Administration of orexin A in the posterior paraventricular nucleus of the thalamus promotes cocaine-seeking behavior and is associated with hypothalamic activation

ABSTRACT Hypothalamic orexin (Orx) neurons that project to the paraventricular nucleus of the thalamus (PVT) have received growing interest because of their role in drug-seeking behavior. When injected in the posterior PVT (pPVT), OrxA reinstated extinguished cocaine-seeking behavior in rats that had long access (LgA) to cocaine for 6 h/day after an intermediate period of abstinence (I-Abst, 2-3 weeks). Considering the long-lasting nature of drug-seeking behavior and that the PVT sends projections to the hypothalamus, the present study examined whether ( i ) OrxA’s priming effect is preserved after a period of protracted abstinence (P-Abst, 4-5 weeks) in LgA rats and ( ii ) the neural activation pattern (i.e., Fos + and Fos + /Orx + cells) in the lateral hypothalamus (LH), dorsomedial hypothalamus (DMH), and perifornical area (PFA) following intra-pPVT OrxA administration that may explain OrxA-induced reinstatement in LgA animals. As reported previously, OrxA administration in the pPVT triggered cocaine-seeking behavior after I-Abst. With P-Abst, the priming effect of OrxA was absent. An intra-pPVT injection of OrxA produced a strong increase in neuronal activation (i.e., Fos expression) in the LH/DMH/PFA at I-Abst but not at P-Abst. The analysis of the activation (Fos + ) of Orx neurons (Orx + ) revealed an increase in Fos + /Orx + expression in the LH/DMH/PFA at I-Abst only, thus paralleling the behavioral data. These data indicate that shortly after abstinence, PVT↔LH/DMH/PFA connections are strongly recruited in animals with a history of cocaine dependence. The lack of effect at P-Abst suggests that the function of Orx receptors and connectivity of the PVT↔LH/DMH/PFA circuit undergo significant neuroadaptations following P-Abst. SIGNIFICANCE STATEMENT A better understanding of the pathophysiological changes associated with cocaine addiction is needed to develop efficient pharmacotherapies. The paraventricular nucleus of the thalamus (PVT) and orexin (Orx) transmission within the PVT have been implicated in maladaptive (compulsive) behavior that is characteristic of drug addiction. The present study shows OrxA injections in the posterior PVT reinstates cocaine-seeking behavior in animals with a history of cocaine dependence, and this effect disappears after protracted abstinence, paralleled by the neuronal activation pattern in the hypothalamus. In subjects with a history of cocaine dependence, the function of Orx receptors and connectivity of the PVT↔ LH/DMH/PFA circuit undergo significant neuroadaptations.