No abstract

Although orexin-A peptide was recently found to inhibit the brain reward system, the exact neural substrates for this phenomenon remain unclear. The aim of the present study was to investigate the role of orexin neurons in intra-cranial self-stimulation behavior and to clarify the pathways through which orexin-A inhibits the brain reward system. Immunohistochemical examination using Fos, a neuronal activation marker, revealed that the percentage of activated orexin cells was very low in the lateral hypothalamus even in the hemisphere ipsilateral to self-stimulation, suggesting that orexin neurons play only a small part, if any, in performing intra-cranial self-stimulation behavior. Intra-ventral tegmental area administration of orexin-A (1.0 nmol) significantly increased the intra-cranial self-stimulation threshold. Furthermore, the threshold-increasing effects of intra-ventral tegmental area or intracerebroventricular orexin-A were inhibited by administration of the nonspecific corticotropin-releasing factor receptor antagonist, d-Phe-CRF(12-41) (20 μg). Following intra-ventral tegmental area infusion of orexin-A, the percentage of cells double-labeled with corticotropin-releasing factor and Fos antibodies increased in the central nucleus of the amygdala but not in the bed nucleus of the stria terminalis, and brain microdialysis analyses indicated that dopamine efflux in both the central nucleus of the amygdala and bed nucleus of the stria terminalis were enhanced. Taken together, the present findings suggest that intra-ventral tegmental area or intracerebroventricular administration of orexin-A exerts its threshold-increasing effect via subsequent activation of the corticotropin-releasing factor system.

No abstract

No abstract

Fos immunostaining was used as a marker of neuronal activity following intracranial self-stimulation (ICSS) of the medial forebrain bundle (MFB) in the rat, and was combined with immunostaining for tyrosine hydroxylase (TH), serotonin (5-HT), gamma-aminobutyric acid (GABA), or NR1 (one of the glutamate N-methyl- D-aspartate receptor subunits) for purposes of neurochemical identification. ICSS induced a significant but different degree of increase in the number of Fos-immunopositive (Fos+) cells in the six brainstem monoaminergic nuclei examined, which included the ventral tegmental area (VTA), substantia nigra pars compacta (SNc), dorsal raphe nucleus (DR), median raphe nucleus (MR), locus coeruleus (LC), and A7 noradrenaline cells. Densely labelled Fos+ cells were observed in the LC following ICSS, and many of these Fos+ cells were colocalized with TH. Similarly, many of Fos+ cells in the A7 and DR/MR were colocalized with TH and 5-HT, respectively. By contrast, a smaller number of Fos+ cells was detected in the VTA and SNc following the ICSS, and in these regions the majority of Fos+ cells were not colocalized with TH. Although results among regions quantitatively differed, the ICSS induced a significant increase in the number of double-labelled cells (GABA+/Fos+ or NR1+/Fos+) in all of the VTA, DR, and LC, in which the ICSS produced an ipsilaterally weighted increase in Fos-like immunoreactivity. These results suggest that ICSS of the MFB induces differential Fos expression within monoaminergic and GABAergic neurons in brainstem monoaminergic nuclei under modulation by glutamatergic afferents.