Behavioral pharmacology of stress: Focus on CNS corticotropin-releasing factor.
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Animals↗
Biomedical subjects
G F Koob
Publications and source records attributed to G F Koob.
Corticotropin releasing factor and amphetamine exaggerate partial agonist properties of benzodiazepine antagonist Ro 15-1788 in the conflict test.
The central nervous system stimulants corticotropin releasing factor (CRF) and amphetamine were administered in combination with the benzodiazepine ligands Ro 15-1788 and FG 7142 in order to assess their benzodiazepine agonist and antagonist receptor properties in an operant conflict test in rats. Ro 15-1788, which was without behavioral activity in this test when given alone, reversed the suppression of punished responding produced by CRF and amphetamine in a dose-dependent manner. Chlordiazepoxide, which produced a release of punished responding by itself, also reversed the suppression of punished responding produced by CRF but not that of amphetamine. The benzodiazepine inverse agonist FG 7142, in contrast, enhanced the rate suppressing actions of both CRF and amphetamine. In a locomotor activity test, Ro 15-1788 failed to block the locomotor activation observed with CRF and amphetamine. The results suggest that "anxiety" or stress-enhancing compounds may enhance the partial agonist properties of Ro 15-1788 in certain test situations.
Amphetamine↗
The propensity for schedule-induced polydipsia is related to differences in conditioned avoidance behaviour and in defense reactions in a defeat test.
In line with previous research showing that animals predisposed to develop schedule-induced polydipsia when submitted to intermittent distribution of food show differential behavioural and neurochemical characteristics, the present experiments investigated the nature of defense reactions to aversive situations in rats that do or do not develop schedule-induced polydipsia. It was found that rats that engage in excessive drinking during intermittent feeding display more rapid active avoidance learning in a 2-way shuttle-box and show less freezing when confronted with an aggressive resident male in a defeat test than those that do not develop schedule-induced polydipsia. These results are consistent with the hypothesis that individual differences in the propensity to exhibit oral consummatory activities in conditions of mild stress are related to the ability to shift behavioural programmes in response to external stimulation.
Aggression↗
Localization of brainstem sites which mediate alfentanil-induced muscle rigidity in the rat.
Previous work has demonstrated that direct injections of methylnaloxonium (MN), a relatively lipophobic quaternary opiate antagonist, in the area of the nucleus raphe pontis (RPn) significantly attenuated alfentanil-induced rigidity. It was hypothesized that other hindbrain sites, particularly the other raphe nuclei, might play a role in this rigidity. Therefore, a study was performed in which 57 rats, divided into four groups, were implanted with chronic guide cannulae directed at brain sites anterior, lateral, or posterior to the RPn. After each animal was pretreated with intracerebral injections of MN, alfentanil (0.5 mg/kg) was administered subcutaneously. Electromyographic activity was recorded from the gastrocnemius muscle as a measure of hindlimb rigidity. Each animal was subsequently injected at 4 to 5 day intervals with MN two additional times at sites 1 and 2 mm deeper, respectively, than the initial injection. Data were thus obtained on animals treated with either MN or saline at 3 successive histologically identified sites which were either anterior, lateral or posterior to the RPn. The administration of MN into two specific sites in the region just lateral to the nucleus raphe pontis significantly [F(1,38) = 18.68 and 5.02 respectively, p less than 0.05] reversed the rigidity produced by systemic alfentanil administration. There was a weak effect of MN injections anterior to the RPn but this could not be localized to any one site. These results suggest that discrete brainstem regions involved in opiate action can be sensitively and selectively identified by direct intracranial injections of a lipophobic opiate antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)
Alfentanil↗
Methysergide potentiates the hyperactivity produced by MDMA in rats.
Although some substituted amphetamines, like MDA, produce a combination of sympathomimetic stimulation and perceptual alterations, the psychoactive qualities of MDMA are less distinctive. MDMA binds to serotonergic receptors and has been shown to potently deplete brain serotonin concentrations. Biochemical and behavioral evidence suggests that MDMA may also act on the dopamine system. The present study explored the effects of blocking serotonin receptors on MDMA and amphetamine induced locomotor hyperactivity in rats. Locomotor activity was measured in photocell cages for 120 minutes following injection of methysergide (0, 2.5, 5, 10 mg/kg) or methysergide in combination with amphetamine (0.5 mg/kg) or MDMA (10 mg/kg). Methysergide, which had no effect on its own, significantly potentiated the locomotor hyperactivity produced by MDMA but not amphetamine. Thus, the intrinsic serotonergic agonist properties of MDMA may actually counteract the indirect sympathomimetic effects thought to be responsible for the locomotor hyperactivity MDMA produces.
3,4-Methylenedioxyamphetamine↗
The effects of Ro 15-4513 on the behavioral actions of ethanol in an operant reaction time task and a conflict test.
Ro 15-4513, an analogue of the benzodiazepine receptor antagonist Ro 15-1788, has been reported to selectively block the anxiolytic and intoxicating properties of ethanol in rats. To examine the specificity and selectivity of this ethanol antagonism, the effects of Ro 15-4513 were tested on the actions of ethanol in an operant reaction time and conflict test in rats. The operant reaction time task involved holding down a lever for 0.25-2.0 seconds to obtain food, and animals treated with 1 g/kg of ethanol showed a significant disruption in performance. This disruptive effect was reversed by Ro 15-4513 in doses of 1.5-5.0 mg/kg. Ro 15-4513 was also tested in an operant conflict paradigm sensitive to alcohol effects. Ro 15-4513 (0, 1.5, 3.0, 6.0 mg/kg) produced a significant decrease in both punished and unpunished responding in the conflict test. Ethanol (0.75 g/kg), pentobarbital (5 mg/kg) and chlordiazepoxide (5 mg/kg) all produced a significant release of punished responding that was blocked by pretreatment with 6.0 mg/kg Ro 15-4513, but again Ro 15-4513 suppressed responding on its own at this dose. These results suggest that Ro 15-4513 has inverse agonist properties that may explain its ethanol-antagonist action.
Animals↗
Centrally administered hypothalamic growth hormone-releasing factor stimulates food intake in free-feeding rats.
Intracerebroventricular injections of rat hypothalamic growth hormone-releasing factor (rhGRF) were examined for effects on food intake in free-feeding rats. It was found that, in picomole doses, rhGRF had a stimulatory effect on food intake. Examination of higher doses of rhGRF revealed a decrease in the facilitatory effects and an inhibitory trend at the highest dose (4 nanomoles). The present results are consistent with previous results from our laboratory showing that central injections of rhGRF stimulate food intake in food-deprived rats.
Animals↗
The role of mesolimbic dopamine in conditioned locomotion produced by amphetamine.
Daily administration of psychomotor stimulants in a distinctive environment can impart on the environment stimulantlike properties. Rats injected with amphetamine (0.75 mg/kg, sc) daily for 5 days exhibited a robust unconditioned locomotor response, measured in photocell cages, and showed a conditioned locomotor response when treated with saline on the 6th day. This conditioned locomotor response was found to be significantly attenuated by 6-hydroxydopamine (6-OHDA) lesions of the nucleus accumbens when the lesion was made either pre- or postconditioning. Similarly, although rats with 6-OHDA lesions of the nucleus accumbens exhibited a robust supersensitive unconditioned locomotor hyperactivity in response to apomorphine (0.1 mg/kg, sc), they did not show a conditioned response on the test day. These results suggest that the mesolimbic dopamine system may be responsible for both the unconditioned and conditioned locomotor responses to psychomotor stimulant drugs. Further, conditioned locomotion depends on a critical interaction between the physiological release of presynaptic dopamine and occupation of postsynaptic receptors.
Animals↗
The functional output of the mesolimbic dopamine system.
In summary, the nucleus accumbens, located at the interface of the limbic projections from the amygdala, hippocampus, and cingulate cortex, and receiving extrapyramidal fibers from midbrain DA-containing nuclei, is well situated to form neural circuitry that mediates the behaviorally activating properties of several stimulants. Efferent GABAergic fibers projecting from the nucleus accumbens to the ventral pallidum translate integrated limbic and extrapyramidal information to lower motor circuitry; some of this information appears to be carried by ventral pallidal efferent fibers projecting to the dorsomedial nucleus of the thalamus. It seems very possible that activation of this circuitry by positive reinforcing environmental stimuli, through the release of endogenous DA or opiate compounds, might contribute to motivated behavior. Indeed, environmentally generated locomotor activity can be blocked by disruption of this circuitry following destruction of N. Acc. DA terminals. It is also tempting to speculate that pathological changes in activity within this system might disrupt normal reinforcement contingencies, and contribute to the affective components of both psychiatric and neurologic disease states.
Animals↗
Propranolol antagonizes the enhanced conditioned fear produced by corticotropin releasing factor.
A series of experiments examined the effects of systemic administration of the beta adrenergic antagonist propranolol on the enhanced conditioned fear and the locomotor hyperactivity induced by central administration of corticotropin releasing factor (CRF). In Experiment 1, CRF (0.5 microgram) was shown to reduce responding in both the conditioned stimulus (cs) and the pre-cs components of an on-the-base-line conditioned suppression schedule. The effects of CRF on cs, but not pre-cs responding were antagonized by propranolol, at doses (2.5, 5.0 and 10.0 mg/kg) that did not affect responding themselves. This reversal of the anxiogenic effects of CRF by propranolol was specific to l- and not d-propranolol, showing that it did not result from nonspecific membrane stabilization. Propranolol also failed to reverse the reduced responding induced by the benzodiazepine inverse agonist FG 7142 in this schedule. In Experiment 2, propranolol was shown to potentiate the locomotor hyperactivity induced by CRF in a familiar photocell cage. These results suggest that activation of beta adrenoceptors may be an important mechanism in the behavioral inhibition induced by CRF, and that the neurochemical mechanisms that underlie the "anxiogenic" and the "activating" behavioral effects of CRF are neuropharmacologically distinct.
Animals↗
Stimulant and hallucinogenic behavioral profiles of 3,4-methylenedioxymethamphetamine and N-ethyl-3,4-methylenedioxyamphetamine in rats.
The effects of methylenedioxymethamphetamine (0.63-10.0 mg/kg) and N-ethyl-methylenedioxyamphetamine (1.0-10.0 mg/kg) on locomotor and investigatory responses of rats were measured in the Behavioral Pattern Monitor system, a system designed to measure both the quantity and quality of behavioral activity. Horizontal locomotion was increased considerably by these compounds in a dose-related manner. This hyperactivity was accompanied by an initial decrease in investigatory holepokes and rearings followed by a subsequent increase at the highest doses tested. Rats injected with these phenylethylamine derivatives also exhibited thigmotaxis and a tendency to avoid the center of the experimental chamber, a behavioral profile similar to hallucinogen-like drugs. Consequently, a disruption of the spatial patterns of locomotion was also observed. Analyses of these patterns revealed an increasing tendency toward more stereotyped, predictable locomotor paths with increasing dose. Rats circled around the perimeter of the chamber with individual animals demonstrating a predominant though not completely consistent direction of rotation. The methylenedioxymethamphetamine-induced increase in locomotion remained significantly elevated up to 4 hr after injection at a 10 mg/kg dose, whereas other aspects of motor activity returned to base-line levels more rapidly. Thus, methylenedioxymethamphetamine and N-ethyl-methylenedioxyamphetamine seem to possess both psychomotor stimulant properties and elements of a hallucinogen-like behavioral profile.
3,4-Methylenedioxyamphetamine↗
Reinforcement pathways for cocaine.
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Animals↗
The D1 dopamine receptor antagonist SCH 23390 increases cocaine self-administration in the rat.
Rats trained to intravenously self-administer cocaine hydrochloride on a fixed ratio-5 schedule were subjected to a series of systemic injections of the D1 dopamine receptor selective antagonist SCH 23390 and the D2 dopamine receptor selective antagonist spiperone. SCH 23390 produced a dose-dependent increase in cocaine intake at doses of 5, 10 and 20 micrograms/kg, but the D2 antagonist failed to reliably increase responding except at a dose of 10 micrograms/kg. These results suggest that the D1 antagonist may be more effective at blocking mesolimbic dopamine activity, and that selective D1 receptor activation may be an important component of psychostimulant reward.
Animals↗
Behavioral activation by CRF: evidence for the involvement of the ventral forebrain.
Rats injected intracerebroventricularly with corticotropin releasing factor (CRF) at the level of the lateral ventricle or cisterna magna showed a dose-dependent increase in locomotor activity. The increase in locomotor activity from injections of CRF into the cisterna magna was blocked by a cold cream plug in the cerebral aqueduct. An identical plug failed to block the increase in locomotor activity produced by CRF injected into the lateral ventricle. Intracerebral injections of CRF produced a site specific increase in locomotor activity with the largest increases observed from CRF injected into the substantia innominata/lateral preoptic area. Results suggest that the locomotor activating effects of CRF may be due to an activation of CRF receptors in the ventral forebrain, a region rich in CRF cell bodies and projections.
Animals↗
Centrally injected arginine vasopressin (AVP) facilitates social memory in rats.
'Memory' for a juvenile conspecific in male rats can be measured by variation in duration of investigation times when the same juvenile is presented at different intervals. Typically, exposure of an adult male rat to a juvenile results in transient investigatory activity that rapidly declines with repeated exposures at short interexposure intervals (30 min). Longer interexposure intervals (120 min) result in re-investigation with durations similar or greater than the original investigation. Arginine vasopressin (AVP) injected into adult male rats intracerebroventricularly in doses of 0.5-2.0 ng immediately after investigation of the juvenile decreased social investigation of the same juvenile at the long (120 min) interexposure interval. This decrease in investigatory time was similar to that observed after a 30-min interexposure interval in untreated animals. These results support the hypothesis that increasing the availability of AVP in the central nervous system can improve the consolidation of olfactory information and improve conspecific recognition in rats.
Animals↗
Lesions of the dorsomedial nucleus of the thalamus, medial prefrontal cortex and pedunculopontine nucleus: effects on locomotor activity mediated by nucleus accumbens-ventral pallidal circuitry.
A GABAergic nucleus accumbens-ventral pallidum projection is believed to serve as the critical first-order accumbens efferent pathway underlying the behavioral expression of mesolimbic dopamine (DA) activity in the rat. In a series of experiments, we studied the effects of lesions of several ventral pallidal efferent terminal regions on the rat locomotor response to apomorphine following 6-hydroxydopamine denervation of the nucleus accumbens. Lesions of the dorsomedial nucleus of the thalamus (DMT), but not the medial prefrontal cortex or the predunculopontine nucleus, significantly depressed the 'supersensitive' locomotor response to apomorphine. Lesions of the DMT did not depress baseline locomotion, but did diminish the locomotor activation produced by intracerebral injection of the gamma-aminobutyric acid antagonist picrotoxin into the ventral pallidum. These results suggest that accumbens-pallidothalamic circuitry plays a crucial role in translating the effects of mesolimbic DA activity to lower motor circuitry responsible for locomotor behavior in the rat.
Animals↗
Modulation of social memory in male rats by neurohypophyseal peptides.
Adult male rats spend a great amount of time investigating novel juveniles. In contrast, rats re-exposed to the same juvenile 30 min after the initial exposure display little investigatory behavior. If the re-exposure occurs 2 h later, the juvenile is thoroughly investigated. These results have been interpreted to mean that rats form a transient memory for a particular juvenile. In the present study, memory was enhanced when the initial exposure to the juvenile was followed by another exposure to the same juvenile (retroactive facilitation) and impaired when exposure to the original juvenile was followed by exposure to another juvenile (retroactive interference). Arginine vasopressin had retroactive facilitating effects on social memory and these effects were blocked by the vasopressor antagonist dPTyr(Me)AVP. Moreover, the antagonist had retroactive interfering effects, since it impaired the recognition of a familiar juvenile. Oxytocin shared the same inhibitory pattern of action. These results suggest that neurohypophyseal peptides may have a prepotent role in modulating the mnemonic processing of chemosensory information associated with social interactions.
Animals↗
Rewarding properties of beta-endorphin as measured by conditioned place preference.
The role of beta-endorphin as a possible mediator in the reinforcing properties of opiates was investigated using a conditioned place preference paradigm. Heroin, a synthetic opiate known to have reinforcing properties, produced a strong preference for an environment previously paired with heroin injection at all doses tested (0.25, 0.5, 1.0, 2.0 mg/kg SC). No such place preference was observed following saline injections. Rats also showed dose-dependent place preference for the environment paired with beta-endorphin when injected intracerebroventricularly (significant dose was 2.5 micrograms). At higher doses (5.0 and 10.0 micrograms) rats showed no preference for the paired environment, but were catatonic. Pretreatment with naloxone (0.04, 0.2, 1.0 mg/kg SC) attenuated the rewarding effect of beta-endorphin (2.5 micrograms) at all doses tested. The lowest dose of naloxone which had no aversive effect when tested alone could also significantly block the positive effect of beta-endorphin. The reinforcing dose of beta-endorphin (2.5 micrograms) also produced an increase in locomotor activity, when tested in photocell cages. This suggests that the hyperactivity induced by beta-endorphin may contribute to the preference for an environment previously paired with the same drug. The reinforcing effect of beta-endorphin is most probably mediated by the mu and/or delta opioid subtype receptor, since beta-endorphin has a high affinity for these receptors. These results demonstrate positive reinforcing properties of beta-endorphin in the central nervous system.
Animals↗