Differential response of arcuate proopiomelanocortin- and neuropeptide Y-containing neurons to the lesion produced by gold thioglucose administration.

The effect of gold thioglucose (GTG) administration on neurons containing feeding-related peptides in the hypothalamic arcuate nucleus was examined in mice. Intraperitoneal GTG injection increased the body weight and produced a hypothalamic lesion that extended from the ventral part of the ventromedial nucleus to the dorsal part of the arcuate nucleus. Neurons containing proopiomelanocortin (POMC) and neuropeptide Y (NPY) present in the dorsal part of the arcuate nucleus were destroyed by GTG. In addition, the peptide-containing fibers that extended from the remaining arcuate neurons were degenerated at the lesion site. The number of POMC-containing fibers in the paraventricular nucleus, dorsomedial nucleus, and lateral hypothalamus was found to have decreased significantly when examined at 2 days and 2 weeks after the GTG treatment. In contrast, the number of NPY-containing fibers in the lateral hypothalamus remained unchanged after the GTG treatment, probably because of the presence of an unaffected NPY-containing fiber pathway passing through the tuberal region and projecting onto the lateral hypothalamus. The number of NPY-immunoreactive fibers in the paraventricular and dorsomedial nuclei showed a moderate but significant decrease at 2 days after the GTG treatment, but it recovered to the normal levels 2 weeks later. The NPY-containing fibers were found to have regenerated across the lesion site 2 weeks later, and this might contribute to the recovery of the NPY-immunoreactive fibers in these regions. The present results first demonstrate that POMC- and NPY-containing neurons in the arcuate nucleus respond differently to the lesion produced by the GTG treatment.

Immunolesions of glucoresponsive projections to the arcuate nucleus alter glucoprivic-induced alterations in food intake, luteinizing hormone secretion, and GALP mRNA, but not sex behavior in adult male rats.

Metabolic signals such as insulin, leptin and glucose are known to alter hypothalamic function. Although insulin and leptin are known to directly alter hypothalamic areas that regulate reproduction, the mechanisms by which glucose alters reproductive function are not as clear. Catecholaminergic neurons in the A1/C1 region in the hindbrain are glucose-responsive and project to the arcuate nucleus. To determine if this pathway is involved in the regulation of sex behavior and luteinizing hormone (LH) secretion, this catecholaminergic pathway was lesioned with injections of saporin conjugated with anti-dopamine-beta-hydroxylase (DSAP) or unconjugated saporin (SAP) in adult male rats. Rats were given glucoprivic challenges and feeding and sex behavior was observed. As was expected, the DSAP-treated rats showed decreased feeding during glucoprivation (250 mg/kg 2-deoxy-D-glucose, 2DG) compared to SAP controls. Glucoprivation caused a significant reduction in sex behavior in both SAP and DSAP animals equally, compared to saline treatments (p < 0.05). At the end of the experiment, animals were given a final challenge with 2DG or saline, euthanized by decapitation and trunk blood was assayed for plasma LH levels. In situ hybridization analysis revealed that 2DG treatment caused a significant reduction in GALP mRNA in SAP controls compared to saline treatment. This reduction in GALP mRNA was prevented with DSAP treatment. In SAP animals, 2DG elicited a significant decrease in plasma LH levels (p < 0.05); this reduction in plasma LH was absent in the DSAP-treated male rats. These data indicate that the A1/C1 efferents to the ventromedial hypothalamus are involved in the glucostatic regulation of GALP mRNA, feeding behavior and LH secretion, but not sex behavior in the adult male rat.

A hypothalamic endorphinic lesion attenuates acquisition of cocaine self-administration in the rat.

The present study explores the role of beta-endorphin-producing neurons of the arcuate nucleus in the behavioral effects of cocaine (i.e. acquisition of cocaine self-administration). Eight-week-old female rats were treated with a single estradiol valerate injection that causes a progressive lesion that is specific to beta-endorphin-producing neurons throughout the arcuate nucleus. Cocaine acquisition was suppressed following estradiol valerate pretreatment, while water reinforced behavior was similar to controls. Since estradiol valerate treated rats exhibit low estrogen plasma levels, estrogen replacement was performed but cocaine self-administration acquisition remained suppressed. In addition, analysis of beta-endorphin, dopamine, and DOPAC tissue levels confirmed the specificity of the endorphinic lesion resulting from estradiol valerate treatment. The suppression of cocaine self-administration acquisition following estradiol valerate treatment provides evidence for a significant role for beta-endorphin in cocaine reward.

Orexin-A-sensitive site for energy expenditure localized in the arcuate nucleus of the hypothalamus.

Orexin-A is a unique hypothalamic neuropeptide that stimulates both food intake and energy expenditure, although orexigenic peptides usually have coordinated effects on fat storage by increasing food intake and decreasing energy expenditure. Here we investigated the site of action of orexin-A-induced thermogenesis in urethane-anesthetized rats. Microinjection of 1-10 pmol orexin-A into the arcuate nucleus (Arc) specifically increased whole-body O(2) consumption (VO(2)), an index of energy expenditure; whereas it had no effect on VO(2) when injected into the paraventricular nucleus (PVN), dorsomedial nucleus (DMH), lateral hypothalamus (LH), ventromedial nucleus (VMH) or medial preoptic nucleus (MPO) of the hypothalamus or into in the paraventricular thalamic nucleus (PVT) or pontine locus coeruleus (LC). VO(2) increased immediately after an orexin-A injection into the Arc, and this increase was accompanied by a simultaneous tachycardiac response and a gradual increase in colonic temperature (T(co)), whereas an injection of the saline vehicle into the Arc had no effect. The effective dose of orexin-A into the Arc was 10 times less than that into the cerebral ventricle to induce a similar level of response. In addition, intracerebroventricular administration of orexin-A (100 pmol) elicited a significantly smaller VO(2) response in Arc-lesioned rats than that in sham-operated control rats. These results suggest that the orexin-induced energy expenditure is mediated, at least in part, by the Arc.

Differential effects of electrolytic and chemical hypothalamic lesions on LH pulses in rats.

Electrolytic lesions of the arcuate nucleus were made in anesthetized adult castrated male rats. Luteinizing hormone (LH) pulse frequency averaged 2.4 pulses/h in controls but declined to a mean of 0.5 pulses/h in rats with bilateral damage to the arcuate nucleus. Because these lesions also damaged the median eminence, we tested the possibility that this disruption of LH secretion was due to coincidental damage to fibers of passage projecting to median eminence. Axon-sparing chemical lesions of the arcuate nucleus were made by intracranial injections of N-methyl-DL-aspartate (NMA) in anesthetized adult castrated rats. Mean LH pulse frequency was 2.3 and 2.5 pulses/h in control and NMA-injected rats, respectively. NMA injections destroyed arcuate neuronal cell bodies and produced a proliferation of glial cells within the nucleus. There was no apparent difference in the immunocytochemical staining intensity and distribution of luteinizing hormone-releasing hormone (LHRH) fibers in median eminence in rats receiving NMA or sham injections. These results suggest that the disruptive effects of electrolytic lesions of the arcuate nucleus on pulsatile LH secretion are a result of coincidental damage to LHRH neuronal projections to the median eminence and that neuronal cell bodies within the arcuate nucleus are not necessary for normal pulsatile LH secretion in male rats.