Karen E. Asin

Dopamine agonists and stress produce different patterns of Fos-like immunoreactivity in the lateral habenula

In rats treated systemically with either amphetamine, amfonelic acid or apomorphine, large numbers of cells displaying Fos-like immunoreactivity (FLI) could be seen in the lateral zone of the lateral habenula. The induction of FLI by amphetamine could be blocked either by pretreatment with haloperidol or by 6-hydroxydopamine lesions of ascending dopamine fibers at the level of the lateral hypothalamus. In contrast, a variety of stressors selectively induced FLI in the most medial portion of the lateral habenula. These findings support the concept of a functional differentiation of the medial and lateral regions of the lateral habenula and provide further evidence for involvement of the habenula in the circuitry of the basal ganglia.

Failure to establish a conditioned place preference with ethanol in rats

Previous studies have demonstrated that many drugs of abuse are able to produce a conditioned place preference in rats. We sought to determine if ethanol, injected in a wide range of doses, could also produce a conditioned place preference. Statistical analysis of our results indicated that the IP administration of the drug (50, 100, 150, 300, 600, 800, or 1000 mg/kg) failed to produce either a conditioned place preference or aversion compared to vehicle injected control rats. Under similar testing conditions a conditioned place preference was obtained with amphetamine (2 mg/kg) and this preference was not secondary to conditioned hyperactivity. In another experiment, rats were injected with ethanol through indwelling jugular cannulae at doses similar to those reported [24,26] to support (1, 2 mg/kg) or not to support (8 mg/kg) self-administration by rats. We also failed to obtain a conditioned place preference using these doses. Blood and brain ethanol levels, determined 1, 2 or 5 minutes after the administration of 2 mg/kg (IV) indicated very low ethanol levels. These results may suggest that rats do not self-administer ethanol for its intoxicating properties, and that the affective state produced by ethanol administration per se is not readily conditionable to environmental cues.

Evidence that electrolytic median raphe lesions increase locomotion but not exploration

Abstract Electrolytic lesions of the median raphe nucleus were found to increase locomotion but decrease rearing in the open field. Additionally, these lesions reduced the amount of time that rats spent sniffing at a novel object placed in the open field on their first encounter with it. In a test of exploratory behavior in a T-maze, median raphe lesions eliminated the preference for entering a novel arm displayed by sham operated animals. These results suggest that, although median raphe lesions increase locomotion, they may actually decrease exploration.

A68930: a potent agonist selective for the dopamine D1 receptor

A68930, (1R,3S)-1-aminomethyl-5,6-dihydroxy-3-phenylisochroman HCl, is a potent (EC50 = 2.5 nM), partial (intrinsic activity = 66% of dopamine) agonist in the fish retina dopamine-sensitive adenylate cyclase model of the D1 dopamine receptor. In the rat caudate-putamen model of the D1 dopamine receptor, A68930 is a potent (EC50 = 2.1 nM) full agonist. In contrast, A68930 is a much weaker (EC50 = 3920 nM) full agonist in a biochemical model of the dopamine D2 receptor. The orientation of the 3-phenyl substituent in the molecule is critical for the affinity and selectivity of the molecule towards the dopamine D1 receptor. A68930 also displays weak alpha 2-agonist activity but the molecule is virtually inactive at the alpha 1- and beta-adrenoceptors. When tested in rats bearing a unilateral 6-OHDA lesion of the nigro-neostriatal neurons, A68930 elicits prolonged (greater than 20 h) contralateral turning that is antagonized by dopamine D1 receptor selective doses of SCH 23390 but not by D2 receptor selective doses of haloperidol. In this lesioned rat model, A68930 increases 2-deoxyglucose accumulation in the lesioned substantia nigra, pars reticulata. When tested in normal rats, A68930 elicits hyperactivity and, at higher doses, produces a forelimb clonus.

The effects of electrolytic median raphe lesions on two measures of latent inhibition

This study investigates the effects of median raphe lesions on the ability of conditioned stimulus preexposure to impair the acquisition of a shuttlebox avoidance and a taste aversion task. Control rats, who were exposed to the conditioned stimulus prior to its signaling of shock, were impaired relative to nonpreexposed controls in the subsequent acquisition of a shuttlebox avoidance response. In contrast, the performance of rats with median raphe lesions was not affected by preexposure to the conditioned stimulus. Using a taste aversion paradigm, however, lesioned and control subjects showed similar fluid intakes of a flavored solution following a 7-day preexposure period prior to pairing with illness. It is suggested that the appearance of latent inhibition in median raphe-lesioned rats may depend on the saliency of the conditioned stimulus.

Straight alley acquisition and extinction and open field activity following discrete electrolytic lesions of the mesencephalic raphe nuclei.

Open field behavior and the acquisition and extinction of a food-rewarded straight alley task were examined in rats with discrete electrolytic lesions of the midbrain raphe nuclei. Increased open field activity was seen following lesions of either the median or dorsal nucleus of the raphe, although the effect of median lesions was much more pronounced. Acquisition and extinction of a runway task were impaired following lesions of the median, but not dorsal, nucleus when trials were separated by 8 min. Animals with combined lesions of the dorsal and median raphe were behaviorally indistinguishable from those subjects with median raphe lesions alone. In a second experiment, it was determined that the acquisition deficit could be eliminated by a decrease in the intertrial interval, suggesting that the original deficit was not due to a motor impairment following median raphe lesions. Although other investigators have reported raphe involvement in aversively motivated behaviors the current study provides the first demonstration that the median raphe is also involved in the performance of tasks which are appetitively motivated. Additionally, we provide the first evidence that deficits in food-rewarded behaviors similar to those seen following damage to certain limbic structures can be produced by lesions within the midbrain.

Evidence against serotonin involvement in the hyperactivity produced by injections of muscimol into the median raphe nucleus.

Microinjections of muscimol into the median raphe nucleus were found to result in pronounced hyperactivity which could not be attenuated by the serotonin depletion produced either by systemic treatment with p-chlorophenylalanine or by intra-raphe injections of 5,7-dihydroxytryptamine. Furthermore, hyperactivity could not be produced by intra-median raphe injections of serotonin or of fenfluramine, compounds which would be expected to inhibit serotonergic raphe cells. These results argue strongly against an essential involvement of serotonin in mediating the effects of intra-median raphe muscimol injections. Muscimol failed to produce hyperactivity, however, when injected into rats who had previously received an electrolytic median raphe lesion. This finding suggests that muscimol injected into the median raphe produces hyperactivity as a result of an action on local cell bodies, rather than by diffusion to a distant site. The simplest explanation of the current results is that muscimol injected into the median raphe produces hyperactivity as a result of an inhibition of nonserotonergic cells within the median raphe nucleus.

Effects of selective CCK receptor agonists on food intake after central or peripheral administration in rats.

In this paper report the effects of peripheral (intraperitoneal, i.p.) and central (intracerebroventricular, i.c.v.) injection of selective cholecystokinin (CCK) receptor agonists on food intake in the rat. Stimulation of peripheral and central CCK-A receptors by the selective CCK-A receptor agonist A-71623 suppressed intakes of a liquid diet in both deprived and sated rats. In contrast, i.c.v., but not i.p., injections of the selective CCK-B receptor agonist A-63387, reduced food intakes, although on a molar basis the effect was much less than that seen with A-71623. Although these results stress the relative importance of the CCK-A receptor in the effects of exogenous CCK-8 administration on feeding, stimulation of the CCK-B receptor may still be involved in the control of feeding following the endogenous release of CCK.

Differential effects of serotonergic and catecholaminergic drugs on ingestive behavior

The serotonergic agonists fenfluramine and fluoxetine and the catecholaminergic agonists amphetamine and phenylpropanolamine are well known to cause a reduction in intake in rats. In the studies reported here we investigated the effects of these drugs on the microstructure of licking behavior of the rat ingesting 0.4 M sucrose. The purpose was to examine the similarities in the behavioral effects within and between these two classes of anorectic agents. The serotonergic agonists fenfluramine and fluoxetine caused a reduction in intake primarily by reducing the size of bursts and clusters of licking within the test meal without affecting the duration of the meal, suggesting a reduction in the palatability of the test solution. The catecholamine agonists amphetamine and phenylpropanolamine reduced intake primarily by reducing the number of bursts and clusters without affecting their size, suggesting a fractionation in the organization of the normal pattern of ingestion. The differences between the two serotonin and the two catecholamine agonists on the microstructure of the licking behavior suggest a different effect of the two neurotransmitters on the motor system that controls ingestive behavior. The similarities between the two different agonists within each class suggests a common neurotransmitter mechanism responsible for these two different effects on the behavior of the animals.

Evidence that serotonergic projections to the substantia nigra in the rat arise in the dorsal, but not the median, raphe nucleus

Following microinjections of the fluorescent retrograde tracer Fast blue into the substantia nigra, large numbers of retrogradely labeled cells were observed in the dorsal raphe nucleus. Using immunocytochemical techniques it could be demonstrated that the majority of these cells contained serotonin-like-immunoreactivity. In contrast, careful examination of the region of the median raphe nucleus revealed no suggestion of a significant projection from the median raphe to the substantia nigra.