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Biomedical subjects

George F Koob

Publications and source records attributed to George F Koob.

At least 73 records · Page 4Linked to original sources
PubMed2004

Enhanced alcohol self-administration after intermittent versus continuous alcohol vapor exposure.

BACKGROUND: Ethanol self-administering rats exhibit enhanced responding during withdrawal from continuous exposure to ethanol vapor. This study compared self-administration of ethanol during withdrawal from continuous versus intermittent ethanol vapor. METHODS: Experiment 1 examined self-administration of ethanol in rats trained to self-administer ethanol after continuous, intermittent (14 hr on and 10 hr off), or no (i.e., controls) ethanol vapor exposure. Exposure time was equalized such that the intermittent group received 4 weeks of exposure and the continuous group received 2 weeks of exposure. Four self-administration tests were conducted 2 hr after removal from vapor, and each test was separated by 3 to 4 days of ethanol vapor. Experiment 2 examined self-administration of ethanol after 2 weeks of intermittent vapor either 2 or 8 hr after removal from vapor. Experiment 3 addressed the specificity of the increased responding for ethanol by examining saccharin self-administration after 2 weeks of intermittent vapor. RESULTS: Four weeks of intermittent exposure produced an increase in ethanol self-administration during the first withdrawal relative to controls and relative to animals receiving 2 weeks of continuous exposure. The continuous group was indistinguishable from controls on the first test and gradually increased their responding across tests. Two weeks of intermittent exposure also increased ethanol self-administration, and there was no difference in this effect 2 or 8 hr after removal from vapor. There was no difference in saccharin self-administration in control rats and those given 2 weeks of intermittent exposure. CONCLUSIONS: The finding that intermittent exposure produces more rapid increases in self-administration of ethanol relative to continuous exposure suggests that intermittent exposure may be associated with a more rapid escalation of the allostatic processes responsible for excessive ethanol self-administration. The mechanisms that drive the increases in drinking during withdrawal are similar after 2 and 8 hr of withdrawal and seem to be specific to ethanol.

Animals↗
PubMed2004

Nicotine withdrawal in adolescent and adult rats.

Previous research with animal models has demonstrated that adolescent rats display heightened sensitivity to the reinforcing and stimulant effects of nicotine relative to adult rats. Little work has focused on the response of adolescent rats to measures of nicotine withdrawal. To test the hypothesis that adolescent rats may be differentially sensitive to withdrawal relative to their adult counterparts, the present study was designed to compare precipitated withdrawal in adolescent and adult rats following chronic nicotine administration. Adult and adolescent rats were prepared with subcutaneous osmotic minipumps that delivered either saline or nicotine (9 mg/kg per day, salt; N =12 per group). All rats were challenged with the nicotinic receptor antagonist mecamylamine (1.5 mg/kg) on day 7 of chronic nicotine treatment. Twenty minutes after the injection, overt somatic signs of withdrawal (i.e., eye blinks, writhes, body shakes, teeth chatter, gasps, and ptosis) were recorded for 10 min. Adult rats were observed on postnatal day 73-77, and adolescent rats were tested on postnatal day 36-40. The results revealed a robust increase in mecamylamine-induced withdrawal signs in adult rats receiving chronic nicotine relative to adult rats receiving saline. In contrast, mecamylamine did not precipitate withdrawal signs in adolescent rats receiving chronic nicotine. These results indicate that there is decreased sensitivity to the somatic aspects of nicotine withdrawal in adolescent rats that may maximize the reinforcing effects of nicotine during adolescence by minimizing the aversive effects of abstinence.

Adolescent↗
PubMed2004

The therapeutic potential of CRF1 antagonists for anxiety.

Preclinical studies suggest that the brain corticotropin-releasing factor (CRF) systems mediate anxiety-like behavioural and somatic responses through actions at the CRF1 receptor. CRF1 antagonists block the anxiogenic-like effects of CRF and stress in animal models. Cerebrospinal fluid levels of CRF are elevated in some anxiety disorders and normalise with effective treatment, further implicating CRF systems as a therapeutic target. Prototypical CRF1 antagonists are highly lipophilic, non-competitive antagonists of peptide ligands. Modification of the chemotype and the identification of novel pharmacophores are yielding more drug-like structures with increased hydrophilicity at physiological pHs. Newer compounds exhibit improved solubility, pharmacokinetic properties, potency and efficacy. Several clinical candidates have entered Phase I/II trials. However, unmet challenges await resolution during further discovery, clinical development and therapeutic application of CRF1 antagonists.

Animals↗
PubMed2003

Changes in response to a dopamine receptor antagonist in rats with escalating cocaine intake.

RATIONALE AND OBJECTIVES: Prolonged access to cocaine self-administration (long access or LgA) produces an escalation in drug intake not observed with limited access to the drug (short access or ShA). The present study tested the hypothesis that escalating use of cocaine is associated with chronic alterations in dopamine neurotransmission. METHODS: After escalation of cocaine self-administration, ShA and LgA rats were challenged with different subcutaneous doses of cis-flupenthixol (10-270 micro g/kg), a highly selective dopamine receptor antagonist. RESULTS: In both groups, increasing doses of cis-flupenthixol first produced an increase in the number of cocaine injections and then a dramatic suppression of behavior. This biphasic dose-effect function-which replicates previous findings from this laboratory-was shifted to the left in LgA rats relative to ShA rats, thereby decreasing the threshold dose at which behavior was completely suppressed. CONCLUSIONS: These data support the hypothesis that alterations in dopamine neurotransmission contribute to escalation of cocaine self-administration.

Animals↗
PubMed2003

Locomotor suppressive and anxiolytic-like effects of urocortin 3, a highly selective type 2 corticotropin-releasing factor agonist.

Murine urocortin 3 (mUcn 3), a member of the corticotropin releasing factor (CRF) peptide family, was recently identified. Of known agonists, this neuropeptide displays the highest degree of selectivity in binding to the CRF(2) receptor. These experiments sought to test the hypothesis that CRF(2) receptors have a role in modulating stress by examining intracerebroventricular (i.c.v.) administration of mUcn 3 in animal models of activation and anxiety. To investigate the effects of mUcn 3 on motor activity, rats were injected with mUcn 3 (0, 0.1, 1.0 or 10 microg, i.c.v.) 10 min prior to testing and activity was monitored for 6 h. To determine changes in novelty-induced exploration, rats were injected with mUcn 3 (0, 0.1, 1.0 or 10 microg, i.c.v.) 10 min prior to testing and examined in the elevated plus maze. Finally, delayed effects of mUcn 3 were tested in rats injected with 1.0 microg of mUcn 3 or vehicle 30 or 60 min prior to testing in the elevated plus maze. Injections of mUcn 3 significantly decreased locomotor activity in rats during the first hour of testing. In the elevated plus maze, mUcn 3 injections significantly increased open arm preference compared to vehicle when tested using a 10-min pretreatment interval. mUcn treated rats tested in the elevated plus maze following the delayed pretreatment interval did not differ from controls. These data demonstrate that injection of mUcn 3 leads to acute locomotor suppressive effects and decreases in stress-like behaviors, indicating an anxiolytic-like action for mUcn 3, and suggests a possible role of the CRF(2) receptor in the regulation of stress-related behavior.

Animals↗
PubMed2003

Effects of naltrexone alone and in combination with acamprosate on the alcohol deprivation effect in rats.

Previous research in our laboratory has shown that responding for ethanol increases after a period of imposed deprivation during which no ethanol is available (the alcohol deprivation effect). This selective increase in responding for ethanol was blocked by chronic administration of acamprosate. In the present study the effects of naltrexone and the combination of naltrexone+acamprosate on oral ethanol self-administration were examined following an imposed period of abstinence. Male Wistar rats were trained to respond for ethanol (10% w/v) or water in a two-lever free-choice condition. After training, separate groups of rats received chronic injections (2 x /day) of saline, naltrexone, or naltrexone+acamprosate during a 5-day period of abstinence. Ethanol self-administration was tested in all groups of rats on the last day of abstinence, 30 min after the last drug injection. Responding for ethanol increased significantly following the deprivation period in animals treated with saline. Chronic administration of naltrexone and the combination naltrexone+acamprosate blocked the increased ethanol consumption following the imposed abstinence period on post-deprivation Day 1. On post-deprivation Day 2, the combination of acamprosate with naltrexone blocked the rebound increase in ethanol consumption observed in animals treated with a low dose of naltrexone. These results support the hypothesis that naltrexone and acamprosate are effective in modulating aspects of alcohol-seeking behavior, and under certain situations may be more effective in combination.

Acamprosate↗
PubMed2003

Animal models of motivation for drinking in rodents with a focus on opioid receptor neuropharmacology.

Ethanol, like other drugs of abuse, has motivating properties that can be developed as animal models of self-administration. A major strength of the operant approach where an animal must work to obtain ethanol is that it reduces confounds due to palatability and controls for nonspecific malaise-inducing effects. In the domain of opioid peptide systems, limited access paradigms have good predictive validity. In addition, animal models of excessive drinking-either environmentally or genetically induced-also appear sensitive to blockade or inactivation of opioid peptide receptors. Ethanol availability can be predicted by cues associated with positive reinforcement, and these models are sensitive to the administration of opioid antagonists. Perhaps most exciting are the recent results suggesting that the key element in opioid peptide systems that is important for the positive reinforcing effects of ethanol is the mu-opioid receptor. How exactly ethanol modulates mu-receptor function will be a major challenge of future research. Nevertheless, the apparently critical role of the mu receptor in ethanol reinforcement refocuses the neuropharmacology of ethanol reinforcement in the opioid peptide domain and opens a novel avenue for exploring medications for treating alcoholism.

Alcohol Deterrents↗
PubMed2003

Neuroadaptive mechanisms of addiction: studies on the extended amygdala.

A conceptual structure for drug addiction focused on allostatic changes in reward function that lead to excessive drug intake provides a heuristic framework with which to identify the neurobiologic neuroadaptive mechanisms involved in the development of drug addiction. The brain reward system implicated in the development of addiction is comprised of key elements of a basal forebrain macrostructure termed the extended amygdala and its connections. Neuropharmacologic studies in animal models of addiction have provided evidence for the dysregulation of specific neurochemical mechanisms not only in specific brain reward circuits (opioid peptides, gamma-aminobutyric acid, glutamate and dopamine) but also recruitment of brain stress systems (corticotropin-releasing factor) that provide the negative motivational state that drives addiction, and also are localized in the extended amygdala. The changes in the reward and stress systems are hypothesized to maintain hedonic stability in an allostatic state, as opposed to a homeostatic state, and as such convey the vulnerability for development of dependence and relapse in addiction.

Adaptation, Physiological↗
PubMed2003

Neuropharmacological sequelae of persistent CNS viral infections: lessons from Borna disease virus.

Borna Disease Virus (BDV) is a neurotropic RNA virus that is worldwide in distribution, causing movement and behavior disorders in a wide range of animal species. BDV has also been reported to be associated with neuropsychiatric diseases of humans by serologic study and by recovery of nucleic acid or virus from blood or brain. Natural infections of horses and sheep produce encephalitis with erratic excited behaviors, hyperkinetic movement or gait abnormalities; naturally infected cats have ataxic "staggering disease." Experimentally infected primates develop hyperactivity, aggression, disinhibition, then apathy; prosimians (lower primates) have hyperactivity, circadian disruption, abnormal social and dominance behaviors, and postural disorders. However, the neuropharmacological determinants of BD phenotypes in laboratory and natural hosts are incompletely understood. Here we review how experimentally infected rodents have provided models for examining behavioral, pharmacologic, and biochemical responses to viral challenge, and how rodents experimentally infected as neonates or as adolescents are providing models for examining age-specific neuropharmacological adaptations to viral injury.

Animals↗
PubMed2003

Chronic opioid exposure produces increased heroin self-administration in rats.

The purpose of this study was to determine the significance of chronic opioid exposure on the level of heroin self-administration in the rat. Rats were divided into morphine (M, subcutaneous morphine pellets) and placebo (P, subcutaneous placebo pellets) groups and self-administered several different doses of heroin during daily limited access 1-h sessions and prolonged access 8-h sessions. No effects on heroin self-administration occurred when the rats were implanted with morphine pellets and allowed to self-administer heroin in a limited access paradigm (1-h group). However, rats with morphine pellet implantation showed a rapid escalation (Days 0-3 post-pellet) in heroin self-administration in the more prolonged access group (8 h group) compared to placebo-pelleted animals also with 8-h access. Ultimately, placebo-pelleted 8-h exposed animals showed an escalation in heroin self-administration but this effect was delayed until Days 16-18 post-pellet. These results suggest that passive administration of morphine sufficient to produce and maintain dependence facilitates escalation in heroin intake.

Animals↗
PubMed2003

Nibbling at CRF receptor control of feeding and gastrocolonic motility.

Inadequate pharmacological tools, until recently, hindered the understanding of the roles of corticotropin-releasing factor (CRF) receptor subtypes in appetite regulation and gastrocolonic motor function. Now, novel ligands that are selective for CRF(1) or CRF(2) receptors are helping to uncover the specific functions of CRF receptor subtypes. Central or peripheral CRF(2) receptor activation suppresses feeding independently of CRF(1) receptors. In the rat, central administration of CRF(2) receptor agonists promotes satiation without eliciting the malaise, behavioral arousal or anxiogenesis associated with CRF(1) receptor agonists. Conversely, central administration of CRF(1) receptor agonists elicits short-onset anorexia independently of CRF(2) receptor activation. With respect to gastrointestinal motor function, stress inhibits gastric motility through CRF(2) receptor-dependent central autonomic and peripheral myenteric systems. By contrast, stress stimulates colonic motility via CRF(1) receptor-dependent sacral parasympathetic and colonic myenteric mechanisms. These findings have important physiological implications and suggest targeted approaches for the pharmacotherapy of obesity and stress-related functional gastrointestinal and eating disorders.

Animals↗
PubMed2003

Antagonism of corticotropin-releasing factor attenuates the enhanced responsiveness to stress observed during protracted ethanol abstinence.

One of the most critical attributes of chronic abstinence from alcohol is a state of anxiety, which can lead to mood disturbances and negative affect that can last for months or even years in alcoholics. Within hours after their final exposure to ethanol in experimental conditions, laboratory animals also exhibit an anxiety-like state. This state is accompanied by an enhanced stress response and can persist for weeks after withdrawal. One possible mechanism underlying these behavioral changes observed weeks after withdrawal is increased corticotropin-releasing factor (CRF) activity. In the present study, we sought to examine the role of CRF in the regulation of behavior in the elevated plus-maze during protracted abstinence by using intracerebroventricular administration of the CRF receptor antagonist [D-Phe(12),Nle(21,38),CalphaMeLeu(37)]rCRF((12-41)) (D-Phe-CRF((12-41))). Rats were surgically implanted with a guide cannula aimed at the lateral ventricles and subsequently fed a nutritionally complete ethanol [10% (vol./vol.)] or control liquid diet for 21 days. Rats were further divided into groups receiving microinjections of D-Phe-CRF((12-41)) or vehicle and 15 min of restraint stress, or D-Phe-CRF((12-41)) or vehicle and no restraint. Six weeks after removal of the liquid diet, rats were injected and then placed in a restraint tube or returned to their home cages for 15 min before testing in the elevated plus-maze. Rats with a history of ethanol dependence explored the open arms of the plus-maze significantly less when exposed to restraint stress compared with findings for all other groups, an effect attenuated by pretreatment with D-Phe-CRF((12-41)). Results of the current experiment demonstrated that continuous exposure to ethanol over a 3-week period leads to an increased behavioral responsiveness to stress, which seems to be regulated by CRF.

Animals↗
PubMed2003

Neuroactive steroids: new biomarkers of cognitive aging.

Intensive studies in animals established that neuroactive steroids display neuronal actions and influence behavioral functions. We describe here investigations on the role of neuroactive steroids in learning and memory processes during aging and suggest their role as biomarkers of cognitive aging. Our work demonstrated the role of the steroid pregnenolone (PREG) sulfate as a factor underlying an individual's age-related cognitive decline in animals. As new perspectives of research we argue that knowing whether neuroactive steroids exist as endogenous neuromodulators and modulate physiologically behavioral functions is essential. To this end, a new approach using the sensitive, specific, and accurate quantitative determination of neuroactive steroids by mass spectrometry seems to have potential for examining the role of each steroid in discrete brain areas in learning and memory alterations, as observed during aging.

Aging↗
PubMed2003

Conditioned facilitation of brain reward function after repeated cocaine administration.

Cocaine lowers brain reward thresholds, reflecting increased brain reward function. The authors investigated whether, similar to acute cocaine administration, cocaine-predictive conditioned stimuli would lower intracranial self-stimulation (ICSS) thresholds. Rats received a saline injection for 5 days, a cocaine injection (10 mg/kg) for 20 consecutive days, then saline for 5 additional days. Thresholds were measured immediately before and 10 min after each injection. The initial 5 saline injections had no effect on thresholds, whereas cocaine significantly lowered thresholds for 20 days. There was no tolerance or sensitization to this effect of cocaine over days. During the last 5 days when cocaine administration was substituted with saline, rats demonstrated a conditioned lowering of thresholds during the 2nd daily ICSS session. These data demonstrate that cocaine-predictive conditioned stimuli induce a conditioned facilitation of brain reward function.

Animals↗
PubMed2003

Low dose cocaine self-administration transiently increases but high dose cocaine persistently decreases brain reward function in rats.

This study investigated the effects of self-administered cocaine on brain reward function, measured by intracranial self-stimulation (ICSS) reward thresholds in rats. Self-administration of 10 and 20 cocaine injections (0.25 mg per injection, equivalent to 4.94 +/- 0.23 and 9.88 +/- 0.46 mg/kg, self-administered over 40 +/- 6.9 and 99 +/- 11.9 min, respectively) lowered reward thresholds 15 min later, indicating a facilitation of rewarding ICSS, but had no effect at 2, 24 or 48 h after administration. Thus, self-administration of low cocaine doses did not cause persistent changes in brain reward function. Forty cocaine injections (19.64 +/- 0.94 mg/kg; self-administered over 185 +/- 10.9 min) also transiently lowered reward thresholds 15 min later, while significant threshold current elevations were observed at 2 and 24 h after administration, indicating persistent withdrawal-like reward deficits. Finally, 80 cocaine injections (39.53 +/- 1.84 mg/kg, self-administered over 376 +/- 19.9 min) significantly elevated thresholds 2 and 48 h after self-administration, but not at 24 h. Threshold currents also tended to be elevated 15 min after self-administration. Overall, these data suggest that as the amount of self-administered cocaine increases the motivation to consume further cocaine may be shifted, from obtaining the rewarding actions of cocaine to avoidance and alleviation of a cocaine-induced negative affective state.

Animals↗
PubMed2003

Escalation of cocaine self-administration does not depend on altered cocaine-induced nucleus accumbens dopamine levels.

Previous studies showed that prolonged access to cocaine or heroin self-administration (long access, or LgA) produces an escalation in drug intake not observed with limited access to the drug (short access, or ShA). The present experiment employed in vivo microdialysis to test the role of alterations in drug pharmacokinetics and/or efficacy in increasing dopamine (DA) levels in the nucleus accumbens (NAcc) during cocaine intake escalation. In experiment 1, both ShA and LgA rats were challenged with passive intravenous administration of cocaine (0.125-1 mg/injection). Regardless of the doses tested, there was no difference between groups in the ability of cocaine to increase NAcc DA levels and no group differences in the temporal profile of dialysate cocaine levels. In experiment 2, cocaine and DA concentrations were measured during cocaine self-administration. Self-administration produced sustained increases of DA in the NAcc with LgA rats maintaining greater steady levels of DA (750% of baseline) than ShA rats (400% of baseline). The difference in the LgA versus ShA rats was not due to differences in the efficacy of cocaine to elevate DA levels, or in the rate of cocaine metabolism, but was directly related to the amount of self-administered cocaine. These findings show that changes in cocaine efficacy or pharmacokinetics do not play a critical role in cocaine intake escalation.

Animals↗
PubMed2003

Acutely administered ethanol participates in testosterone synthesis and increases testosterone in rat brain.

BACKGROUND: The interaction of alcohol and testosterone has long been of interest, mainly due to the effect of alcohol on aggression and sexual behavior. To date, there have been very few, if any, studies examining the effect of acute alcohol administration on testosterone concentrations in the brain. The administration of 1,1-dideuteroethanol ([1,1-2H2]ethanol) provided the opportunity to trace the deuterium label into newly synthesized deuterotestosterone in brain samples to determine whether ethanol oxidation was directly linked to testosterone synthesis. METHODS: Unoperated and adrenalectomized-gonadectomized (ADX/GDX) rats were given either ethanol or [1,1-2H2]ethanol in a single intraperitoneal dose of 2 g/kg body weight. We used gas chromatography/mass spectrometry to accurately determine both the amount of steroids present and the degree of deuterium incorporation into specific steroids isolated from brain samples. RESULTS: Thirty minutes after alcohol administration, the level of total testosterone increased 4-fold in the frontal cortex and 3-fold in the plasma of unoperated male Wistar rats. The relative increase in the abundance of monodeuterated testosterone 30 min after [1,1-2H2]ethanol administration was significant (p < 0.05) in both brain and plasma. ADX/GDX animals treated with alcohol had testosterone concentrations that were 5% of those found in unoperated animals dosed with ethanol. CONCLUSIONS: Acutely administered ethanol increased brain concentrations of testosterone 4-fold in male Wistar rats. ADX/GDX surgery reduced brain concentrations of testosterone in response to alcohol by 95%. The deuterium labeling of testosterone after [1,1-2H2]ethanol showed that ethanol oxidation is directly linked to testosterone biosynthesis and that the deuterium-labeled testosterone is present in the central nervous system. These results demonstrate that peripherally administered ethanol directly contributes to the concentrations of testosterone in the central nervous system and that the testosterone found in brain samples is primarily synthesized in the periphery. These findings may be important for understanding the behavioral changes associated with acute alcohol consumption.

Animals↗