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Biomedical subjects

G F Koob

Publications and source records attributed to G F Koob.

At least 235 records · Page 13Linked to original sources
PubMed1992

Differences in one-way active avoidance learning in mice of three inbred strains.

DBA/2J, C57BL/6J, and C3H/HeJ mice were given 10 one-way avoidance training trials per day, using an unconditioned stimulus intensity that provided equivalent motivation for learning to mice of all three strains, and were found to differ in their abilities to learn and retain the response. DBA/2J mice acquired the response in fewer days than did the mice of the other two strains, although C57BL/6J mice eventually reached a level of performance similar to that of DBA/2J mice. Both the rate of acquisition and the level at which avoidance performance stabilized were significantly lower in C3H/HeJ, than in DBA/2J or C57BL/6J, mice. In addition, DBA/2J mice showed a significantly greater task retention from one testing day to the next than did C57BL/6J or C3H/HeJ mice.

Animals↗
PubMed1992

Responding to acoustic startle during chronic ethanol intoxication and withdrawal.

Ethanol (EtOH) withdrawal is characterized by a hyperexcitable state that includes anxiety, tremor, muscle rigidity and seizures. The present three experiments examined the effects of EtOH dependence and withdrawal on the acoustic startle response, an easily quantifiable measure of behavioral reactivity to exteroceptive stimuli. Two intensities of startle stimuli, 105 and 120 dB pulses, were presented to rats during chronic EtOH exposure and during EtOH withdrawal. Prepulse inhibition, which is a sensitive measure of sensorimotor gating processes associated with filtering sensory stimulation, was also assessed during chronic EtOH exposure and withdrawal. Prepulse inhibition was induced by the presentation of a weak 80 dB acoustic stimulus 100 ms prior to a 120 dB stimulus pulse. After 14 days of EtOH liquid diet administration the magnitude of responses elicited by 105 and 120 dB startle stimuli was less in ethanol-treated subjects during continued EtOH access than in animals fed a control liquid diet. When EtOH liquid diet treatment was continued for an additional 3-day period and animals were tested 8 h after withdrawal from EtOH, withdrawn animals were more reactive to startle stimuli at both intensities than were animals maintained on the EtOH liquid diet. A time-course experiment with repeated startle testing at 4, 8, and 12 h post-EtOH exposure revealed significant increases in responding to the 105 dB startle intensity at 8 h post-EtOH exposure. The ability of animals to respond to a prepulse stimulus was not affected during chronic EtOH treatment, but was reduced during withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)

Acoustic Stimulation↗
PubMed1992

Oral ethanol self-administration in rats is reduced by the administration of dopamine and glutamate receptor antagonists into the nucleus accumbens.

The purpose of this study was to assess the role of endogenous dopamine and glutamate systems within the nucleus accumbens in modulating responses for oral ethanol reinforcements (10% w/v) in a free-choice operant task. Pretreatment with both systemic (100 micrograms/kg) and intra-nucleus accumbens microinjection of fluphenazine (2 and 4 micrograms), a dopamine receptor antagonist, significantly decreased responding for ethanol, without significantly affecting responses for water. Ethanol self-administration was also attenuated by microinjection into the nucleus accumbens of 2-amino-5-phosphopentanoic acid (AP-5, 3 and 6 micrograms), a competitive NMDA receptor antagonist. These results suggest that dopamine and glutamate neurotransmission in the nucleus accumbens may regulate ethanol self-administration and its reinforcing effects.

2-Amino-5-phosphonovalerate↗
PubMed1992

Corticotropin-releasing factor modulates dietary preference in nutritionally and physically stressed rats.

In order to evaluate the action of central nervous system Corticotropin-Releasing Factor (CRF) in the control of feeding behavior the present studies employed a dietary self-selection task sensitive both to overall appetite as well as preferential intake of familiar versus unfamiliar foods. Prior to the diet selection test, one group of nutritionally stressed animals was fed a protein deficient diet in order to increase the preference for unfamiliar foods relative to nutritionally replete subjects. Both CRF (0.05 and 0.5 micrograms ICV) and physical restraint (30 min) attenuated selectively the consumption of a novel food choice by deficient animals without affecting concurrent intake of familiar food. Further, CRF administration did not alter water intake or consumption of either diet by the replete control group suggesting that the peptide produced a stress dependent, enhanced response to novelty without a general effect on appetite. The CRF antagonist, alpha-helical CRF9-41 (1, 5 and 25 micrograms ICV), increased familiar diet consumption in nutritionally deficient subjects without affecting the self-selection pattern or replete controls. Chlordiazepoxide (5 mg/kg) also increased selectively the intake of familiar food suggesting that this action is the anxiolytic complement of the effect of stress in this paradigm. The CRF antagonist (5 and 25 micrograms) reversed the anorexia produced by CRF (0.5 micrograms) as well as that induced by restraint stress. These results favor a direct role for endogenous CRF systems in coordinating the behavioral responses to dietary stress.

Animals↗
PubMed1992

Desmethylimipramine attenuates cocaine withdrawal in rats.

Depression and anhedonia are two major symptoms of cocaine withdrawal in humans. Hence, pharmacological treatments effective in depression might also alleviate the symptoms of cocaine withdrawal. In the present study, the effects of acute and repeated administration of a tricyclic antidepressant, desmethylimipramine (DMI), were investigated in naive and cocaine-withdrawing rats. An animal model of cocaine withdrawal was used that employs the elevation in intracranial self-stimulation (ICSS) thresholds following the termination of prolonged periods of cocaine self-administration as a measure of an animal's "anhedonic" state. The influence of chronic DMI treatment on beta-adrenergic receptor binding and affinity was also correlated with the behavioral signs of cocaine withdrawal. Neither acute nor repeated DMI treatment influenced reward functions in rats that were not undergoing cocaine withdrawal. However, repeated DMI treatment significantly down-regulated beta-adrenergic receptors, and shortened the duration of the post-cocaine "anhedonia" (elevation in thresholds). Furthermore, the magnitude of the beta-adrenergic receptor down-regulation correlated significantly with the degree of effectiveness of DMI treatment in reversing the post-cocaine "anhedonia". However, chronic DMI treatment did reduce the amount of cocaine self-administered by the animals. The reversal of the post-cocaine anhedonia in this animal model of cocaine withdrawal by chronic DMI treatment demonstrates the potential usefulness of the model in identifying new pharmacotherapies for cocaine withdrawal. In addition, the results indicate that tricyclic antidepressants may be able to ameliorate some of the symptoms of cocaine withdrawal.

Analysis of Variance↗
PubMed1992

Precipitation of morphine withdrawal syndrome in rats by administration of mu-, delta- and kappa-selective opioid antagonists.

The acute effects of opioid drugs are generally hypothesized to be mediated by multiple receptors, for which three types of binding sites have been established. In order to evaluate the selective participation of each type of opioid receptor in opiate withdrawal, the opiate withdrawal syndrome, precipitated by the intraventricular acute administration of mu-, delta- and kappa-selective opioid antagonists was investigated. After implantation of the cannula into the lateral ventricle, rats were made physically dependent by subcutaneous insertion of two 75-mg pellets of morphine (base). D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) (5-5000 ng), a mu-selective opioid antagonist, naltrindole (62-2000 ng), a delta-selective antagonist or nor-binaltorphimine (nor-BNI) (600-20,000 ng), a kappa-selective antagonist, were administered 72 hr after implantation of the pellets. All three drugs elicited some signs of morphine withdrawal but they differed in both their potency and their efficacy. The most efficacious and the most potent was CTAP, eliciting 8 of the 14 withdrawal signs at doses of 5-5000 ng. Nor-BNI was less efficacious and less potent, eliciting a significant increase in 5 of the 14 withdrawal signs in a dose range of 600-20,000 ng. Naltrindole was the least potent and least efficacious of the three drugs, eliciting a significant increase of only 2 withdrawal signs after intraventricular administration of 2000 ng. In a second experiment, the withdrawal syndrome was precipitated by the combined administration of CTAP+naltrindole or CTAP+nor-BNI. The severity of withdrawal, obtained with these two combinations, was similar to that observed with CTAP alone. These results support the importance of the mu receptor in the expression of central opiate dependence and suggest a minor role for delta and kappa receptors.

Animals↗
PubMed1992

Construct validity of a self-stimulation threshold paradigm: effects of reward and performance manipulations.

A discrete-trial current-threshold intracranial self-stimulation (ICSS) paradigm has been used extensively to examine the effects of drugs on reward thresholds. However, there is little work to date validating that this specific procedure measures reward. The purpose of the present study was to establish the construct validity of this procedure by testing the procedure's ability to measure reward effects and to discriminate these reward effects from performance effects. The discrete-trial ICSS procedure provides four measures: current thresholds, response latency, extra responses and time-out responses. The effects of a performance manipulation (variations in the force required to operate the manipulandum) and of a reward manipulation (variations in the train duration of the electrical stimulation) were evaluated on the four measures. Reward effects were reflected primarily in changes in thresholds, with no effect on any of the other three measures. Conversely, performance effects were reflected primarily in changes in response latency, extra responses and time-out responses, with only a small effect on thresholds. Finally, the paradigm's potential as a useful tool in the elucidation of the neurobiological basis of reward was demonstrated by investigating the effects of two pharmacological agents, cocaine and curare, on the four measures derived from the discrete-trial current-threshold ICSS procedure. The results suggest that the discrete-trial current-threshold procedure can readily discriminate reward from performance treatments.

Animals↗
PubMed1992

Pregnane steroid alphaxalone attenuates anxiogenic behavioral effects of corticotropin releasing factor and stress.

The 3 alpha-hydroxy A-ring-reduced steroid alphaxalone was examined for its ability to block stress-induced behavioral effects. Alphaxalone (3 and 6 mg/kg, IP) significantly antagonized the response-suppressing effects of corticotropin releasing factor (CRF) (0.5 micrograms, ICV) on punished responding in a conflict paradigm. In the plus maze, alphaxalone (3 and 6 mg/kg, IP) blocked the anxiogenic behavioral effects produced by a prior ambient-temperature swim stress. These doses of alphaxalone produced no intrinsic effects on plasma ACTH levels, nor did they attenuate CRF-induced increases in plasma ACTH. These findings support the hypothesis that some pregnane steroids may be involved in the modulation of an animal's behavioral response to stress and suggest that these effects may occur independently of the hypothalamic-pituitary-adrenocortical axis.

Adrenocorticotropic Hormone↗
PubMed1992

Drugs of abuse: anatomy, pharmacology and function of reward pathways.

Drugs of abuse are very powerful reinforcers, and even in conditions of limited access (where the organism is not dependent) these drugs will motivate high rates of operant responding. This presumed hedonic property and the drugs' neuropharmacological specificity provide a means of studying the neuropharmacology and neuroanatomy of brain reward. Three major brain systems appear to be involved in drug reward--dopamine, opioid and GABA. Evidence suggests a midbrain-forebrain-extrapyramidal circuit with its focus in the nucleus accumbens. Data implicating dopamine and opioid systems in indirect sympathomimetic and opiate reward include critical elements in both the nucleus accumbens and ventral tegmental areas. Ethanol reward appears to depend on an interaction with the GABAA receptor complex but may also involve common elements such as dopamine and opioid peptides in this midbrain-forebrain-extrapyramidal circuit. These results suggest that brain reward systems have a multidetermined neuropharmacological basis that may involve some common neuroanatomical elements.

Animals↗
PubMed1992

Neural substrates of opiate withdrawal.

Drug withdrawal is an integral part of most types of dependence and, to a large extent, opiate withdrawal has been considered the prototypic, classic measure of opiate dependence. The opiate withdrawal syndrome is characterized by multiple behavioral and physiological signs such as behavioral activation, ptosis, diarrhea, 'wet dog' shakes and motivational dysfunction, which may be represented in the CNS at multiple sites. It seems that the activating effects associated with the opiate withdrawal syndrome may be mediated by the nucleus locus coeruleus. Other signs such as wet dog shakes may involve sites in the hypothalamus important for temperature regulation. Certain other signs such as diarrhea and lacrimation may be dependent on peripheral opiate receptors. The motivational aspects of opiate withdrawal as demonstrated by the aversive stimulus effects or negative reinforcing effects (e.g. disrupted lever-pressing for food and place aversions) may involve those elements of the nucleus accumbens that are known to be important for the acute reinforcing effects of opiates in nondependent rats. Evidence exists at the cellular and molecular level for both 'within-system' and 'between-system' adaptations to dependence. Elucidation of the neural networks, cellular mechanisms and molecular elements involved in opiate withdrawal may provide not only a model for our understanding of the adaptive processes associated with drug dependence but also of those associated with other chronic insults to CNS function.

Animals↗
PubMed1992

Bromocriptine reverses the elevation in intracranial self-stimulation thresholds observed in a rat model of cocaine withdrawal.

Cocaine use frequently occurs in episodic prolonged binges. Following such a cocaine binge, the user suffers from severe depression mixed with irritability, anxiety, anergia and anhedonia. These symptoms constitute the cocaine withdrawal syndrome. Since cocaine's rewarding effects are mediated by enhanced dopaminergic neurotransmission in the mesocorticolimbic system, it is possible that a long-acting dopamine agonist might block the withdrawal effects associated with the termination of a prolonged bout of cocaine self-administration. An animal model of post-cocaine anhedonia was developed using the elevation in intracranial self-stimulation (ICSS) thresholds following the termination of prolonged periods of cocaine self-administration as a measure of an animal's "anhedonic" state. In the present study, an attempt was made to reverse the postcocaine elevation in ICSS thresholds with acute administration of a dopaminergic agonist, bromocriptine. Rats were allowed to self-administer cocaine for 24 hours continuously. Four hours after the termination of the self-administration session, animals were injected with either vehicle or bromocriptine (1, 2, or 4 mg/kg, IP). Two hours later (6 hours post cocaine), the animals' self-stimulation thresholds were assessed. Confirming previous work, treatment with the vehicle following a cocaine "binge" resulted in elevated ICSS thresholds compared to predrug baseline levels or to control rats' thresholds. Bromocriptine, at doses that had no effect on ICSS thresholds in control rats, reversed the postcocaine anhedonia in a dose-related manner. These results indicate that bromocriptine-like drugs (pharmacological agents that enhance dopaminergic neurotransmission) may be able to ameliorate some of the effects of cocaine withdrawal on mood and motivational state. In addition, the results of the present study indicate that the proposed animal model of cocaine withdrawal could be useful in the discovery and development of new pharmacotherapies for cocaine withdrawal.

Analysis of Variance↗
PubMed1992

Increases in extracellular dopamine in the nucleus accumbens by cocaine are inversely related to basal levels: effects of acute and repeated administration.

Repeated administration of cocaine enhances several of the behavioral and neurochemical responses to subsequent cocaine injections, an effect that has been attributed, in part, to decreased somatodendritic autoreceptor sensitivity of mesocorticolimbic dopamine (DA) neurons. Such changes in autoregulation may not only modify the direct effects of cocaine on extracellular DA levels but also result in tonically increased basal DA release in the terminal areas of the mesocorticolimbic DA system. The present study was therefore designed to investigate the effects of repeated cocaine administration on basal extracellular DA concentrations in the nucleus accumbens (NAC) using in vivo microdialysis procedures in halothane-anesthetized rats. We subsequently examined the relationship between basal DA levels and the increase in extracellular DA produced by an acute injection of cocaine, and determined whether this relationship was altered by prior, repeated exposure to cocaine. Rats received one daily intraperitoneal injection of cocaine (30 mg/kg) or its vehicle (saline) for 10 consecutive days. On days 1, 3, or 7 after termination of the repeated cocaine treatment, extracellular DA levels in the NAC were determined under basal conditions and following a single intraperitoneal cocaine challenge injection (10 mg/kg) in separate groups of rats. Repeated cocaine administration produced a substantial increase in basal DA release in the NAC that was most prominent on day 1 post-cocaine (mean +/- SEM: 10.7 +/- 2.55 nM vs 3.55 +/- 0.56 nM) but was no longer apparent on day 7 post-cocaine. Higher extracellular DA levels were also observed after cocaine challenge in rats that received repeated cocaine treatments. Similar to the increase in basal release, this effect was most pronounced on day 1 post-cocaine (23.6 +/- 4.36 nM vs 12.61 +/- 1.76 nM) but did not persist through day 7 post-cocaine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Role of different brain structures in the expression of the physical morphine withdrawal syndrome.

The aim of this study was to investigate the neuroanatomical regions implicated in the expression of the physical signs of morphine withdrawal by using local intracerebral injections of methylnaloxonium in dependent rats. Guide cannulas were implanted and aimed at the lateral ventricle, nucleus accumbens, central amygdala, anterior hypothalamus, medial thalamus, periaqueductal gray matter, locus coeruleus and nucleus raphe magnus. After surgery, rats were made physically dependent by s.c. implantation of two 75-mg morphine pellets. Methylnaloxonium, a quaternary derivative of naloxone (31-1000 ng), was administered 72 hr after pellet implantation. Methylnaloxonium administered i.c.v. induced a withdrawal syndrome similar to systemic naloxone, although several signs such as diarrhea, salivation, lacrimation and rhinorrhea did not appear, suggesting possible peripheral mediation. The most sensitive site for methylnaloxonium-precipitated withdrawal was the locus coeruleus. Signs such as jumping, rearing and locomotor activity were particularly frequent after methylnaloxonium injections into the locus coeruleus. Rearing and locomotor activity were also strongly increased after methylnaloxonium administration into the periaqueductal gray matter. Wet dog shakes were mainly observed after methylnaloxonium administration into the anterior preoptic hypothalamus and nucleus raphe magnus. Injections of methylnaloxonium into the amygdala produced a weak withdrawal syndrome, and the nucleus accumbens and medial thalamus were the least sensitive structures. These results suggest that the locus coeruleus, and secondarily the periaqueductal gray matter, play an important role in the precipitation of the physical signs of opiate withdrawal, mainly in the expression of its motor component. The expression of other signs of withdrawal appear to be multisite determined.

Animals↗
PubMed1991

Anxiolytic activity of steroid anesthetic alphaxalone.

The synthetic steroid anesthetic alphaxalone (3 alpha-hydroxy-5 alpha-pregnane-11,20-dione) was studied in two behavioral paradigms known to be sensitive to anxiolytic drugs. In an elevated plus maze, alphaxalone produced an anxiolytic profile, significantly increasing the percentage of entries made into the open arms as well as the percentage of time spent on the open arms. In the conflict test, alphaxalone (6 and 8 mg/kg) produced a significant dose-dependent increase in punished responding and a decrease (8 mg/kg) in unpunished responding. The pattern of responding was similar to that observed with the benzodiazepine agonist chlordiazepoxide (2-8 mg/kg). The increase in punished responding was not altered by the benzodiazepine antagonist Ro 15-1788 and only partially blocked by the picrotoxinin receptor ligand isopropylbicyclophospate (10 and 15 micrograms/kg). The gamma-aminobutyric acid agonists picrotoxin (1 mg/kg) and bicuculline (1 mg/kg) also failed to suppress the rate-increasing effects of alphaxalone in the conflict test. Chronic administration of alphaxalone for 1 week produced no tolerance to the anxiolytic behavioral effects. In addition, no changes in pain threshold were noted with alphaxalone (8 mg/kg) in the tail-flick analgesia test. These results suggest that the pharmacologic substrates for the anxiolytic actions of alphaxalone may be independent of either the benzodiazepine or picrotoxinin binding sites of the gamma-aminobutyric acid/benzodiazepine receptor complex.

Anesthetics↗
PubMed1991

Brain sites mediating opiate-induced muscle rigidity in the rat: methylnaloxonium mapping study.

Previous work has demonstrated that direct injections of methylnaloxonium (MN), a hydrophilic quaternary opiate antagonist, in the area of the nucleus raphe pontis (RPn) significantly attenuated alfentanil-induced muscle rigidity in the rat. To extend these observations and to explore further the regions important for opiate-induced rigidity, rats were implanted with chronic guide cannulae aimed at discrete brain sites with an emphasis on the region from the periaqueductal grey (PAG) to the RPn. Each animal was pretreated by a blinded observer with an intracerebral injection of MN (125 ng total dose) or saline, and electromyographic (EMG) activity was recorded from the gastrocnemius muscle. Alfentanil (ALF; 500 micrograms/kg) was then administered subcutaneously and the magnitude of tonic EMG activity was assessed as a measure of hindlimb rigidity. The administration of MN into the pontine raphe nucleus (RPn) and also into the more lateral nucleus reticularis tegmenti pontis significantly attenuated ALF rigidity compared with saline-pretreated controls. Within the midbrain, MN selectively reversed rigidity when injected into the periaqueductal grey (PAG). The dorsal PAG appeared to be a more important site than the ventral PAG. There was no significant effect on ALF rigidity of MN injections into brain regions between the ventral PAG and the RPn while MN injections into the deep layers of the superior colliculus, lateral to the dorsal PAG, partially attenuated ALF rigidity. In contrast, rigidity was not consistently reversed after MN injections into the basal ganglia, the dorsal superior colliculus, or the region of the decussation of the dorsal tegmentum. This study provides strong evidence that nuclei of the reticular formation, specifically the PAG, raphe pontis, and reticularis tegmenti pontis that are known to play a role in other opioid-mediated behaviors, are important in opiate-induced muscle rigidity in the rat. These results could have implications for the prevention of this undesirable effect of high-dose opiate administration.

Alfentanil↗
PubMed1991

Methylnaloxonium diffuses out of the rat brain more slowly than naloxone after direct intracerebral injection.

The value of intracerebral injections as a means of relating brain structure and function is dependent on the degree of site specificity of the injection. The purpose of this study was to compare the distribution over time of naloxone and its quaternary derivative, methylnaloxonium, after intracerebral microinjection. One microliter of tritiated naloxone (NAL) or methylnaloxonium (MN 10.0 ng, 12.8 nCi for both drugs) was infused directly into the n. raphe pontis. Each animal was then decapitated at a specific time (2.5, 5.0, 15, 30, or 60 min), the brain was removed and dissected into hindbrain, cerebellum, midbrain and cortex. Tritium beta emissions of brain homogenates were measured 1 day later, MN remained better localized to the injection site than did the same volume of the more lipophilic NAL. Within 15 minutes, less than 5% of the NAL remained in the hindbrain compared with nearly 40% of the MN. These results that MN may be a better probe than NAL for investigating the relationship of opioid receptor anatomy and function, particularly for dependent variables requiring sustained time courses.

Animals↗