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G F Koob

Publications and source records attributed to G F Koob.

At least 271 records · Page 15Linked to original sources
PubMed1989

Characterization of opioid receptors in rat nucleus accumbens following mesolimbic dopaminergic lesions.

The present study investigated the cellular localization of mu, delta and kappa opioid receptors in the rat nucleus accumbens in relation to dopaminergic neurons. Dopaminergic terminals were destroyed by intra-accumbens injections of the neurotoxin 6-hydroxydopamine (6-OHDA). Fourteen days after dopaminergic denervation, receptor binding assays and quantitative in vitro autoradiography with highly selective radioligands demonstrated that the density of mu opioid receptors in the nucleus accumbens was decreased by 30 +/- 6%. There was no change in delta or kappa receptors in the accumbens, a finding which indicates that the loss of mu opioid receptors was specific. A time course study demonstrated that the loss of mu receptors lagged behind the depletion of dopamine by about 5 days. Destruction of intrinsic neuronal cell bodies and dendrites by injection of ibotenic acid into the accumbens resulted in a loss of 36 +/- 3% of mu opioid receptors. Co-injection of 6-OHDA and ibotenic acid decreased mu receptors by 41 +/- 4%, only slightly more than the loss caused by ibotenic acid alone. These results suggest that only a small number of mu opioid receptors in the nucleus accumbens are located on dopaminergic terminals and are consistent with the possibility that the loss of opioid receptors following denervation of dopaminergic fibers in the accumbens is the result of transsynaptic degeneration.

Animals↗
PubMed1989

Cocaine reinforcement and extracellular dopamine overflow in rat nucleus accumbens: an in vivo microdialysis study.

Addictive properties of cocaine have been suggested to be mediated by an interplay of depletion (craving) and re-elevation (reinforcement) of dopamine (DA) levels in limbic brain area. In this study, direct measurement of dopamine in the extracellular fluid of rats freely self-administering cocaine was evaluated using in vivo microdialysis. Acute cocaine administration was associated with enhanced accumulation of DA in the nucleus accumbens, correlated with enhanced locomotor activity. In contrast, the increased DA overflow observed in drug-naive animals was attenuated in animals self-administering cocaine who had previous regular repeated (9-day) exposure to the drug. The results suggest that the absolute amount of DA in the extracellular space is not the critical factor correlated with the self-administration behavior. Additionally, the results indicate that the reduced ability of cocaine to re-elevate DA to first-time drug use is not due to a reduction of DA in the tissue or reduced DA synthesis, but may instead be associated with alterations of release and reuptake processes.

Animals↗
PubMed1989

Microinjection of a glutamate antagonist into the nucleus accumbens reduces psychostimulant locomotion in rats.

In order to study a possible modulatory effect of glutamatergic afferents to the nucleus accumbens (NAC) on psychostimulant-induced locomotion, L-glutamic acid diethyl ester (GDEE), a glutamate antagonist, was injected in the NAC of rats acutely treated with cocaine, amphetamine or caffeine. GDEE at the doses of 5, 10, and 20 micrograms/side significantly reduced locomotion induced by cocaine (20 mg/kg, i.p.). Amphetamine-induced hyperactivity was also reduced by GDEE, whereas caffeine-induced hyperactivity was not significantly decreased by GDEE. This suggests that glutamatergic afferents to the NAC modulate the effects of psychostimulants and also dopamine function in the mesolimbic system.

Amphetamine↗
PubMed1989

Dorsal pallidum as a functional motor output of the corpus striatum.

A major function of the dopamine in the striatum is to control the activity of its efferent systems which contain primarily GABAergic neurons. Direct intracerebral injections of haloperidol into the corpus striatum impaired the performance of rats trained to depress a lever in a sensitive reaction time task. Rats were trained to depress a lever until the presentation of a visual conditioned stimulus and then to release the lever within a time limit of 500 ms to obtain a food reward. The increase in reaction time produced by dopamine blockade of the corpus striatum was mimicked by injection of a GABA agonist muscimol in nanogram quantities into the region of the dorsal pallidum, but not into the substantia nigra reticulata. Injections of a GABA agonist into the substantia nigra impaired performance by increasing the number of anticipatory responses (increased number of lever releases before the conditioned stimulus). These results suggest that the dorsal pallidum may play an important role in the response initiation associated with activation of the corpus striatum, and that the dorsal pallidum may form a significant part of parallel striatal outputs that have different functional significance.

Animals↗
PubMed1989

Nucleus accumbens as a substrate for the aversive stimulus effects of opiate withdrawal.

Previous studies from our laboratory using methylnaloxonium, a hydrophilic antagonist, showed that opiate receptors in the region of the nucleus accumbens are important for the acute reinforcing effects of heroin in non-dependent rats. A similar increased sensitivity to the response disruptive effects of intracerebrally injected methylnaloxonium in opiate dependent rats was observed in a fixed-ratio (FR) baseline of operant behaviors. These results suggest that the same opiate receptors in the region of the nucleus accumbens important for the positive reinforcing stimulus properties of opiates may also be responsible for the response disruptive, aversive stimulus properties of opiate withdrawal. These results also suggest that the neural substrates of some aspects of dependence may be partly related to those of the reinforcing effects of opiates. In particular, it is hypothesized that "euphoria" and "dysphoria" induced by opiates may reflect opponent motivational processes operating at a cellular level within the nucleus accumbens.

Animals↗
PubMed1989

MDMA produces stimulant-like conditioned locomotor activity.

Daily administration of a drug in a distinctive environment establishes contingencies that support Pavlovian conditioning. Environmental cues that are paired with the drug injection and that predict the onset of drug action can become conditioned stimuli. Ultimately, the conditioned stimuli come to predict the availability of drug and develop the potential to engender conditioned drug responses. Various psychostimulant drugs can produce conditioned locomotion when tested in the presence of environmental cues that were repeatedly associated with the drug experience. The ability of amphetamine and cocaine to produce conditioned locomotion was demonstrated in the present study. Stimulant-like properties of methylenedioxy-methamphetamine (MDMA) have been reported in locomotor paradigms, drug discrimination procedures, and human subjective questionnaires. MDMA (5 mg/kg), paired for 5 days to a distinct environment signalled by the presence of a distinct odor, produced enhanced locomotion during a test probe with the odor alone indicating that MDMA can also produce conditioned locomotion. The observation that the stimulus properties of MDMA can also become associated with environmental cues supports the hypothesis that some of the behavioral effects of MDMA resemble those of other classical psychostimulants such as amphetamine and cocaine.

3,4-Methylenedioxyamphetamine↗
PubMed1989

CCK-8 injected into the nucleus accumbens attenuates the supersensitive locomotor response to apomorphine in 6-OHDA and chronic-neuroleptic treated rats.

Postsynaptic dopamine-cholecystokinin (CCK) interactions in the nucleus accumbens were studied in two behavioral preparations of DA receptor supersensitivity: chronic-neuroleptic treated and 6-hydroxydopamine (6-OHDA) denervated rats. Subcutaneous (SC) injections of apomorphine (APO; 0.15 mg/kg) in experiment 1 produced marked hyperlocomotion in rats following 12 days of pretreatment with cis-[Z]-flupenthixol (2 mg/kg; twice per day). Bilateral intra-accumbens (N.Acc.) microinjections of CCK-8 (2 ng and 2 micrograms) reliably reduced APO-stimulated hyperlocomotion. An intermediate CCK dose (20 ng) was without effect. No change in APO responsivity following chronic vehicle treatment was observed and the baseline APO response was not altered by CCK at any dose. Denervation of mesolimbic dopamine (DA) terminals by intra-N.Acc. injections of 6-hydroxydopamine (6-OHDA; 8 micrograms/side) in experiment 2 similarly resulted in intense locomotor hyperactivity after APO stimulation (0.1 mg/kg; SC). Bilateral intra-N.Acc. injections of CCK-8 (1, 10, 100 ng, and 1 micrograms) significantly attenuated the supersensitive locomotor response to APO. As in experiment 1, CCK produced "biphasic" dose-response effects with strong attenuation that persisted throughout the entire 60-min test at both high (1 microgram) and low (1 ng) doses. Intermediate CCK doses (10 and 100 ng) produced only short-term reductions in activity. Hypomotility induced by APO in SHAM-lesioned rats was not effectively reversed by CCK treatments. CCK had no effect on unstimulated baseline locomotor activity in either 6-OHDA or SHAM-lesioned rats. These results provide further evidence that CCK-8 modulates mesolimbic DA activity by functionally opposing the postsynaptic effects of DA in the region of the nucleus accumbens.

Animals↗
PubMed1989

Low doses of corticotropin-releasing factor potentiate amphetamine-induced stereotyped behavior.

Corticotropin-releasing factor (CRF) is a 41-amino acid polypeptide that is critically involved in the activation of the hypothalamic-pituitary adrenal axis during stress. In addition, it has been suggested that extrahypothalamic CRF may be important in initiating behavioral responses to stressful events. In the present experiment, we examined the effects of central administration of CRF on amphetamine-induced stereotyped behavior. Amphetamine-induced stereotyped behavior has been considered as a behavioral strategy to cope with excessive arousal. Low doses of CRF (0.02 and 0.1 micrograms), administered into the lateral ventricle (ICV), were shown to potentiate amphetamine (4.0 mg/kg; SC)-induced stereotyped behavior, as measured by the Creese and Iversen rating scale and behavioral observations. These low doses of CRF specifically enhanced the tendency for rats to sniff with their heads down 20 min after injection, and induced licking behavior later during testing. In contrast, the rats treated with a higher dose of CRF (0.5 micrograms, ICV) showed more locomotor activity throughout the test, but did not differ from the saline-treated animals in the intensity of amphetamine-induced stereotyped behavior.

Amphetamine↗
PubMed1989

A role for the mesolimbic dopamine system in the psychostimulant actions of MDMA.

Methylenedioxymethamphetamine (MDMA) is a phenylethylamine with a chemical structure that resembles both the amphetamines and mescaline and has both stimulant and perception altering properties. The stimulant properties of MDMA were assessed in photocell cages designed to measure locomotor activity in rats. MDMA, over a range of doses (2.5-10.0 mg/kg, SC) produced locomotor hyperactivity which lasted up to 4 h. Further studies examined the role of the mesolimbic dopamine system in the hyperactivity induced by MDMA. 6-Hydroxydopamine lesions of the Nucleus accumbens attenuated the locomotor response produced by MDMA. The well characterized attenuation of the locomotor response produced by amphetamine was also demonstrated in the same rats. The present study demonstrates similarities in the stimulant properties of MDMA and amphetamine, and also suggests that as with amphetamine, the locomotor activation associated with MDMA may involve the presynaptic release of dopamine in the region of the Nucleus accumbens. However, MDMA may have a more unusual pharmacological profile because of its longer duration of action, neurotoxic potential, and differences in the qualitative aspects of its psychoactive effects.

3,4-Methylenedioxyamphetamine↗
PubMed1989

Effects of corticotropin releasing factor, desipramine and haloperidol on a DRL schedule of reinforcement.

Rats were trained on a schedule of differential-reinforcement-of-low-rate (DRL) which has been proposed to be differentially sensitive to antidepressant drugs. Desipramine and haloperidol decreased response rate and increased reinforcement rate. CRF decreased response rate and failed to change reinforcement rate. Amphetamine produced the opposite pattern of increased response rate and decreased reinforcement rate. These results question the specificity of the DRL task as a screen for antidepressants and suggest that drugs that moderately lower response rate may produce a behavioral profile on this task similar to that of tricyclic antidepressants.

Amphetamine↗
PubMed1989

Norepinephrine stimulates behavioral activation in rats following depletion of nucleus accumbens dopamine.

Intraventricular (ICV) infusion of norepinephrine (NE) produces locomotor activation in rats that is greatly potentiated by prior depletion of whole brain catecholamines by ICV injection of 6-hydroxydopamine (6OHDA). In a series of experiments, the neural substrates of this potentiated locomotor response were examined. One group of animals received ICV infusion of 6OHDA to deplete whole brain catecholamines. Other rats were pretreated with desmethylimipramine (DMI) and then received 6OHDA infusions into the nucleus accumbens (NAC) to selectively deplete dopamine (DA) from this region. One week later, all animals were tested for their locomotor response to ICV infusion of NE. Both groups of rats exhibited a greatly potentiated locomotor response to ICV NE compared to corresponding sham-lesioned animals. Both ICV and NAC 6OHDA-injected animals also exhibited a supersensitive locomotor response to the DA receptor agonist apomorphine. These results suggest that NE-induced locomotor activation in ICV 6OHDA-treated rats results from the actions of NE on supersensitive NAC DA receptors.

Animals↗
PubMed1989

Potentiation of acoustic startle by corticotropin-releasing factor (CRF) and by fear are both reversed by alpha-helical CRF (9-41).

A series of experiments were performed to investigate the effects of alpha-helical CRF [9-41] (AHCRF), a structural analogue and functional antagonist of corticotropin-releasing factor (CRF), on CRF- and fear-potentiated acoustic startle amplitude. Intracerebroventricular (ICV) administration of the CRF antagonist AHCRF reversed the potentiation of startle amplitude that was produced by ICV administration of CRF (1.0 micrograms). Doses of AHCRF that antagonized CRF-potentiated startle amplitude also reversed the potentiation of startle produced by conditioned "fear" but failed to lower startle baseline or antagonize strychnine-potentiated acoustic startle. These results suggest that CRF and "fear" may potentiate acoustic startle through overlapping neural substrates.

Acoustic Stimulation↗
PubMed1989

Neurochemical mechanisms involved in behavioral effects of amphetamines and related designer drugs.

The motor activation produced by psychomotor stimulants has been long associated with the midbrain dopamine systems. While focused stereotyped behavior produced by high doses of indirect sympathomimetics is blocked by removal of dopamine terminals in the corpus striatum (Creese and Iversen 1975), the locomotor activation produced by low doses of indirect sympathomimetics is blocked by removal of dopamine terminals in the region of the nucleus accumbens (Kelly et al. 1975). This dopaminergic substrate for psychostimulant effects appears selective for the indirect sympathomimetics in that dopamine lesions to the region of the nucleus accumbens do not block caffeine, scopolamine, heroin, or CSF-induced locomotor activation (Swerdlow and Koob 1985; Vaccarino et al. 1986). The neurochemical sites for psychomotor stimulant reward are likely to be the presynaptic dopamine terminals located in the region of the nucleus accumbens, frontal cortex, and other forebrain structures that originate in the ventral tegmental area. Note, however, that intracranial self-administration of cocaine is elicited from the frontal cortex, but not from the nucleus accumbens (Goeders and Smith 1983). Thus, concomitant activation of structures other than the nucleus accumbens may be an important part of the circuitry involved in initiation of cocaine intravenous self-administration, as has been hypothesized for the opiates (Smith and Lane 1983; Smith et al. 1982). In addition, these neuropharmacological studies provide evidence to show that, in the rat, the neural/neurochemical substrates for processing the reinforcing and stimulant properties of psychomotor stimulants may be similar, if not identical. Parallel manipulations using dopamine receptor antagonists and 6-OHDA lesions produce parallel results. How far this parallelism continues in further processing is under current investigation; however, such an overlap brings additional impetus to earlier hypotheses relating reinforcement and motor function (Glickman and Schiff 1967). The motor activation produced by MDMA and MDE has similarities to classic psychostimulants, but also some important differences. In the BPM system, the stimulant-like properties of these drugs were reflected in significant increases in horizontal locomotor activity measured across a wide dose range. Interestingly, medium to high doses of MDMA or MDE produced a transient decrease in horizontal locomotion for the first 10 minutes, followed by a sustained increase. The increase in holepokes and rearings that typically accompanies the increase in ambulation seen with amphetamine itself or other indirect sympathomimetics (Geyer et al. 1986) was not observed with MDMA or MDE.(ABSTRACT TRUNCATED AT 400 WORDS)

Amphetamines↗
PubMed1988

Aversive properties of opiate receptor blockade: evidence for exclusively central mediation in naive and morphine-dependent rats.

The motivational effects of exclusively peripheral or central opiate receptor blockade were studied using place conditioning. Place aversions were observed with intraventricular (i.c.v.) methylnaloxone (MN) in both naive (200-1000 ng) and morphine-dependent rats (50-500 ng). Subcutaneous MN (0.03-10 mg/kg) was ineffective in naive rats; in dependent rats a small aversion was seen at the highest dose. Place aversions were not necessarily associated with behavioral signs of withdrawal. The data suggest that the aversive properties of opioid receptor antagonism are centrally mediated in both naive and dependent rats, and that their enhancement in morphine-dependent subjects results from a sensitized central mechanism rather than from the recruitment of a peripheral component.

Animals↗
PubMed1988

Cellular and molecular mechanisms of drug dependence.

The molecular and cellular actions of three classes of abused drugs--opiates, psychostimulants, and ethanol--are reviewed in the context of behavioral studies of drug dependence. The immediate effects of drugs are compared to those observed after long-term exposure. A neurobiological basis for drug dependence is proposed from the linkage between the cellular and behavioral effects of these drugs.

Animals↗
PubMed1988

Septal vasopressin modulates social memory in male rats.

Adult male rats that are confronted with a sexually immature conspecific display a dramatic reduction in investigatory behavior upon re-exposure to the same juvenile when this exposure takes place 30 min after the initial exposure, but not when it is delayed by an interval of 2 h. This behavioral change may be used to measure the duration of the memory that the test animal forms of the stimulus animal. Vasopressin injected directly into the lateral septum of adult male rats at a dose of 0.1 ng facilitated this form of memory, whereas local injection of a specific hydrophilic vasopressor antagonist, desGlyNH2d(CH2)5Tyr(Me)AVP, impaired it. These findings suggest that vasopressinergic innervation of the lateral septum may be physiologically involved in the modulation of social memory in male rats.

Animals↗