Biomedical subjects

G F Koob

Publications and source records attributed to G F Koob.

At least 307 records · Page 17Linked to original sources

PubMed1987

Nucleus accumbens opiate-dopamine interactions and locomotor activation in the rat: evidence for a pre-synaptic locus.

Locomotor activation produced by the indirect dopamine (DA) agonist amphetamine is reversed by the opiate-receptor antagonist naloxone. Since amphetamine-stimulated locomotion results from the release of DA within the nucleus accumbens (N.Acc.), it is possible that these effects of naloxone result either from a decrease in the pre-synaptic release of DA within the N.Acc. or from a disruption of the effects of DA at, or distal to, the post-synaptic DA receptor. In the present study, we investigated the effects of naloxone on the locomotor-activating properties of dopamine injected directly into the nucleus accumbens. Naloxone (0-2 mg/kg) had no significant effect of DA-stimulated locomotion; the lowest dose of naloxone tested (0.5 mg/kg) was shown to significantly disrupt the locomotor activation produced by amphetamine (0.5 mg/kg). In separate animals, very high doses of naloxone (5.0 mg/kg) had no significant effect on locomotor activation produced by the DA receptor agonist apomorphine in rats following 6-hydroxydopamine (6OHDA) denervation of the N.Acc. These results indicate that naloxone must disrupt amphetamine-stimulated locomotion through its action presynaptic to N.Acc. DA receptors.

Amphetamine↗

PubMed1987

Corticotropin-releasing factor antagonist blocks stress-induced fighting in rats.

Corticotropin-releasing factor (CRF) has been shown to have potent central nervous system-activating effects when administered intracerebroventricularly (i.c.v.). In the present experiment, this activating effect was exaggerated by use of a stress-motivated behavioral paradigm. Low doses of CRF (0.01 and 0.1 micrograms/rat) administered i.c.v. facilitated stress-induced fighting. More importantly, alpha-helical CRF-(9-41), a CRF antagonist, blocked stress-induced fighting produced by higher levels of stress. These results suggest that CRF in the central nervous system may have a role in mediating behavioral responses to stress.

Aggression↗

PubMed1987

Hypertonic saline mimics the effects of vasopressin on inhibitory avoidance in the rat.

Rats tested in a step-through inhibitory avoidance task were administered hypertonic saline (2 ml of 0.25. 0.5, and 1.0 M intraperitoneally) or arginine vasopressin (1.0, 2.0, and 4.0 micrograms) injected subcutaneously (sc) after the training trial where the rats received a mild footshock (0.2 mA, 3 s). Both hypertonic saline and vasopressin produced significant increases in latency to reenter 24 h later. These treatments failed to increase reentry latencies in animals that received the same procedure but no shock. The facilitation of inhibitory avoidance produced by hypertonic saline was reversed by sc administration of 25 micrograms of the vasopressor (V-1) vasopressin antagonist, dPtyr(Me)AVP. The results suggest that the endogenous release of vasopressin can be behaviorally significant in situations of acute homeostatic challenge.

Animals↗

PubMed1987

Ketanserin pretreatment reverses alfentanil-induced muscle rigidity.

Systemic pretreatment with ketanserin, a relatively specific type-2 serotonin receptor antagonist, significantly attenuated the muscle rigidity produced in rats by the potent short-acting opiate agonist alfentanil. Following placement of subcutaneous electrodes in each animal's left gastrocnemius muscle, rigidity was assessed by analyzing root-mean-square electromyographic activity. Intraperitoneal ketanserin administration at doses of 0.63 and 2.5 mg/kg prevented the alfentanil-induced increase in electromyographic activity compared with animals pretreated with saline. Chlordiazepoxide at doses up to 10 mg/kg failed to significantly influence the rigidity produced by alfentanil. Despite the absence of rigidity, animals that received ketanserin (greater than 0.31 mg/kg i.p.) followed by alfentanil were motionless, flaccid, and less responsive to external stimuli than were animals receiving alfentanil alone. Rats that received ketanserin and alfentanil exhibited less rearing and exploratory behavior at the end of the 60-min recording period than did animals that received ketanserin alone. These results, in combination with previous work, suggest that muscle rigidity, a clinically relevant side-effect of parenteral narcotic administration, may be partly mediated via serotonergic pathways. Pretreatment with type-2 serotonin antagonists may be clinically useful in attenuating opiate-induced rigidity, although further studies will be necessary to assess the interaction of possibly enhanced CNS, cardiovascular, and respiratory depression.

Adjuvants, Anesthesia↗

PubMed1987

Depletion of dopamine in the caudate nucleus but not in nucleus accumbens impairs reaction-time performance in rats.

Impairment of the dopaminergic system in the brain induced by dopamine-receptor antagonists or by specific neurotoxin terminal lesions results in motor disturbances in rats. In order to specify further the role of the different dopamine pathways in the brain on motor function, the performance of rats trained in an operant reaction-time task was examined after systemic administration of a dopamine-receptor antagonist, alpha-flupenthixol, and after specific destruction of dopamine neurons by 6-hydroxydopamine perfusion into the nucleus accumbens or caudate nucleus. Rats were trained to press a lever and release it as quickly as possible after a light-cue conditioned stimulus (CS). Reaction time was measured from the CS to the release of the lever for each trial. alpha-Flupenthixol (0.2 and 0.4 mg/kg) injected intraperitoneally impaired the reaction-time performance of the rats. While disruption of dopamine activity in the nucleus accumbens did not affect the performance of the rats, lesions of the dopamine terminals of the nigrostriatal pathway in the corpus striatum (59% decrease in posterior striatal dopamine) significantly impaired reaction-time performance. These results show that moderate decreases in dopamine function restricted to the corpus striatum can disrupt sensitive motor performance, and support the hypothesis that dopamine in the corpus striatum has a role in the initiation of complex goal-directed responses.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1987

Neural substrates of opioid tolerance and dependence.

Opiate dependence is not represented by a single neuronal substrate but probably reflects actions at multiple functional sites in the central nervous system. Classical measures of opiate dependence such as escape reactions and wet dog shakes may be elicited by neural substrates in the medial thalamus and periaqueductal gray. Our work and others suggests that the region in the nucleus accumbens and its afferent and efferent connections may be an important substrate to reinforcing properties of opiates. The nucleus accumbens is also an important substrate for the reinforcing properties of stimulant drugs. These data suggest that opiate dependence may represent functional changes not only in neural substrates responsible for physical dependence, but also in brain sites responsible for the reinforcing actions of opiates. It should be noted that there was inability in the early days when the endorphins first came to the forefront, to show correlations between changes in opiate binding and endorphin levels associated with dependence. This may be due to a failure to identify functionally significant substrates that may be implicated from what one would call the top-down approach. Perhaps the "neurohumor" that Dr. Cochin was thinking about is an opioid peptide located in brain regions high in opiate receptors and functionally sensitive to opiate antagonists. New work isolating particular loci for opiate actions may point to potential sites and neurochemical substrates for opiate dependence.

Animals↗

PubMed1986

Alcohol reverses the proconflict effect of corticotropin-releasing factor.

Alcohol has tension reducing properties in man that are reflected in a release of punished responding in a rat operant conflict test. In contrast, corticotropin releasing factor (CRF), injected centrally produces a suppression of punished and non-punished responding in the conflict test consistent with its hypothesized role in mediating behavioral responses to stress. Alcohol in a dose of 0.75 g/kg reversed the suppressive effects of 0.5 microgram CRF injected intracerebroventricularly on punished responding but augmented the suppression of unpunished responding by CRF. Results suggest that one mechanism for the tension reducing properties of acute alcohol intoxication may involve a suppression of brain CRF systems.

Animals↗

PubMed1986

"Selective" D-1 and D-2 receptor antagonists fail to differentially alter supersensitive locomotor behavior in the rat.

The dopamine receptor antagonists SCH 23390 and spiperone show highly selective in vitro affinity for D-1 and D-2 dopamine receptor subtypes, respectively. We studied the effects of these selective antagonists on the supersensitive locomotor response to apomorphine in rats following 6- hydroxydopamine (6OHDA) lesions of the nucleus accumbens (N. Acc.). Both D-1 and D-2 receptor antagonists produced dose-dependent blockade of the supersensitive locomotor response at doses that did not depress baseline locomotor activity. The behavioral properties of these D-1 and D-2 receptor antagonists were further examined using a simple step-down motor task. Both antagonists produced catalepsy as evidenced by dose-dependent increases in step- down latency. These results indicate that drugs with distinct in vitro dopamine binding affinities cannot be distinguished on the basis of their ability to inhibit supersensitive locomotor activity or simple motor tasks in rats in vivo.

Animals↗

PubMed1986

The role of the nucleus raphe pontis and the caudate nucleus in alfentanil rigidity in the rat.

Attempts to eliminate or reduce the rigidity induced with high-dose narcotic anesthesia in the operating room have been only partially successful. Previous investigations of opioid receptor sites mediating this rigidity have implicated two central regions: the nucleus raphe pontis (NRP) within the reticular formation and the caudate nucleus (CN) within the basal ganglia. The present study used systemically administered alfentanil (ALF), a potent, short-acting fentanyl analog, and intracerebrally infused methylnaloxonium (MN), a quaternary derivative of naloxone, to elucidate further the functional role of the NRP and CN in rigidity. ALF (0.5 mg/kg s.c.) produced a reliable model of rigidity, as documented by gastrocnemius electromyography. The onset of this rigidity was within 60 s of ALF administration, with a total duration of approximately 40-50 min. Intracerebroventricular (i.c.v.) injections of 2.0 or 4.0 micrograms of MN 15 min prior to ALF treatment prevented rigidity, while 0.125 or 0.5 microgram had no significant effect on rigidity. MN injected directly into the NRP at doses as low as 0.125 microgram significantly antagonized ALF-induced rigidity, while injections of MN into the caudate nucleus at doses as high as 4.0 micrograms failed to antagonize ALF-induced rigidity. These observations demonstrate that injection of MN into the NRP is at least 16-fold more effective in blocking ALF-induced rigidity than MN injected into the ventricle and, more importantly, at least 32-fold more effective than MN injected into the CN. The results suggest that the NRP may be an important site for the neural control of muscular rigidity associated with high-dose narcotic administration.

Alfentanil↗

PubMed1986

'Catatonia' produced by alfentanil is reversed by methylnaloxonium microinjections into the brain.

Alfentanil, a short-acting and powerful analgesic, when injected peripherally to rats (0.5 mg/kg) produced a catatonic state characterized by a rigid akinesia. The present study was designed to explore the neuroanatomical location of the opiate receptors mediating the alfentanil induced catatonia. The catatonic effect of alfentanil was measured using a bar test and depression of locomotor activity in rats tested in photocell cages during an active nocturnal phase of their cycle. Methylnaloxonium HCl (MN), a quaternary derivative of naloxone which does not readily cross the blood-brain barrier, injected into the lateral ventricle significantly reduced the catatonia at doses of 0.125-2.0 micrograms as measured in both the locomotor and bar test. MN perfusion of similar doses directly into the nucleus raphe pontis, but not in the caudate nucleus significantly antagonized the catatonia. These data complement results on alfentanil-induced muscular rigidity (Blasco et al., see companion paper) where EMG indices of rigidity in rats were reversed by microinjections of low doses of MN (0.125 and 0.5 microgram) in the nucleus raphe pontis, but not the caudate nucleus even at a high dose (4.0 micrograms). Together these results suggest that the region of the nucleus raphe pontis is an important neural substrate for opiate-induced muscular rigidity, and that the catatonic state produced by opiates depends on more diffuse opiate receptor activation of which one important component may be the nucleus raphe pontis.

Alfentanil↗

PubMed1986

Activating and 'anxiogenic' effects of corticotropin releasing factor are not inhibited by blockade of the pituitary-adrenal system with dexamethasone.

Central administration of corticotropin releasing factor (CRF) in rats produces pituitary-adrenal activation and a variety of "anxiogenic-like" effects. The present study was designed to explore the contribution of the peripheral pituitary-adrenocortical axis in mediating these CRF responses. Intraventricularly administered CRF produced suppression of responding in the conflict test and a marked locomotor activation. Neither behavioral effect was altered by the prior administration of dexamethasone in a dose that blocked pituitary-adrenal activation to CRF. These results support the hypothesis that behavioral effects of CRF are mediated by its action at central sites and not via an action on the pituitary-adrenocortical system.

Animals↗

PubMed1986

Corticotropin releasing factor (CRF) receptor antagonist blocks activating and 'anxiogenic' actions of CRF in the rat.

The effectiveness of a recently synthesized corticotropin releasing factor (CRF) antagonist, alpha-helical CRF9-41, in reversing the locomotor activating and proconflict effects of CRF was evaluated. The CRF receptor antagonist (50, 100 and 200 micrograms, i.c.v.) produced a dose-related attenuation of the response-suppressing effects of CRF in a conflict model of anxiety. The antagonist also effectively suppressed the marked locomotor activation produced by CRF. No discernible intrinsic effects on behavior were noted when the antagonist was administered alone. These results suggest that the behavioral effects of CRF are receptor-mediated phenomena and point to the potential usefulness of a CRF antagonist in understanding the function of endogenous CRF in mediating responses to stressful stimuli.

Animals↗

PubMed1986

The effects of FG 7142 and RO 15-1788 on the release of punished responding produced by chlordiazepoxide and ethanol in the rat.

Previous results in our laboratory have shown that both chlordiazepoxide and ethanol will release punished responding in a rat operant conflict test using incremental shock. In the present study, a benzodiazepine antagonist and a benzodiazepine inverse agonist were used to explore the neurochemical basis for this behavioral action. N-methyl-beta-carboline-3-carboxamide (FG 7142) at high doses (20 and 40 mg/kg) produced suppression of both punished and unpunished responding, and reversed the release of punished responding produced by both chlordiazepoxide and ethanol, but only at doses that produced an effect on its own. FG 7142 thus acted to oppose the actions of both ethanol and benzodiazepines but in an additive, not interactive, manner. In contrast, RO 15-1788 produced no changes when injected by itself in doses as high as 12 mg/kg and reversed chlordiazepoxide-induced but not ethanol-induced release of punished responding. RO 15-1788 also reversed the decrease in punished responding produced by FG 7142. Results suggest that ethanol does not interact directly with the benzodiazepine binding sites on the GABA/benzodiazepine ionophore complex to produce its anxiolytic action.

Animals↗

PubMed1986

Corticotropin-releasing factor potentiates acoustic startle in rats: blockade by chlordiazepoxide.

A series of experiments was performed to investigate the effects of corticotropin-releasing factor (CRF) on the amplitude of the acoustic startle response (ASR) in rats. Intracerebroventricular (ICV) administration of 1 microgram rat CRF significantly potentiated acoustic startle amplitude; these effects were reversed in a dose-dependent manner by pretreatment with the benzodiazepine chlordiazepoxide (CDP). Doses of CDP that antagonized CRF-potentiated ASR did not lower startle baseline or antagonize amphetamine- or strychnine-potentiated ASR. These results suggest that CRF has "anxiogenic" properties and may serve as a neuroendocrine modulator of stress-enhanced behaviors.

Acoustic Stimulation↗

PubMed1986

Central dopamine hyperactivity in rats mimics abnormal acoustic startle response in schizophrenics.

Schizophrenic patients show loss of the normal inhibition of the acoustic startle response (ASR) when the startle stimulus is preceded by a weak prepulse stimulus. In rats experimentally induced to have locally supersensitive dopamine receptors within forebrain dopamine terminal regions, we find a similar deficit in "prepulse inhibition" of the ASR. Our results suggest that there are intriguing parallels between the aberrant sensory gating of the ASR demonstrated by schizophrenics and that demonstrated by rats during stimulation of supersensitive brain dopamine receptors. Thus, prepulse inhibition of the ASR provides a useful paradigm for investigating the bridge between mesolimbic dopamine overactivity and the specific time-dependent information processing-sensory gating disturbances that have been identified in schizophrenic patients.

Acoustic Stimulation↗

PubMed1986

Supersensitive endocrine response to physostigmine in dopamine-depleted rats: a model of depression?

Depressed patients exhibit an abnormal "supersensitive" increase in the plasma concentration of several pituitary hormones following intravenous injection of the acetyl cholinesterase inhibitor physostigmine (PHY). In the present study, we examined the effects of PHY treatments on the plasma concentrations of prolactin (PRL) and adrenocorticotrophic hormone (ACTH) in the rat. Physostigmine (0-0.6 mg/kg, s.c.) produced a dose-dependent increase in PRL and ACTH immunoreactivity in unoperated animals. Neurotoxin-induced depletion of brain dopamine (DA) or norepinephrine (NE) did not significantly alter baseline plasma PRL or ACTH values. Following depletion of brain DA, but not NE, animals exhibited a "supersensitive" increase in plasma ACTH values, which was evidenced by a sixfold left shift in the dose-response properties of PHY. These results suggest that there are intriguing parallels between the abnormal endocrine response to PHY demonstrated by depressed patients and that demonstrated by rats following depletion of central nervous system (CNS) DA levels.

Adrenocorticotropic Hormone↗

PubMed1986

Blockade of amphetamine but not opiate-induced locomotion following antagonism of dopamine function in the rat.

The effects of pharmacological blockade of dopamine (DA) receptors or 6-OHDA lesions of mesolimbic DA fibers on the locomotor-activating properties of systemic amphetamine (0.35 mg/kg) and heroin (0.5 mg/kg) were examined. Pharmacological blockade of DA receptors or lesions of mesolimbic DA neurons blocked amphetamine but not heroin-induced locomotion. These results show that the opiate receptors essential for opiate-induced locomotor activation are not located on mesolimbic DA neurons. It appears that DA plays a primary role in stimulant-induced locomotion, but may have only a secondary role in opiate locomotion.

Amphetamine↗

PubMed1986

The neural substrates for the motor-activating properties of psychostimulants: a review of recent findings.

Several different classes of pharmacological agents produce syndromes of behavioral activation in humans and infrahumans. While many of these agents, including direct and indirect sympathomimetics, methylxanthines, opiates and several neuropeptides have very distinct neurochemical profiles, it is not clear whether their behavioral stimulant action results from their action on a common neural substrate, or instead from their action on parallel but separate activation "circuits.' Using photocell measurements of motor activity in rats, it has been possible to demonstrate that some agents with very distinct neurochemical identities act on common neural substrates to produce behavioral activation, while other agents act on completely distinct brain regions. Specifically, the locomotor-activating properties of direct and indirect sympathomimetics and opiates appear to result from their action within the basal ganglia, including the ventral striatum and globus pallidus, while the activating properties of caffeine and the neuropeptide, corticotropin releasing factor (CRF) appear to be independent of this circuitry. These findings suggest the presence of at least two separate neural systems capable of mediating behavioral activation.

Animals↗