Insights for developing pharamacological treatments for psychostimulant replapse targeting hypothalamic peptide systems

Effective pharmacotherapeutic treatment options for psychostimulant addiction are lacking, in part due to an incomplete understanding of the complex neural circuitry involved in renewed drug-seeking and relapse. The lateral hypothalamus (LH) has received renewed interest with respect to its role in addiction-related behaviours, prompted largely by the identification of a number of hypothalamic neuropeptides shown to be important mediators of reward-seeking. In particular, orexin (hypocretin) and cocaine- and amphetamine-regulated transcript (CART) have been shown to play largely opposing roles in feeding behaviour and these roles have recently been shown to extend to drug-seeking behaviour. We have previously proposed that these two peptide systems may interact with the ‘classical’ reward circuitry via the paraventricular thalamus (PVT), as this region is densely innervated by both orexin and CART –positive fibres and projects to a number of regions critical to drug-seeking. The present review provides a comprehensive overview of the current literature implicating both orexin and CART in drug-seeking and relapse behaviour and presents a revised summary of the role of the PVT in mediating the actions of these two peptides. In addition, we provide novel data demonstrating that blockade of orexin receptor 1 (OX_R1) signaling within the ventral tegmental area (VTA) alters Fos-protein expression in relapse-relevant regions, including the PVT and the nucleus accumbens shell (NacS). Further, whilst previous findings have shown that blockade of OX_R1 in the VTA prevents reinstatement of Cocaine seeking, we show here that this treatment does not affect natural reward seeking for sweetened condensed milk. In light of the reviewed body of literature, as well as the novel data presented, we discuss the considerations for future pharmacotherapies targeting the orexin and CART systems for relapse prevention.