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Biomedical subjects

G F Koob

Publications and source records attributed to G F Koob.

At least 127 records · Page 7Linked to original sources
PubMed1997

Cocaine- but not food-seeking behavior is reinstated by stress after extinction.

Reinstatement of drug-seeking behavior after extinction constitutes a potential animal model of relapse to drug abuse. In a typical reinstatement experiment, previously drug-trained rats undergo extinction during which responding is no longer followed by drug delivery. After significant extinction is observed, rats are then exposed to an event expected to reinstate drug-seeking behavior. Using this procedure, it has been recently reported that footshock stress leads to reinstatement of drug-seeking in heroin-trained, presently drug-free rats. The purpose of the present study was to assess the generality of this effect of stress. Here we report that 15 min of intermittent footshock (0.86 mA; 0.5 s on, with a mean off period of 40 s) reinstated selectively cocaine-seeking behavior after 14 extinction sessions (rats were previously trained on a FR1 TO 20 s to obtain cocaine at a dose of 0.25 mg/infusion). In contrast, under similar experimental conditions, the same stressor did not reinstate food-seeking in food-trained rats after seven extinction sessions (rats were previously trained on a FR1 TO 20 s to obtain six food pellets). Rather, when the basal level of responding was sufficiently high, footshock stress induced a significant suppression of the instrumental performance. These data are discussed in light of several behavioral mechanisms which may explain the specificity of stress in reinstating drug-seeking behavior and not food-seeking behavior.

Animals↗
PubMed1997

Opponent process model and psychostimulant addiction.

There are many sources of reinforcement in the spectrum of cocaine dependence that contribute to the compulsive cocaine self-administration or loss of control of cocaine intake that constitutes the core of modern definitions of dependence. The development of withdrawal has long been considered an integral part of drug addiction but has lost its impact in the theorization of drug dependence because of new emphasis on the neurobiological substrates for the positive-reinforcing properties of drugs. The present treatise reviews the neurobiological substrates for the acute positive reinforcing effects of cocaine and what is beginning to be known about the neurobiological substrates of cocaine withdrawal. The concept of motivational or affective withdrawal is reintroduced, which reemphasizes opponent process theory as a model for the motivational effects of cocaine dependence. The same neural substrates hypothesized to be involved in the acute reinforcing properties of drugs (basal forebrain regions of nucleus accumbens and amygdala) are hypothesized to be altered during chronic drug treatment to produce the negative motivational states characterizing drug withdrawal. Within these brain regions, both the neurochemical system(s) on which the drug has its primary actions and other neurochemical systems may undergo adaptations to chronic presence of the drug. An understanding of the adaptations of the motivational systems of the brain accompanying cocaine dependence leads to important predictions not only about the etiology, treatment, and prevention of cocaine addiction but also about the vulnerability of these motivational systems in non-drug-induced psychopathology.

Animals↗
PubMed1997

Differences in the liability to self-administer intravenous cocaine between C57BL/6 x SJL and BALB/cByJ mice.

Application of animal models of psychostimulant abuse for experimentation in mice is becoming increasingly important for studying the contribution of genetic differences, as well as the roles of selected (targeted) genes, in specific behaviors. The purpose of this study was to investigate strain differences in cocaine self-administration behavior between C57BL/6 x SJL hybrid mice and BALB/cByJ mice. These two strains were chosen because BALB/cByJ mice have a well-developed behavioral pharmacological profile, and hybrid strains on a C57BL/6 background are commonly used for generating transgenic expressing and knockout mutant mice. C57BL/6 x SJL mice dose-dependently acquired cocaine self-administration (1.0 mg/kg/injection but not 0.25 mg/kg/injection) by responding selectively in the active nose-poke hole and maintaining stable levels of daily drug intake; they also exhibited a characteristic inverted-U-shaped cocaine dose-effect function. BALB/cByJ mice failed to acquire cocaine self-administration at either dose under the same test conditions. The strain differences observed in self-administration did not seem to be attributed to other behavioral differences because the two strains exhibited similar amounts of spontaneous nose-poking in the absence of reinforcers, and BALB/cByJ mice responded more than C57BL/6 x SJL mice in a food-reinforced nose-poke operant task. Importantly, the dose-effect function for the motor stimulating effects of cocaine (3.8-30 mg/kg intraperitoneally) suggests enhanced sensitivity but reduced efficacy of cocaine in stimulating motor activity in BALB/cByJ mice relative to the C57BL/6 x SJL hybrid mice. These results indicate that the decreased liability of BALB/cByJ mice to acquire cocaine self-administration is not the result of differences in spontaneous activity or performance, but may reflect different sensitivities to the reinforcing, or rate-disrupting, properties of cocaine. The data support an influence of genetic background in the liability to self-administer cocaine. Thus, a hypothesis is proposed that the decreased liability of BALB/cByJ mice to acquire cocaine self-administration is related to differences in brain monoamine systems linked to the high "emotionality" profile of BALB/c mice in novel or fearful situations, including perhaps cocaine administration.

Animals↗
PubMed1997

The neurobiology of drug addiction.

Animals models have begun to provide insights into the neurobiological basis of reinforcement in drug addiction. The reinforcing effects of indirect sympathomimetics such as cocaine and amphetamine appear to depend on release of dopamine in the terminal fields of the mesocorticolimbic dopamine system. The acute reinforcing effects of opiates involve not only an activation of dopamine, but also dopamine-independent elements in the terminal regions of the mesocorticolimbic dopamine system. Nicotine's reinforcing effects may involve both dopaminergic and opioid peptidergic systems. Ethanol's reinforcing effects may result from multiple neurotransmitter interactions including gamma-aminobutyric acid, glutamate, dopamine, opioid peptides, and serotonin. Subtle changes in neurochemical function and signal transduction and transcription mechanisms in sensitive neuronal elements in the extended amygdala may be mediators of chronic drug action that lead to vulnerability to relapse and may provide exciting insight into the neuroadaptations associated with drug addiction.

Animals↗
PubMed1997

Deficits in discriminated learning remain despite clearance of long-term persistent viral infection in mice.

Mice persistently infected with lymphocytic choriomeningitis virus (LCMV) exhibit impaired learning ability. In this report, we determined whether clearance of the virus was associated with restoration of behavioral function. Neonatal Balb/cByJ mice were persistently infected with LCMV and tested as adults in a nonconditional spatial discrimination task. The presence of viral proteins in neurons was confirmed immunohistochemically and infectious virus was quantified in the blood by plaque assay. LCMV-infected adult mice made more errors in a Y-maze avoidance task compared to sham-inoculated controls. After the initial behavioral analysis, infected and control mice received a dose of cytotoxic T-lymphocytes sufficient to clear virus from these mice. Following complete clearance of the virus, mice were re-tested in the behavioral task, 5 months after the original test. No reversal of the learning deficit was seen following viral clearance; mice that had been cleared of the virus and those that remained persistently infected behaved similarly. These data indicate that persistent LCMV infection of the CNS lasting up to 7 months results in discriminated learning impairments that are not reversed by subsequent anti-viral immunocytotherapy.

Aging↗
PubMed1997

The neurobiology of addiction: an overview.

Addiction can be defined in part as a compulsion to use alcohol or other drugs and the occurrence of withdrawal symptoms when long-term consumption ceases. In addition to physical symptoms related to nervous system hyperexcitability, withdrawal includes changes in mental state that may motivate renewed AOD consumption. The manifestations of addiction are associated with changes in nerve cell function by which the brain attempts to adapt to a drug's presence. These functional changes modulate a person's initial response to a drug, the establishment of long-term craving for the drug (i.e., addiction), and the persistent sense of discomfort that leads to relapse after abstinence has been achieved. Research is beginning to reveal how specific brain regions may be integrated to form neural circuits that modulate aspects of addiction.

Alcoholism↗
PubMed1997

Increased ethanol self-administration after a period of imposed ethanol deprivation in rats trained in a limited access paradigm.

A predominant feature in human alcohol abuse is the reported desire or "craving" to consume ethanol along with frequent episodes of drinking after periods of abstinence. These and other factors may be responsible for relapse to uncontrolled ethanol drinking. When relapse occurs after a period of abstinence, ethanol drinking has been shown to be temporarily increased. Two aspects of drug dependence could contribute to these increases. One may be the development of a need state; the other may involve changes in the perception of the positive reinforcing effects of ethanol when reinforcer access is limited. To investigate this phenomenon further, the present study was conducted to examine in nondependent rats the effect of forced time-off on oral ethanol self-administration in a limited access paradigm (30 min/day). Male Wistar rats were trained to respond for ethanol (10% w/v) or water in a two-lever, free-choice condition using a saccharin fading procedure. After the establishment of stable baseline responding for ethanol, various ethanol deprivation periods (3, 5, 7, 14, or 28 days) were imposed, during which no ethanol was available. Responding for ethanol increased as a function of the duration of the deprivation period when compared with baseline levels. This increase was temporary and returned to baseline levels within 2 to 3 days. Given that the shortest time-off period was 5 days and the rats showed no signs of withdrawal, this transient increase in ethanol responding does not seem to be related to the manifestation of dependence and withdrawal, and may be related to changes in ethanol's reinforcement properties. These results with rats may provide a useful tool to elucidate mechanisms underlying human alcohol seeking behavior and relapse.

Alcohol Drinking↗
PubMed1996

Microglia-passaged simian immunodeficiency virus induces neurophysiological abnormalities in monkeys.

Four rhesus macaques were inoculated intravenously with a cryopreserved stock of microglia obtained from a simian immunodeficiency virus (SIV)-infected rhesus macaque. Before infection, three of the four monkeys were trained and tested daily on a computerized neuropsychological test battery. After SIV infection, behavioral testing continued to monitor deficits associated with disease progression. Five additional age-matched, behaviorally trained monkeys served as controls. Neurophysiological testing for visual and auditory evoked responses was accomplished 37-52 weeks after infection in all monkeys. Subsequently, all four SIV-infected monkeys and one control subject were sacrificed, and samples of brain tissue were taken for pathological analysis. SIV-infected monkeys demonstrated abnormal responses in both auditory and visual evoked responses. In addition, around the time of electrophysiological recording, all three SIV-infected, behaviorally trained monkeys exhibited significant decreases in progressive-ratio performance, reflecting a reduction in reinforcer efficacy. One subject also demonstrated impairments in shifting of attentional set and motor ability at that time. Neuropathological evaluation revealed that all four SIV-infected monkeys exhibited numerous perivascular and parenchymal infiltrating T cells. These findings document that SIV causes electrophysiological, behavioral, and neuropathological sequelae similar to what has been observed in the human neuroAIDS syndrome. Our observations further validate the simian model for the investigation of the pathogenesis of AIDS dementia and for the investigation of drugs with potential therapeutic benefits.

AIDS Dementia Complex↗
PubMed1996

Prefrontal cortex dysfunction in Borna disease virus (BDV)--infected rats.

Viruses have been proposed to play a role in the pathogenesis of schizophrenia; however, the mechanisms by which infection could cause the affective, cognitive, and movement disorders of schizophrenia are not understood. The neurotropic RNA virus, Borna disease (BD) virus, linked to schizophrenia by serologic studies, causes movement and behavior disorders in a wide variety of mammalian and bird hosts. BD rats have hyperactivity and stereotyped behaviors similar to those that follow neurotoxic or electrolytic lesions in frontal cortex or its catecholamine afferents in rats. BD rats have high levels of viral nucleic acid in the prefrontal cortex (PFC), abnormal mesocortical dopamine activity (elevated levels of DOPAC in PFC), yet no alteration in specific binding of D1 or D2 receptor radioligands in PFC. Since frontal lobe dysfunction is frequently reported in schizophrenia, the BD rat model may provide insights into pathogenesis and management of this debilitating psychiatric disease.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1996

Appetite-suppressing effects of urocortin, a CRF-related neuropeptide.

The neuropeptide corticotropin-releasing factor (CRF) is well known to act on the central nervous system in ways that mimic stress and result in decreases in exploration, increases in sympathetic activity, decreases in parasympathetic outflow, and decreases in appetitive behavior. Urocortin, a neuropeptide related to CRF, binds with high affinity to the CRF2 receptor, is more potent than CRF in suppressing appetite, but is less potent than CRF in producing anxiety-like effects and activation. Doses as low as 10 nanograms injected intracerebroventricularly were effective in decreasing food intake in food-deprived and free-feeding rats. These results suggest that urocortin may be an endogenous CRF-like factor in the brain responsible for the effects of stress on appetite.

Animals↗
PubMed1996

A neural substrate of hyperactivity in borna disease: changes in brain dopamine receptors.

Rats experimentally infected with the neurotropic RNA virus, Borna disease virus, have a hyperactive movement disorder. Because locomotor activity is modulated by the nucleus accumbens (N. Acc.) dopamine (DA) system, high-affinity DA uptake, DA D1, D2, and D3 receptor binding sites were examined in N. Acc. subregions of normal and infected rats by quantitative receptor autoradiography. The N. Acc. of infected rats had decreased mazindol and D2 and D3 radioligand binding in the core and decreased D3 radioligand binding in rostral subregions. The abnormalities observed in the N. Acc. DA system of infected rats may offer insights into the potential viral pathogenesis of psychiatric conditions with a dopaminergic substrate such as schizophrenia and affective disorders.

Animals↗
PubMed1996

Ethanol self-administration restores withdrawal-associated deficiencies in accumbal dopamine and 5-hydroxytryptamine release in dependent rats.

Basal forebrain dopamine (DA) and 5-HT neurotransmission has been implicated in the mediation of the acute reinforcing actions of ethanol. Neuroadaptation theories predict that compensatory changes in neurochemical systems that are activated by alcohol acutely may underlie symptoms of withdrawal after chronic administration. To test this hypothesis, the release of DA and 5-HT was monitored by microdialysis in the nucleus accumbens of dependent male Wistar rats at the end of a 3-5 week ethanol (8.7% w/v) liquid diet regimen, during 8 hr of withdrawal, and during renewed availability of ethanol involving (1) the opportunity to operantly self-administer ethanol (10% w/v) for 60 min, followed by (2) unlimited access to the ethanol-liquid diet. Results were compared to control groups pair-fed with ethanol-free liquid diet and trained to self-administer either ethanol or water. In nondependent rats, operant ethanol self-administration increased both DA and 5-HT release in the NAC. Withdrawal from the chronic ethanol diet produced a progressive suppression in the release of these transmitters over the 8 hr withdrawal period. Self-administration of ethanol reinstated and maintained DA release at prewithdrawal levels but failed to completely restore 5-HT efflux. 5-HT levels recovered rapidly, however, within 1 hr of reexposure to ethanol liquid diet. These findings suggest that deficits in accumbal monoamine release may contribute to the negative affective consequences ethanol withdrawal and, thereby, motivate ethanol-seeking behavior in dependent subjects.

Animals↗
PubMed1996

Dopamine partial receptor agonists reduce ethanol intake in the rat.

Dopamine neurotransmission is an important neuropharmacological component of ethanol reinforcement in rodents. A recently characterized class of compounds, dopamine partial receptor agonists, appears to possess a unique pharmacological profile on dopamine neurotransmission. The aim of the present study was to test the effects of systemic administration of terguride and SDZ 208-911 (N-[(8 alpha)-2,6-dimethylergoline-8-yl]-2,2-diethylpropanamide), two prototype dopamine partial receptor agonists, in free-feeding, non-deprived rats trained to drink ethanol (10% w/v) and water in 'free-choice' limited access conditions. Both acute and chronic administration of terguride and SDZ 208-911 significantly reduced ethanol intake while water intake was not significantly affected, thus ruling out possible non-specific effects of these drugs on fluid intake. These results suggest that dopamine partial receptor agonists reduce the reinforcing properties of ethanol in the rat, an effect similar to that previously observed with cocaine. Therefore, the pharmacological profile of dopamine partial receptor agonists and their effects in animal models of dependence provide preclinical support to the hypothesis that these compounds may represent a novel pharmacological strategy for intervention in various forms of drug addiction.

Alcohol Drinking↗
PubMed1996

Intravenous heroin and ethanol self-administration by alcohol-preferring AA and alcohol-avoiding ANA rats.

The alcohol-preferring AA rats have previously been shown to drink more solution containing the opioid etonitazene than the alcohol-avoiding ANA rats. The present experiments were initiated to see whether the line difference in opioid and alcohol intake would persist if an intravenous (i.v.) route of self-administration is used. Following establishment of stable heroin responding (0.03 mg/kg per infusion), AA and ANA rats were first subjected to three within-session dose-response determinations during which they were allowed to respond for ascending heroin doses (0.0075, 0.015, 0.03, and 0.06 mg/kg per infusion) and then to one progressive-ratio schedule session. AA rats obtained more heroin infusions than ANAs during the first acquisition sessions but there were no significant differences between the lines either in their baseline heroin responding, across the ascending within-session doses, or on the progressive ratio probe. When, after additional heroin baseline sessions, ethanol (1.0 mg/kg per infusion) was substituted for heroin, AA rats initially increased their responding and showed stable rates for responding across ascending ethanol doses (2.0 and 4.0 mg/kg), whereas ANAs declined below their heroin baseline. These findings give evidence for only an initial line difference in i.v. opiate self-administration but for a sustained difference in i.v. ethanol self-administration, thus suggesting that the differential alcohol drinking of the AA and ANA rats is dependent at least partly on non-oral factors.

Animals↗
PubMed1996

Effects of dopamine agonists and antagonists on cocaine-induced operant responding for a cocaine-associated stimulus.

The present study examined the effects of receptor subtype-selective dopamine agonists and antagonists on (i) cocaine-induced responding for a cocaine-associated stimulus and (ii) on responding for food and cocaine reinforcement. Rats implanted with intravenous catheters were trained to lever-press for food or cocaine reinforcers on an FR5-FR5 multiple schedule, which was preceded by a 5-min component during which only stimuli previously associated with the primary reinforcers were available response-contingently. (i) Non-contingent delivery of cocaine at the beginning of the stimulus component significantly increased responding for the cocaine-associated stimulus, compared to responding for the food-associated cue. Changes in the dose of cocaine administered non-contingently before the stimulus component resulted in an inverted U-shaped dose-effect curve in responding for the cocaine-associated cue. In subsequent experiments, pretreatment with the dopamine D2 receptor agonist bromocriptine (4.0-16.0 mg/kg IP) attenuated the cocaine-induced increase in responding for the cocaine-associated cue. In contrast, pretreatment with low doses of SDZ 208-911, a dopamine D2 partial agonist (0.025-0.1 mg/kg SC), further potentiated the cocaine-induced response. Pretreatment with low and medium doses of the dopamine D1 and D2 receptor subtype-selective antagonists SCH 23390 (D1; 5-10 micrograms/kg SC) and raclopride (D2; 100-200 micrograms/kg SC) blocked responding for cocaine-associated cues, with SCH 23390 acting more selectively than raclopride. At higher doses (SCH 23390: 20 micrograms/kg SC; raclopride: 400 micrograms/kg SC), both drugs produced non-selective effects by inhibiting responses for the food-associated cue. (ii) Varying the dose of cocaine self-administered during the multiple schedule resulted in an inverted U-shaped dose-effect curve during the cocaine components, while the number of food pellets earned remained unchanged. Pretreatment with bromocriptine selectively reduced the number of cocaine infusions obtained. The compensatory increases in responding for cocaine typically associated with SCH 23390, raclopride or SDZ 208-911 pretreatment were also observed under the present schedule conditions, although the effect did not reach statistical significance in the case of SCH 23390 and raclopride, possibly due to methodological constraints. The results indicate that the present rat model of cocaine-seeking behavior is sensitive to pharmacological manipulations and may yield important information regarding the neurobiological mechanisms underlying conditioned and unconditioned reinforcing aspects of cocaine addiction.

Animals↗
PubMed1996

Reinforcement processes in opiate addiction: a homeostatic model.

The development of tolerance and dependence has traditionally been considered an integral aspect of the drug addiction process, and opiate dependence has been studied extensively as a model system in this regard. However, recent emphasis on the positive reinforcing properties of drugs has led to the suggestion that tolerance, dependence, and withdrawal may be of secondary or even negligible importance in motivating compulsive drug use. The current article argues for an integrated view of addiction in the form of a homeostatic neuroadaptation model which emphasizes the motivational significance of both the positive affective state produced by opiates and the negative affective state characteristic of drug withdrawal. The model is supported by evidence at both the behavioral and neural systems levels of analysis. Understanding the important distinction between somatic and affective components of opiate withdrawal is key to recognizing the factors which contribute to the motivational significance of opiate dependence and withdrawal. In addition, the critical role of conditioning processes in the maintenance of compulsive drug use and relapse after periods of abstention is discussed. Finally, it is argued that both the positive reinforcement produced by acute administration of a drug and the negative affective state produced by withdrawal are common to multiple classes of abused drugs, suggesting that an understanding of homeostatic neuroadaptation within motivational systems provides a key to the etiology, treatment and prevention of drug addiction.

Animals↗
PubMed1996

Serotonin1b receptor stimulation enhances dopamine-mediated reinforcement.

The effect of 5-HT1B receptor stimulation on dopamine-mediated reinforcement in rats was investigated using intravenous self-administration of the selective dopamine uptake inhibitor GBR-12909 on an FR5 schedule of reinforcement. Pretreatment with the 5-HT1A/1B receptor agonist CGS-12066B (1-10 mg/kg, IP) dose-dependently reduced the self-administration of GBR-12909 (83 micrograms/injection) by increasing the interval between drug injections, consistent with a enhancement of the reinforcing effects of GBR-12909. Additionally, CGS-12066B pretreatment (3 mg/kg, IP) shifted the dose-effect function for GBR-12909 self-administration to the left. Pretreatment with the selective 5-HT1A receptor agonist 8-OH-DPAT (0.03-1.0 mg/kg, SC) had no significant effect on GBR-12909 self-administration (83 micrograms/injection), indicating that the effect of CGS-12066B is not mediated by the 5-HT1A receptor. Finally, CGS-12066B pretreatment (1-10 mg/kg, IP) did not alter the self-administration of cocaine (0.03-0.5 mg/injection), suggesting that the simultaneous stimulation of multiple 5-HT receptor subtypes by the indirect 5-HT agonist properties of cocaine may mask the effect of 5-HT1B receptor stimulation on DA-mediated reinforcement.

8-Hydroxy-2-(di-n-propylamino)tetralin↗