Functional interaction between OX2 and CB1 receptors in the ventral tegmental area and the nucleus accumbens in response to place preference induced by chemical stimulation of the lateral hypothalamus.

Abstract Orexinergic projections derived from the lateral hypothalamus (LH) to the ventral tegmental area (VTA) and the nucleus accumbens (NAc), play a key role in the acquisition of conditioned place preference (CPP) induced by LH stimulation. On the other hand, there are several studies which support the idea of the existence of a cross-talk between the orexinergic and cannabinoid systems. Nevertheless, the function and how both systems interact in the reward circuit remain unknown. In this study, the authors tried to clarify the role of orexin-2 receptor (OX2r) within the VTA and NAc in the development of reward-related behaviors after chemical stimulation of the LH and also find out the involvement of CB1 cannabinoid receptors in this phenomenon. Animals were implanted by two separate cannulae into the LH and VTA or NAc, unilaterally. The CPP paradigm was done; and conditioning scores were recorded. The results showed that administration of TCS OX2 29 as a selective OX2r antagonist (1, 3 and 10 nM/rat) into the VTA or NAc just 5 min before microinjection of carbachol (250 nM/0.5 μl saline), a cholinergic agonist, into the LH during the 3-day conditioning phase, could dose-dependently inhibit the development of LH stimulation-induced CPP. Furthermore, concurrent injection of ineffective doses of TCS OX2 29 and AM251, as a CB1 receptor antagonist, into the NAc could reduce conditioning scores. The findings of this study showed that the OX2 receptor has a critical role in modulating reward circuit in the VTA and NAc, when the LH was stimulated by carbachol. Moreover, we suggest the existence of an interaction between orexinergic and cannabinoid systems within the VTA and NAc in place preference induced by LH stimulation.