Orexin/hypocretin in the paraventricular nucleus of the thalamus mediates cocaine-seeking behavior in rats

Abstract

Aims:Growing evidence implicates a role for orexin/hypocretin (Orx/Hcrt) neurons that originate in the lateral hypothalamus (LH) and project to the paraventricular nucleus of the thalamus (PVT) in drug addiction. Our working hypothesis is that cocaine-induced dysregulation of the Orx/Hcrt systemmodifies Orx/Hcrt-PVT transmission, an effect that is long-lasting. The aim of this study was to evaluate the influence of cocaine access on Orx/Hcrt-induced cocaine seeking and compare it with behavior motivated toward a highly palatable conventional reinforcer, sweetened condensed milk (SCM). Methods: One hundred fifty-six male Wistar rats were trained to self-administer short-access cocaine (ShA; 2h/day), long-access cocaine (LgA; 6h/day), or SCM (30min/day) and then subjected to daily extinction (2h/day) training. The day after, the rats received intra-PVTmicroinjections of Orx-A/Hcrt-1 (0, 0.25, 0.5, 1, and 2 ffJg) and then placed into operant chambers under extinction conditions. Results: The effects of Orx-A/Hcrt-1-induced reinstatement on cocaine seeking in the ShA groupwere characterized by an inverted U-shaped dose-effect function, with low doses but not high doses eliciting reinstatement. In contrast, Orx-A/Hcrt-1 induced reinstatement in the SCM group at high but not low doses. A leftward shift in the Orx-A/Hcrt-1 dose-effect function was observed for the reinstatement of ShA cocaine seeking compared with SCM seeking. Additionally, Orx-A/Hcrt-1-induced reinstatement in the LgA group produced a left-upward shift of the dose-response function comparedwith SCM group and an upward shift comparedwith the ShA group. Conclusions: These findings suggest that a history of cocaine dependence leads to neuroadaptive changes at the level of the PVT, resulting in “sensitization” of LH-PVT-Orx/Hcrt transmission, reflected by increased sensitivity (i.e., a leftward shift) and exacerbated behavioral responses (i.e., an upward shift) to the to the effects of Orx-A/Hcrt-1. Financial support: Supported by: NIH/NIDADA08467 (FW) and DA033344 (RMF).