Search PubMed⌕ Search

Biomedical subjects

G F Koob

Publications and source records attributed to G F Koob.

At least 55 records · Page 3Linked to original sources
PubMed2000

Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress.

Corticotropin-releasing hormone (Crh) is a critical coordinator of the hypothalamic-pituitary-adrenal (HPA) axis. In response to stress, Crh released from the paraventricular nucleus (PVN) of the hypothalamus activates Crh receptors on anterior pituitary corticotropes, resulting in release of adrenocorticotropic hormone (Acth) into the bloodstream. Acth in turn activates Acth receptors in the adrenal cortex to increase synthesis and release of glucocorticoids. The receptors for Crh, Crhr1 and Crhr2, are found throughout the central nervous system and periphery. Crh has a higher affinity for Crhr1 than for Crhr2, and urocortin (Ucn), a Crh-related peptide, is thought to be the endogenous ligand for Crhr2 because it binds with almost 40-fold higher affinity than does Crh. Crhr1 and Crhr2 share approximately 71% amino acid sequence similarity and are distinct in their localization within the brain and peripheral tissues. We generated mice deficient for Crhr2 to determine the physiological role of this receptor. Crhr2-mutant mice are hypersensitive to stress and display increased anxiety-like behaviour. Mutant mice have normal basal feeding and weight gain, but decreased food intake following food deprivation. Intravenous Ucn produces no effect on mean arterial pressure in the mutant mice.

Animals↗
PubMed2000

Animal models of craving for ethanol.

Craving has various meanings but can be defined generally in terms of a desire for the previously experienced effects of ethanol. Animal models provide a means by which to study the underlying mechanisms associated with craving and are most useful when they fulfill the requirements for predictive validity and reliability. Craving is a key part of the process of addiction that can lead to relapse and is conceptualized as having at least three components: preoccupation/anticipation, binge/intoxication and withdrawal/negative affect. Animal models of craving are hypothesized at this time to involve three domains of motivation to take drugs: excessive drinking, negative affective states and conditioned reinforcement. Excessive drinking includes the alcohol deprivation effect, drinking during withdrawal and drinking after a history of dependence. Models of the negative affective state include increases in brain reward thresholds, and conditioned reinforcement models include cue-induced resistance to extinction or cue-induced reinstatement. Experimental psychology is a rich resource of sensitive behavioral techniques by which to measure hypothetical constructs associated with the motivation to drink ethanol. Rigorous tests of predictive validity and reliability will be necessary to make them useful for understanding the neurobiology of craving and for the development of new medications for treating craving.

Acamprosate↗
PubMed2000

Neural mechanisms underlying nicotine addiction: acute positive reinforcement and withdrawal.

The neurobiology of nicotine addiction is reviewed within the context of neurobiological and behavioral theories postulated for other drugs of abuse. The roles of various neurotransmitter systems, including acetylcholine, dopamine, serotonin, glutamate, gamma-aminobutyric acid, and opioid peptides in acute nicotine reinforcement and withdrawal from chronic administration are examined followed by a discussion of potential neuroadaptations within these neurochemical systems that may lead to the development of nicotine dependence. The link between nicotine administration, depression and schizophrenia are also discussed. Finally, a theoretical model of the neurobiological mechanisms underlying acute nicotine withdrawal and protracted abstinence involves alterations within dopaminergic, serotonergic, and stress systems that are hypothesized to contribute to the negative affective state associated with nicotine abstinence.

Animals↗
PubMed2000

Neurobiology of addiction. Toward the development of new therapies.

Drug addiction is a chronic relapsing brain disorder characterized by neurobiological changes that lead to a compulsion to take a drug with loss of control over drug intake. The hypothesis outlined here is that knowledge of the neurochemical systems involved in the transition from drug use to the compulsive use of addiction will provide the rational basis for development of pharmacotherapies for drug addiction. Much evidence has been obtained in identifying the midbrain-basal forebrain neural elements involved in the positive reinforcing effects of drugs of abuse and more recently in the neural elements involved in the negative reinforcement associated with drug addiction. Key elements for the acute reinforcing effects of drugs of abuse include a macrostructure in the basal forebrain called the extended amygdala that contains parts of the nucleus accumbens and amgydala and involves key neurotransmitters such as dopamine, opioid peptides, serotonin, GABA, and glutamate. Withdrawal from drugs of abuse is associated with subjective symptoms of negative affect, such as dysphoria, depression, irritability and anxiety, and dysregulation of brain reward systems involving some of the same neurochemical systems implicated in the acute reinforcing effects of drugs of abuse. In addition, acute withdrawal is accompanied by recruitment of the brain stress neurotransmitter system, corticotropin-releasing factor. Animal models of craving involve not only conditioning models but also models of excessive drug intake during prolonged abstinence, post-acute withdrawal, that may reflect continued dysregulation of drug reinforcement that could lead to vulnerability to relapse and represent an important focus for pharmacotherapy. Such changes have been hypothesized to involve a change in set point for drug reward that may represent an allostatic state contributing to vulnerability to relapse and re-entry into the addiction cycle. Elucidation of the specific neuropharmacological changes contributing to this prolonged functional dysregulation will be the challenge of future research on the neurobiology of drug addiction.

Animals↗
PubMed2000

Dissociation of locomotor activation and suppression of food intake induced by CRF in CRFR1-deficient mice.

Corticotropin-releasing factor (CRF) systems are involved in locomotor and feeding behaviors. Two distinct CRF receptor subtypes, CRFR1 and CRFR2, are thought to mediate CRF actions in the central nervous system. However, the role for each receptor in locomotor activity and feeding remains to be determined. Using CRFR1 null mutant mice, the present study examined the functional significance of this receptor in ambulation and feeding. CRF treatment of wild-type mice resulted in increased levels of locomotion whereas no change was observed in CRFR1-deficient mice as compared to vehicle-treated mutant mice. In contrast, CRF decreased food-water intake in both wild type and CRFR1-deficient mice equally. These results support an important role for CRFR1 in mediating CRF-induced locomotor activation, whereas other receptor subtypes, likely CRFR2, may mediate the appetite-suppressing effects of CRF-like peptides.

Animals↗
PubMed2000

Reward and somatic changes during precipitated nicotine withdrawal in rats: centrally and peripherally mediated effects.

The negative affective aspects of nicotine withdrawal have been hypothesized to contribute to tobacco dependence. In the present studies in rats, brain stimulation reward thresholds, conditioned place aversions, and somatic signs of withdrawal were used to investigate the role of central and peripheral nicotinic acetylcholine and opioid receptors in nicotine withdrawal. Rats prepared with s.c. osmotic mini-pumps delivering 9.0 mg/kg/day nicotine hydrogen tartrate or saline were administered various doses of the nicotinic antagonists mecamylamine (s.c.), chlorisondamine (s. c. or i.c.v.), dihydro-beta-erythroidine (s.c.), or the opiate antagonist naloxone (s.c.). Nicotine-treated rats receiving mecamylamine or i.c.v. chlorisondamine exhibited elevated thresholds and more somatic signs than saline-treated rats. Nicotine-treated rats receiving s.c. chlorisondamine, at doses that do not readily cross the blood-brain barrier, exhibited more somatic signs than saline-treated rats with no threshold elevations. Naloxone administration produced threshold elevations and somatic signs only at high doses that induced similar magnitude effects in both nicotine- and saline-treated subjects. Mecamylamine or dihydro-beta-erythroidine administration induced conditioned place aversions in nicotine-treated rats but required higher doses than those needed to precipitate threshold elevations. In contrast, naloxone administration induced conditioned place aversions at lower doses than those required to precipitate threshold elevations and somatic signs. These data provide evidence for a dissociation between centrally mediated elevations in reward thresholds and somatic signs that are both centrally and peripherally mediated. Furthermore, threshold elevations and somatic signs of withdrawal appear to be mediated by cholinergic neurotransmission, whereas conditioned place aversions appear to be primarily mediated by the opioid system.

Animals↗
PubMed2000

mu-Opioid receptor knockout mice do not self-administer alcohol.

Opioid peptides long have been hypothesized to play a role in ethanol reinforcement. Neuropharmacological studies have shown that opioid receptor antagonists decrease ethanol self-administration in rodents and prevent relapse in humans. However, the exact mechanism for such powerful effects has remained elusive. The availability of mu-opioid receptor knockout mice has made possible the direct examination of the role of the mu-opioid receptor in mediating ethanol self-administration. In the present experiments, both nosepoke and lever operant ethanol self-administration and several tests of two bottle-choice ethanol drinking were studied in these genetically engineered mice. In no case did knockout mice show evidence of ethanol self-administration, and, in fact, these mice showed evidence of an aversion to ethanol under several experimental conditions. These data provide new evidence for a critical role for mu-opioid receptors in ethanol self-administration assessed with a variety of behavioral paradigms and new insights into the neuropharmacological basis for ethanol reinforcement.

Alcohol Drinking↗
PubMed2000

Altered amygdalar CRF release and increased anxiety-like behavior in Sardinian alcohol-preferring rats: a microdialysis and behavioral study.

BACKGROUND: Dysregulation of the stress-regulatory corticotropin-releasing factor (CRF) system in the central nucleus of the amygdala (CeA) may be a factor in genetically determined alcohol preference. METHODS: To test this hypothesis, basal and restraint stress-induced CRF efflux in the CeA was determined by microdialysis in Sardinian alcohol-preferring (sP) and nonpreferring (sNP) rats. In addition, differences in anxiety-like behavior between sP and sNP rats were evaluated by using the elevated plus maze and conditioned defensive burying tests. RESULTS: Basal dialysate CRF levels in the CeA were elevated in the alcohol-preferring line (sP, 281.2+/-83.96 pg/ml; sNP, 70.2+/-16.76 pg/ml; p < 0.05). In contrast, no differences in whole-tissue CRF content in the CeA were observed (sP, 1143+/-142 ng/mg protein; sNP, 1181+/-139 ng/mg protein). Restraint stress elevated CRF dialysate concentrations in both sP and sNP rats. Rats of the sP line exhibited more anxiety-like behavior than sNP rats in the elevated plus maze but not in the conditioned defensive burying test. CONCLUSIONS: The results suggest that ethanol-preferring sP rats show a dysregulation in basal CRF release within the CeA that may, in turn, heighten ethanol intake and increase susceptibility to anxiogenic stimuli in these animals.

Alcoholism↗
PubMed1999

Role of adenosine A2 receptors in brain stimulation reward under baseline conditions and during cocaine withdrawal in rats.

The present experiments tested the hypothesis that adenosine A2 receptors are involved in central reward function. Adenosine receptor agonists or antagonists were administered to animals that had been trained to self-stimulate in a rate-free brain stimulation reward (BSR) task that provides current thresholds as a measure of reward. The adenosine A(2A) receptor-selective agonists 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine hydrochloride (CGS 21680) (0.1-1.0 mg/kg) and 2-[(2-aminoethylamino)carbonylethyl phenylethylamino]-5'-N-ethylcarboxamido adenosine (APEC) (0.003-0.03 mg/kg) elevated reward thresholds without increasing response latencies, a measure of performance. Specifically, CGS 21680 had no effect on response latency, whereas APEC shortened latencies. Bilateral infusion of CGS 21680 (3, 10, and 30 ng/side), directly into the nucleus accumbens, elevated thresholds but shortened latencies. The highly selective A(2A) antagonist 8-(3-chlorostyryl)caffeine (0.01-10.0 mg/kg) and the A2-preferring antagonist 3,7-dimethyl-1-propargylxanthine (DMPX) (0.3-10.0 mg/kg) did not alter thresholds or latencies, but DMPX (1.0, 10.0 mg/kg) blocked the threshold-elevating effect of APEC (0.03 mg/kg). In another study, repeated administration of cocaine (eight cocaine injections of 15 mg/kg, i.p., administered over 9 hr) produced elevations in thresholds at 4, 8, and 12 hr after cocaine. DMPX (3 and 10 mg/kg), administered before both the 8 and 12 hr post-cocaine self-stimulation tests, reversed the threshold elevation produced by cocaine withdrawal. These results indicate that stimulating adenosine A(2A) receptors diminishes BSR without producing performance deficits, whereas blocking adenosine receptors reverses the reward impairment produced by cocaine withdrawal or by an A(2A) agonist. These findings indicate that adenosine, via A(2A) receptors, may inhibit central reward processes, particularly during the neuroadaptations associated with chronic drug-induced neuronal activation.

Adenosine↗
PubMed1999

A role for corticotropin releasing factor and urocortin in behavioral responses to stressors.

Corticotropin-releasing factor (CRF) and CRF-related neuropeptides have an important role in the central nervous system to mediate behavioral responses to stressors. CRF receptor antagonists are very effective in reversing stress-induced suppression and activation in behavior. An additional CRF-like neuropeptide, urocortin, has been identified in the brain and has a high affinity for the CRF-2 receptor in addition to the CRF-1 receptor. Urocortin has many of the effects of CRF but also is significantly more potent than CRF in decreasing feeding in both meal-deprived and free-feeding rats. In mouse genetic models, mice over-expressing CRF show anxiogenic-like responses compared to wild-type mice, and mice lacking the CRF-1 receptor showed an anxiolytic-like behavioral profile compared to wild-type mice. Results to date have led to the hypothesis that CRF-1 receptors may mediate CRF-like neuropeptide effects on behavioral responses to stressors, but CRF-2 receptors may mediate the suppression of feeding produced by CRF-like neuropeptides. Brain sites for the behavioral effects of CRF include the locus coeruleus (LC), paraventricular nucleus (PVN) of the hypothalamus, the bed nucleus of the stria terminalis (BNST), and the central nucleus of the amygdala. CRF may also be activated during acute withdrawal from all major drugs of abuse, and recent data suggest that CRF may contribute to the dependence and vulnerability to relapse associated with chronic administration of drugs of abuse. These data suggest that CRF systems in the brain have a unique role in mediating behavioral responses to diverse stressors. These systems may be particularly important in situations were an organism must mobilize not only the pituitary adrenal system, but also the central nervous system in response to environmental challenge. Clearly, dysfunction in such a fundamental brain-activating system may be the key to a variety of pathophysiological conditions involving abnormal responses to stressors such as anxiety disorders, affective disorders, and anorexia nervosa.

Animals↗
PubMed1999

Corticotropin-releasing factor, norepinephrine, and stress.

Corticotropin-releasing factor (CRF) and related peptides in the central nervous system appears to have activating properties on behavior and to enhance behavioral responses to stressors. CRF and urocortin injected into the brain produces increases in arousal as measured by locomotor activation and increased responsiveness to stressful stimuli. These effects of CRF appear to be independent of the pituitary adrenal axis and can be reversed by specific and selective CRF antagonists alpha-helical CRF9-41 and D-Phe CRF12-41. Perhaps more importantly, CRF antagonists can reverse behavioral responses to many stressors. These results suggest that endogenous CRF systems in the brain may have a role in mediating behavioral responses to stressors. Norepinephrine systems emanating from the nucleus locus coeruleus also long have been hypothesized to be involved in mediating behavioral constructs associated with alertness, arousal, and stress. Pharmacologic, physiologic, and neuroanatomic evidence supports an important role for a CRF-norepinephrine interaction in the region of the locus coeruleus in response to stressors that may be modality-specific where CRF neurons activate the locus coeruleus. One may hypothesize that another norepinephrine-CRF interaction may occur in the terminal projections of the forebrain norepinephrine systems in the paraventricular nucleus of the hypothalamus, the bed nucleus of the stria terminalis, and the central nucleus of the amygdala where norepinephrine stimulates CRF release. Such a feed-forward system may be particularly important in situations where an organism must mobilize not only the pituitary adrenal system but also the central nervous system, in response to environmental challenge. However, such a feed-forward mechanism in a fundamental brain-activating system may be particularly vulnerable to dysfunction and thus, may be the key to a variety of pathophysiologic conditions involving abnormal responses to stressors such as anorexia nervosa, anxiety, and affective disorders.

Animals↗
PubMed1999

Antagonism of heroin and morphine self-administration in rats by the morphine-6beta-glucuronide antagonist 3-O-methylnaltrexone.

In mice, 3-O-methylnaltrexone blocks the analgesic actions of morphine-6beta-glucuronide and heroin at doses which are inactive against morphine. We found a similar selectivity in rats. 3-O-Methylnaltrexone antagonized the analgesic actions of 6-acetylmorphine in Sprague-Dawley rats and heroin in Wistar rats at doses that were inactive against morphine. Inclusion of a fixed dose of 3-O-methylnaltrexone significantly shifted the analgesic dose-response curves for 6-acetylmorphine and heroin without altering the morphine dose-response curves. In a self-administration model, 3-O-methylnaltrexone treatment significantly increased both heroin and morphine intake during the first hour, suggestive of an antagonist effect. This effect at doses of 3-O-methylnaltrexone which were inactive against morphine analgesia implied a role for the morphine-6beta-glucuronide opioid receptor in the reinforcing properties of heroin and morphine.

Animals↗
PubMed1999

Performance norms for a rhesus monkey neuropsychological testing battery: acquisition and long-term performance.

A computerized behavioral battery based upon human neuropsychological tests (CANTAB, CeNeS, Cambridge, UK) has been developed to assess cognitive behaviors of rhesus monkeys. Monkeys reliably performed multiple tasks, providing long-term assessment of changes in a number of behaviors for a given animal. The overall goal of the test battery is to characterize changes in cognitive behaviors following central nervous system (CNS) manipulations. The battery addresses memory (delayed non-matching to sample, DNMS; spatial working memory, using a self-ordered spatial search task, SOSS), attention (intra-/extra-dimensional shift, ID/ED), motivation (progressive-ratio, PR), reaction time (RT) and motor coordination (bimanual task). As with human neuropsychological batteries, different tasks are thought to involve different neural substrates, and therefore performance profiles should assess function in particular brain regions. Monkeys were tested in transport cages, and responding on a touch sensitive computer monitor was maintained by food reinforcement. Parametric manipulations of several tasks demonstrated the sensitivity of performance to increases in task difficulty. Furthermore, the factors influencing difficulty for rhesus monkeys were the same as those shown to affect human performance. Data from this study represent performance of a population of healthy normal monkeys that will be used for comparison in subsequent studies of performance following CNS manipulations such as infection with simian immunodeficiency virus (NeuroAIDS) or drug administration.

Analysis of Variance↗
PubMed1999

Chronic morphine treatment alters NMDA receptor-mediated synaptic transmission in the nucleus accumbens.

In a study of a possible substrate underlying morphine addiction, we examined NMDA receptor-mediated synaptic transmission of core nucleus accumbens neurons after chronic morphine treatment, using intracellular recording in a slice preparation of rat. We evoked pharmacologically isolated NMDA EPSCs by local stimulation and elicited inward currents by NMDA superfusion. In control slices, Mg(2+) and phorbol 12,13-diacetate (PDAc), a protein kinase C activator, strongly inhibited and increased, respectively, NMDA EPSC amplitudes. The PDAc effects were likely postsynaptic because PDAc enhanced the currents evoked by superfused NMDA to the same extent that it did the NMDA EPSCs. Chronic morphine treatment significantly decreased NMDA EPSC amplitudes and the sensitivity of NMDA EPSCs to Mg(2+) and PDAc, as well as the kinetics of the decay (inactivation rate) of the EPSCs (from 97 +/- 2.5 msec in untreated rats to 78.7 +/- 1.8 msec in slices from treated rats). One week after withdrawal, the Mg(2+) and PDAc effects were still significantly less than those in control slices. Interestingly, 1 week of withdrawal led to an increased NMDA EPSC inactivation rate compared with controls. These data demonstrate that chronic morphine treatment significantly alters NMDA receptor-mediated synaptic transmission in the accumbens, and these effects persist 1 week after withdrawal. These long-term effects may represent an important neuroadaptation in opiate dependence.

Afferent Pathways↗
PubMed1999

Reduced anxiety-like and cognitive performance in mice lacking the corticotropin-releasing factor receptor 1.

Corticotropin-releasing factor (CRF) has been hypothesized to be involved in the pathophysiology of anxiety, depression, cognitive and feeding disorders. Two distinct CRF receptor subtypes, CRFR1 and CRFR2, are thought to mediate CRF actions in the CNS. However, the role for each receptor subtype in animal models of neuropsychiatric disorders remains to be determined. Using CRFR1 deficient mice, the present study investigated the functional significance of this CRF receptor subtype in anxiety-like and memory processes. CRFR1 knockout mice displayed an increased exploratory behavior in both the Elevated Plus-maze (EPM) and the Black and White (B-W) test box models of anxiety, indicating an anxiolytic-like effect of the CRFR1 gene deletion. In contrast, during the retrieval trial of a two-trial spatial memory task wild type mice made more visits to and spent more time in the novel arm as opposed to the two familiar ones of a Y-maze apparatus. No increase in the level of exploration of the novel arm by the CRFR1 deficient mice was observed. This indicates that CRFR1 knockout mice are impaired in spatial recognition memory. These results demonstrate that genetic deletion of the CRFR1 receptor can lead to impairments in anxiety-like and cognitive behaviors, supporting a critical role for this receptor in anxiety and cognitive biological processes.

Animals↗
PubMed1999

The role of the striatopallidal and extended amygdala systems in drug addiction.

Evidence suggests that the acute reinforcing actions of drugs of abuse may be mediated by specific elements of the striatopallidal and extended amygdala systems. These include the shell of the nucleus accumbens, the central nucleus of the amygdala, and the sublenticular extended amygdala. Chronic administration of drugs of abuse, including cocaine, amphetamines, nicotine, alcohol, and tetrahydrocannabinol leads to an increasing dysregulation of brain reward systems that is characterized by decreases in reward function. Withdrawal from chronic administration of cocaine, amphetamine, nicotine, alcohol, and tetrahydrocannabinol raises thresholds for brain stimulation reward. Neurochemical elements in the extended amygdala may mediate these changes, including decreases in dopamine and serotonin neurotransmission in the nucleus accumbens and increases in the brain-stress neurotransmitter, corticotropin-releasing factor, in the central nucleus of the amygdala. The combination of decreases in function of neurotransmitters involved in the positive-reinforcing properties of drugs of abuse with recruitment of brain-stress systems within the extended amygdala provides a powerful mechanism for allostatic changes in hedonic set point that can lead to the compulsive drug-seeking and drug-taking behavior characteristic of addiction.

Amygdala↗