Search PubMed⌕ Search

Biomedical subjects

G F Koob

Publications and source records attributed to G F Koob.

At least 181 records · Page 10Linked to original sources
PubMed1994

SDZ 208-911, an amino-ergoline with partial dopamine agonist properties, dose dependently increases cocaine self-administration in the rat.

Brain dopamine neurotransmission appears to be an important component of the neural pathways involved in the maintenance of intravenous (IV) cocaine self-administration in rats. The effects of a novel partial dopamine agonist, SDZ 208-911, on intravenous cocaine self-administration in rats was studied. SDZ 208-911 at a dose range of 0.025-1.6 mg/kg SC dose-dependently increased the number of lever presses and drug intake in rats exposed to limited (3-h) daily access to cocaine on a continuous reinforcement schedule (0.75 mg/kg per injection). This behavioral profile is similar to that observed following administration of dopamine antagonist drugs and has been hypothesized to reflect a compensatory increase in drug intake due to a reduction of the reinforcing efficacy of the drug, probably because of functional antagonism at the receptor site. These results suggest that dopamine partial agonists may act as functional dopamine antagonists in the face of pharmacologically induced activation of brain dopamine function.

Animals↗
PubMed1994

Effect of corticotropin-releasing factor antagonist on behavioral and neuroendocrine responses during exposure to defensive burying paradigm in rats.

Defensive burying behavior is a coping strategy in rodents in response to an aversive stimulus where fear will facilitate burying and treatment with anxiolytics will result in less burying. To test the hypothesis that endogenous corticotropin-releasing factor (CRF) is involved in the defensive burying response, the effects of an ICV CRF antagonist were tested on defensive burying behaviors as well as the plasma adrenocorticotropic hormone (ACTH) and plasma corticosterone response. Rats were allowed to self-administer one mild electric shock (1.0 mA) through a probe mounted on the wall of the home cage by briefly touching it. Following this shock, control rats typically display burying behavior, as defined as moving the bedding material toward and/or over the shock probe. A CRF antagonist, alpha-hel CRF9-41, was administered ICV (1, 5, and 25 micrograms) 1 min after they received the shock. The 5 micrograms dose of the CRF antagonist significantly attenuated the time spent in defensive burying compared to vehicle-treated controls. The 5 and 25 micrograms doses of alpha-hel CRF9-41 increased the latency to display defensive burying. However, the enhanced release of plasma ACTH and plasma corticosterone concentrations in the stressed animals was not significantly modified over the 15-min period by either of the three doses of CRF antagonist. The results suggest that endogenous CRF is involved in the expression of defensive burying behavior and that the brain CRF receptors modulating the behavioral response may be different from the CRF receptors modulating the hormonal response of defensive burying.

Adrenocorticotropic Hormone↗
PubMed1994

Corticotropin-releasing factor and schedule-induced polydipsia.

Two experiments examined the effects of ICV-administered corticotropin-releasing factor (CRF) and alpha-helical CRF (9-41), a CRF antagonist, on the performance of schedule-induced polydipsia (SIP). Infusions of CRF into the lateral ventricle dose-dependently (0.02, 0.1, and 0.5 micrograms) attenuated both the volume of water consumed and licking on a fixed-time 60-s schedule. This effect of CRF on schedule-induced drinking was accompanied by a reduction in the number of nose pokes made into the food tray, suggesting that CRF may attenuate SIP through an action on appetitive motivation. Neither the temporal distribution of responding nor the locomotor activity induced by the schedule was affected by CRF. In marked contrast to these effects of exogenous CRF on the performance of SIP, infusions of alpha-helical CRF (1, 5, and 25 micrograms) into the lateral ventricle did not affect the performance of schedule-induced polydipsia. The implications of these results for the hypothesis that SIP is a coping response to stress are discussed.

Animals↗
PubMed1994

Lisuride reduces intravenous cocaine self-administration in rats.

The maintenance of intravenous (i.v.) cocaine self-administration appears to depend upon activation of dopamine terminals within mesocorticolimbic areas. Since the nonaddictive ergot derivative lisuride is a direct dopamine receptor agonist, the present study was designed to investigate whether administration of lisuride to rats trained to lever-press for IV self-administration of cocaine could affect the intake of cocaine. IP administration of several doses of lisuride reduced, in a dose-dependent manner, cocaine self-administration. In a control experiment, lisuride did not increase the psychomotor-activating properties of cocaine as measured by locomotor activity, suggesting that lisuride did not simply potentiate the activating effects of cocaine. The present results show that lisuride reduced IV cocaine self-administration in rats; the possibility of a new therapeutic approach to the treatment of cocaine abuse in humans using lisuride may therefore deserve clinical attention.

Animals↗
PubMed1994

Dopamine receptor agonists, partial agonists and psychostimulant addiction.

Despite the epidemic growth of psychostimulant addiction over the past years, few pharmacological means of intervention are available to date for clinical treatment. This is of importance since the withdrawal syndrome that follows abstinence from drugs such as cocaine and the amphetamines is characterized, among other symptoms, by intense craving for the abused drug, and this is considered a critical factor leading into relapse of drug use. In this article, Luigi Pulvirenti and George Koob focus on the modulatory role shown by drugs acting at the dopamine receptor on the various phases of psychostimulant dependence in preclinical models and in human studies, and suggest that a class of compounds with partial agonist properties at the dopamine receptor may have therapeutic potential.

Amphetamines↗
PubMed1994

Corticotropin-releasing factor and neuropeptide Y: role in emotional integration.

The amygdala complex integrates stressful stimuli and is critical in transducing their aversive value into autonomic, endocrine and behavioural responses. Stimulation within the amygdala complex produces signs of fear without a relevant external object, while lesions in this region abolish normal fear responses. In a manner characteristic of phylogenetically old limbic brain areas, the complex neurochemical anatomy of the amygdala involves a large number of phylogenetically old peptide mediators. The distribution and connectivity of these peptide systems have been extensively studied, but less is known about their functional role. Recent evidence suggests that two neuropeptides, corticotropin-releasing factor (CRF) and neuropeptide Y (NPY) exert a reciprocal regulation of responsiveness to stressful stimuli, possibly via an interaction of these two systems in the amygdala.

Amino Acid Sequence↗
PubMed1994

Behavioral effects of persistent lymphocytic choriomeningitis virus infection in mice.

Lymphocytic choriomeningitis virus (LCMV) is a nonlytic murine virus that provides a valuable model system for studying the behavioral correlates of CNS viral infection. Newborn or immunosuppressed mice infected with LCMV develop a persistent tolerant infection characterized by continuous viral production. Virus can be found in various body organs including lung, liver, kidney, and brain. In brain, neurons are the predominant CNS cells infected and the greatest number of persistently infected neurons are found in the cerebral cortex, hippocampus, other limbic structures and parts of the hypothalamus. Despite continuous infection throughout the animal's life, neurons show no structural injury or dropout. Mice from the DBA/2J strain were infected with LCMV (1000 plaque-forming units) within 18 h of birth and tested for behavioral function as adults. Plaque assays indicated persistent infection in virus-injected mice. Mice were tested for their ability to learn a Y-maze spatial discrimination to avoid the onset of a mild footshock (0.43 mA). The number of correct avoidance responses made during training was taken as a measure of acquisition performance. The virus-infected mice showed a deficit in acquisition of the Y-maze discrimination compared to that seen in vehicle-injected and noninjected controls. Following additional training to reach control levels of performance, the infected mice and the controls were injected with the cholinergic antagonist scopolamine. Scopolamine (2.0 mg/kg) disrupted the performance of the infected mice significantly more than control performance, suggesting that a cholinergic dysfunction accounted for some of the learning deficit. A separate group of virus-infected mice exhibited hypoactivity during the first exposure to a locomotor testing apparatus.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Anti-stress action of a corticotropin-releasing factor antagonist on behavioral reactivity to stressors of varying type and intensity.

Central administration of a Corticotropin-Releasing Factor (CRF) antagonist is well documented to attenuate a variety of behavioral responses to several distinct stressors; however, it is not yet clear whether the activation of CRF neurons is dependent on the type or intensity of the experimental stressor, or rather on the particular behavioral response to stress under study. To test the generality of the stress-protective effect of the CRF antagonist, alpha-helical CRF9-41, (1, 5 or 25 micrograms intracerebroventricularly), the present experiments employed a sensitive index of anxiogenic-like behavior by measuring suppression in exploration on the elevated plus-maze following exposure to social, swim, or restraint stressors. A 1 but not 5 or 25 micrograms dose of the CRF antagonist administered just prior to social, swim, or restraint stress reversed the stress-induced inhibition of exploratory behavior. Chlordiazepoxide and the steroid anesthetic, alphaxalone, also attenuated the anxiogenic-like effect of restraint stress and elevated the baseline exploratory behavior of nonstressed control groups. Although the stressors produced a graded secretion of adrenocorticotropin (ACTH) with the ranking restraint > swim > social, the relative amplitude of behavioral reactivity to social, swim, and restraint stress was comparable. The relative efficacy of the CRF antagonist to reverse the stressor effects was also comparable. These results suggest that antagonism of activated brain CRF systems attenuates the behavioral response to stress regardless of the type or intensity of the stressor as measured by ACTH secretion.

Adrenocorticotropic Hormone↗
PubMed1994

IL-1 beta potentiates the acetylcholine-induced release of vasopressin from the hypothalamus in vitro, but not from the amygdala.

In addition to the magnocellular hypothalamic nuclei, arginine vasopressin (AVP)-containing neurons have also been identified in limbic structures, including the hippocampus and amygdala. In the present study, we compared the qualitative properties of the in vitro release of AVP from the dissected hypothalamus with the in vitro release from the dissected amygdala and used these release systems to evaluate the interactions with neurotransmitters and cytokines. The areas of the paraventricular nucleus and supraoptic nucleus that contain the AVP neurons and that receive cholinergic innervation are also interleukin (IL)-1 beta immunoreactive. Acetylcholine or high KCl (60 mM) induces AVP release in both regions, and the AVP release is calcium dependent. Acetylcholine-induced AVP release is antagonized by atropine or mecamylamine, indicating that both muscarinic and nicotinic receptors are mediating the cholinergic effect in these brain regions. IL-1 beta (100 U/ml) had no effect on the basal AVP release from the hypothalamus, but significantly potentiated the acetylcholine-induced AVP release, lowering the threshold from 500 to 100 nM. This effect was completely blocked in the presence of neutralizing antibodies to IL-1 beta, atropine (10 microM) or mecamylamine (10 microM). IL-6, like IL-1 beta, also potentiated acetylcholine-induced AVP release, but to a lesser extent. Neither tumor necrosis factor-alpha nor interferon-gamma had any effect on the basal or acetylcholine-induced AVP release from the hypothalamus. None of the cytokines tested had any effect on the basal or acetylcholine-induced AVP release from the amygdala. Our results suggest a hypothalamic site of action of IL-1 beta and IL-6 on the acetylcholine-induced AVP release. The stimulatory effects of IL-1 and IL-6 on adrenocorticotropin release have been ascribed to an increased release of corticotropin-releasing factor (CRF). These data further suggest that, in addition to CRF, AVP plays a role in the bidirectional communication between neuroendoc ine and immune systems. Understanding the mode of interaction between IL-1 beta and IL-6 with AVP could clarify pathophysiologic or toxic effects of high brain levels of these cytokines.

Acetylcholine↗
PubMed1994

Effects of mesolimbic dopamine depletion on responding maintained by cocaine and food.

The hypothesis that mesolimbic dopamine is selectively involved in cocaine reinforcement was investigated in the rat. Animals were trained under a multiple schedule in which responding was reinforced by intravenous cocaine (0.75 mg/kg/injection) or food (45-mg pellets) under fixed-ratio 15 schedule requirements in alternate 30-min components of a 2-hr daily session. Infusion of the catecholaminergic neurotoxin 6-hydroxydopamine, but not the vehicle solution, into the region of the nucleus accumbens and olfactory tubercle produced selective reductions in cocaine self-administration without significantly altering responding maintained by food within the same sessions. This effect was reproduced in intact animals by substituting saline for cocaine in the self-administration component. These results support the hypothesis that the reinforcing effects of cocaine are dependent upon mesolimbic dopamine and demonstrate that cocaine self-administration can be disrupted in animals without altering behavior maintained by a nondrug reinforcer.

Animals↗
PubMed1994

Relative sensitivity to naloxone of multiple indices of opiate withdrawal: a quantitative dose-response analysis.

In addition to classic somatic signs of opiate withdrawal, a number of behavioral measures are known to be sensitive, reliable indices of naloxone-precipitated opiate withdrawal in rats. It has been suggested that some behavioral indices of withdrawal may be more sensitive to precipitation by naloxone than some somatic signs of withdrawal. The purpose of the present study was to permit a quantitative assessment of the relative sensitivity to naloxone of a variety of behavioral and somatic indices of opiate withdrawal. Male Wistar rats were implanted s.c. with either two morphine (each 75 mg of base) or two placebo pellets. No sooner than 3 days after implantation, naloxone dose-response functions were determined with several behavioral paradigms and ratings of a variety of somatic withdrawal signs. In dependent rats, very low (0.004 or 0.01 mg/kg) doses of naloxone produced the following behavioral effects: 1) a reduction in spontaneous locomotor activity, 2) a disruption of schedule-controlled (fixed ratio 15) operant responding for food, 3) an elevation in intracranial self-stimulation thresholds and 4) a conditioned place aversion. These same doses of naloxone produced no significant effects in nondependent (placebo pellet-implanted) rats. The ED50 values for naloxone precipitation of all behavioral signs of withdrawal were below 0.013 mg/kg; the ED50 values for naloxone precipitation of most somatic withdrawal signs were higher. The behavioral measures used in these studies therefore represent highly sensitive indices of opiate withdrawal.

Animals↗
PubMed1994

Effects of dopamine D-1 and D-2 antagonists on cocaine self-administration under different schedules of reinforcement in the rat.

The effects of three dopamine D-1 receptor antagonists (SCH23390, SCH39166 and A69024) and three dopamine D-2 antagonists (raclopride, eticlopride and spiperone) on cocaine self-administration maintained under different schedules of reinforcement were examined in the rat. Intravenous cocaine self-administration was maintained under a fixed-ratio (FR) 5 schedule with a 20-sec timeout (TO) after each reinforcement or a FR 15 with a 2-min TO multiple schedule of cocaine (0.25 mg i.v.) and food (45 mg) reinforcement. With the exception of raclopride, all of the antagonists altered the self-administration of cocaine in a manner similar to decreasing the unit dose of cocaine under the schedule in effect, reflected by increased self-administration under the FR 5 TO 20-sec schedule and decreased self-administration under the FR 15 TO 2-min multiple schedule. Moreover, a low dose of either of the benzazepine dopamine D-1 antagonists SCH23390 or SCH39166, but not the other compounds, selectively reduced cocaine self-administration without altering responding for food under the multiple schedule. Conversely, a low dose of raclopride or A69024 selectively decreased food-reinforced responding without altering cocaine self-administration under the multiple schedule. These results suggest that benzazepine dopamine D-1 antagonists, at low doses, may attenuate the reinforcing properties of cocaine more selectively than other dopamine receptor antagonists. The results also demonstrate the advantages of using different schedules to investigate the effects of dopamine D-1 and D-2 antagonists on cocaine self-administration.

Animals↗
PubMed1994

Overproduction of corticotropin-releasing factor in transgenic mice: a genetic model of anxiogenic behavior.

Corticotropin-releasing factor (CRF) is released in response to various stressors and regulates adrenocorticotropin secretion and glucocorticoid production. In addition to its endocrine functions, CRF acts as a neuromodulator in extra-hypothalamic systems and has been shown to play a role in behavioral responses to stress. CRF overproduction has been implicated in affective disorders such as depression and anorexia nervosa. A transgenic mouse model of CRF overproduction has been developed in order to examine the endocrine and behavioral effects of chronic CRF excess. CRF transgenic animals exhibit endocrine abnormalities involving the hypothalamic-pituitary-adrenal axis such as elevated plasma levels of ACTH and glucocorticoids. The present series of experiments tested the hypothesis that chronic overproduction of CRF throughout the life-span of these animals may lead to an anxiogenic behavioral state. CRF transgenic mice and normal littermate controls were tested by measuring locomotor activity in a novel environment and through the use of an elevated plus-maze as indices of anxiety. CRF transgenic animals exhibited an increase in anxiogenic behavior, an effect known to occur following central administration of CRF in mice and rats. Injection of the CRF antagonist alpha-helical CRF 9-41 into the lateral cerebral ventricles reversed the anxiogenic state observed in the CRF transgenics. This finding supports the possibility that central CRF overproduction may mediate the anxiogenic behavior exhibited in this animal model. Thus, CRF transgenic mice represent a genetic model of CRF overproduction that provides a valuable tool for investigating the long-term effects of CRF excess and dysregulation in the CNS.

Adrenocorticotropic Hormone↗
PubMed1994

Characterization of a novel and potent corticotropin-releasing factor antagonist in rats.

The present study examined the ability of two analogs of human/rat corticotropin-releasing factor (h/rCRF), [Met18, Lys23, Glu27,29,40, Ala32,41, Leu33,36,38] h/rCRF9-41 (alpha-hel CRF9-41) and [D-Phe12, Nle21,38, C alpha MeLeu37] h/rCRF12-41 (D-Phe CRF12-41), to antagonize CRF- and stress-induced behavioral changes in rats. The potency and duration of action of D-Phe CRF12-41 in vivo was compared with that of alpha-hel CRF9-41, the most effective CRF antagonist studied to date. When administered i.c.v., both CRF antagonists dose-dependently reduced the locomotor activity induced by rat CRF (0.5 microgram/rat i.c.v.) and attenuated the social stress-induced anxiogenic-like effect, as measured by the elevated plus-maze. However D-Phe CRF12-41 was 5 times more potent and remained effective for a longer period (> 1.5 hr) than alpha-hel CRF9-41. High doses of alpha-hel CRF9-41 (25 micrograms/rat), by itself, exhibited weak agonist effects, which were not observed with D-Phe CRF12-41 at the same doses. These results demonstrate that a N-terminus-shortened CRF antagonist that encompasses the substitution D-Phe12 has significantly higher biological potency and an extended duration of action without intrinsic agonist effects in these in vivo systems. The availability of potent and effective CRF antagonists will provide valuable tools for exploring the functional role of brain CRF and may ultimately lead to an understanding of the biological basis of stress-related illnesses.

Amino Acid Sequence↗
PubMed1994

Role for the mesocortical dopamine system in the motivating effects of cocaine.

The search for a neurobiological substrate for the stimulant and reinforcing properties of cocaine has focused for some time on a particular part of the forebrain, the mesocorticolimbic dopamine (DA) system. This mesocorticolimbic DA system innervates the region of the nucleus accumbens (NACC) (ventral striatum) in the anterior part of the basal forebrain and appears to play a critical role in mediating the acute reinforcing effects of cocaine and amphetamine. This chapter reviews the role of mesocorticolimbic DA in the reinforcing properties of psychomotor stimulants as measured by intravenous (IV) drug self-administration in rats. In addition, the primary neuropharmacological mechanism for cocaine reinforcement provides a rich substrate for studying nondopaminergic modulation of the reinforcing actions of cocaine.

Animals↗
PubMed1993

The role of limbic and hypothalamic corticotropin-releasing factor in behavioral responses to stress.

CRF in the central nervous system appears to have activating properties on behavior and to coordinate behavioral responses to stress. These behavioral effects of CRF appear to be independent of the pituitary-adrenal axis and can be reversed by a CRF antagonist, alpha-helical CRF9-41. The CRF antagonist reverses not only decreases in behavior associated with stress, but also increases in behavior associated with stress, thus suggesting that the role of CRF is stress dependent and not intrinsic to a given behavioral response. Further, microinjection of alpha-helical CRF9-41 and immunotargeting of CRF neurons in separate brain compartments reveal a link between the anatomical sites that contain CRF and the nature of the behavioral response to stress that can be modified by suppression of endogenous CRF activity therein. Hence, consistent with the dual role of other hypothalamic-releasing factors in integrating hormonal and neural mechanisms by acting both as secretagogues for anterior pituitary hormones and as extrapituitary peptide neurotransmitters, CRF may coordinate coping responses to stress at several bodily levels (Fig. 6). Moreover, dysfunction in such a fundamental homeostatic system may be the key to a variety of pathophysiological conditions including mental disorders.

Animals↗
PubMed1993

The effects of 6-hydroxydopamine lesions of the nucleus accumbens and the mesolimbic dopamine system on oral self-administration of ethanol in the rat.

Rats readily learn to self-administer ethanol using a procedure where ethanol is introduced in the presence of a sweetener. After gradual removal of the sweetener, sufficient quantities of ethanol are self-administered in non fluid-, non food-deprived rats to produce reliable blood ethanol concentrations. Previous studies using this self-administration model have shown that dopamine receptor antagonists injected systemically or directly into the terminal regions of the mesolimbic dopamine system decrease lever pressing for ethanol, suggesting an important role for dopamine in ethanol reinforcement. The purpose of the present study was to test the hypothesis that the mesolimbic dopamine system is a critical substrate for ethanol reinforcement. Results of this study show that 6-hydroxydopamine (6-OHDA)-induced lesions of the mesolimbic dopamine system, sufficient to produce a 93% depletion of dopamine in the nucleus accumbens, an 85% depletion in the olfactory tubercle, an 82% depletion in the frontal cortex and a 78% depletion in the amygdala, failed to alter ethanol self-administration as measured by the total lever presses. However, the 6-OHDA lesion rats showed an altered pattern of responding for ethanol: an increase in the slope of the regression line of cumulative responses vs. time and an increase in the frequency of responding at inter-response intervals of 4-6 and 6-8 s post 6-OHDA lesion; suggesting that this lesion produced a subtle change in motor or attentional function. The results of this study indicate that while the mesolimbic dopamine system may contribute to the reinforcing actions of ethanol, it is not critical for maintaining ethanol reinforcement.

Administration, Oral↗