Stimuli linked to ethanol availability activate hypothalamic CART and orexin neurons in a reinstatement model of relapse

Background: There has been a recent upsurge of interest in the role of hypothalamic feeding peptides, in particular, orexin (hypocretin), in drug-seeking behavior. However, the potential role of other hypothalamic feeding peptides, such as cocaine- and amphetamine-regulated transcript (CART), in conditioned reinstatement has yet to be explored. Methods: Animals were exposed to environmental stimuli previously associated with ethanol availability (EtOH S(+)), and sections from the hypothalamus and paraventricular thalamus (PVT), a recipient of CART and orexin innervation, were dual labeled for Fos-protein and either CART or orexin. Results: Significantly larger numbers of Fos-positive arcuate nucleus CART and hypothalamic orexin neurons were seen in animals exposed to the EtCH S(+) compared with nonreward S(-) animals. Presentation of the EtOH S(+) also increased numbers of Fos-positive PVT neurons. Fos-positive PVT neurons were observed to be closely associated with orexin and CART terminal fields. Conclusions: Taken together, these findings suggest that activation of hypothalamic neuropeptide systems maybe a common mechanism underlying drug-seeking behavior.