechanism of action for the behavioral effects of peripheral arginine vasopressin (AVP) administration. We have demonstrated a clear performance improvement in a one trial appetitive task designed to measure the memory-learning process. This behavioral effect is blocked by peptide analogs which block the pressor response to AVP. From these data, and from other data obtained in aversively motivated tasks, we hypothesize that peripheral AVP injections induce effects of physiological-endocrinological origin and that these peripheral signals (e.g. vasopressor actions) alert and arouse the animal, thus helping to improve its association of environmental events. This hypothesis is similar to that proposed by others regarding peripheral hormones and memory and still leaves open the possibility that vasopressin in the brain acts independently of the above proposed action for peripherally derived vasopressin.

Animals↗

PubMed1984

Comparative effects of tetrahydrocannabinol on psychostimulant-induced behaviors.

The behavioral effects of delta-9-tetrahydrocannabinol (THC), one of the major psychoactive cannabinoids in marijuana, were tested in two models of psychostimulant-induced behaviors in rats (locomotor behavior and stereotyped gnawing) induced by amphetamine (AMPH) and methylphenidate (MEPH). Pretreatment with THC (10 mg/kg gavage) almost doubled the amount of AMPH-induced gnawing but produced no effect on AMPH-induced locomotor behavior. In contrast to AMPH, THC produced no direct effect on MEPH-induced gnawing but caused a strong suppression of MEPH-induced locomotor activity. In addition, there was no additional interaction between THC and reserpine as measured by suppression of MEPH-induced gnawing. This result was unexpected in view of the powerful interaction between THC and reserpine reported previously. Because of the clear THC-induced dissociation of the behavioral effects of these two psychostimulants (AMPH and MEPH), our working hypothesis is that THC affects motor behaviors by some non-dopaminergic mechanism.

Amphetamine↗

PubMed1984

Effects of alpha-flupenthixol and naloxone on CRF-induced locomotor activation.

Corticotropin-releasing factor injected intracerebroventricularly in a dose of 1 microgram produced a prolonged locomotor activation (3 h) in rats previously habituated to the test cage environment. This activation was reversed by alpha-flupenthixol (intraperitoneally), a dopamine receptor antagonist, only at cataleptic doses and not at all by naloxone (subcutaneously) in doses of 0.02-5.0 mg/kg. The effective dose 50% (ED50) for the alpha-flupenthixol reversal of locomotor activity induced by corticotropin-releasing factor was 0.13 mg/kg; similar to the 0.14 mg/kg ED50 needed to reverse the locomotor activation produced by caffeine (10 mg/kg s.c.). The ED50 necessary to reverse amphetamine (0.75 mg/kg s.c.) locomotion with this drug was 0.07 mg/kg. The results suggest that the corticotropin-releasing factor acts independently of direct activation of the dopamine or opioid peptide systems.

Animals↗

PubMed1984

Effects of opiate antagonists and their quaternary derivatives on heroin self-administration in the rat.

Quaternary derivatives of naloxone and naltrexone, methyl naloxonium chloride(ORG 10908) and naltrexone methobromide ( MRZ 2663BR ), respectively, were compared with the parent compounds for their ability to antagonize the reinforcing properties of heroin as measured in an operant, i.v., self-administration paradigm. As expected, lower doses (up to 0.2 mg/kg) of naloxone and naltrexone produced dose-dependent increases in heroin self-administration, but at higher doses (10-30 mg/kg) these drugs produced transient decreases (20-100 min) in self-administration followed by recovery. Naltrexone was approximately 1.5 times more potent than naloxone in increasing heroin self-administration at the lower doses (up to 0.2 mg/kg) and had a slightly longer duration of action. The quaternary derivatives were ineffective as antagonists of heroin self-administration in doses 200 times greater than the effective antagonist dose of naloxone or naltrexone. These results support the hypothesis that the acute reinforcing properties of i.v. opiates associated with the sensation of the "rush" involve opiate receptors located within the central nervous system and do not involve peripheral opiate receptors.

Animals↗

PubMed1983

Cholecystokinin produces conditioned place-aversions, not place-preferences, in food-deprived rats: evidence against involvement in satiety.

The net reinforcing/aversive properties of cholecystokinin (CCK) were measured using a conditioned place-preference paradigm. Both sated and food-deprived rats showed a dose dependent aversion to an environment previously paired with CCK that was correlated with the effects of CCK on feeding. In contrast, all rats showed a conditioned preference for an environment previously paired with food. These results demonstrate the aversive properties of CCK and suggest that the decrease in feeding that follows peripheral administration of CCK results from a CCK-induced malaise.

Animals↗