Mechanisms of activation of nucleus accumbens neurons by cocaine via sigma-1 receptor-inositol 1,4,5-trisphosphate-transient receptor potential canonical channel pathways

Cocaine promotes addictive behavior primarily by blocking the dopamine transporter, thus increasing dopamine transmission in the nucleus accumbens (nAcc); however, additional mechanisms are continually emerging. Sigma-1 receptors (sigma(1)Rs) are known targets for cocaine, yet the mechanisms underlying cri R-mediated effects of cocaine are incompletely understood. The present study examined direct effects of cocaine on dissociated nAcc neurons expressing phosphatidylinositol-linked D-1 receptors. Endoplasmic reticulum-located sigma(1)Rs and inositol 1,4,5-trisphosphate (IP3) receptors (IP(3)Rs) were targeted using intracellular microinjection. IP3 microinjection robustly elevated intracellular Ca2+ concentration, [Ca2+](i) While cocaine alone was devoid of an effect, the IP3-induced response was sigma R-1-dependently enhanced by cocaine co-injection. Likewise, cocaine augmented the [Ca2+](i) increase elicited by extracellularly applying an IP3-generating molecule (ATP), via cri Rs. The cocaine-induced enhancement of the IP3/ATP-mediated Ca2+ elevation occurred at pharmacologically relevant concentrations and was mediated by transient receptor potential canonical channels (TRPC). IP3 microinjection elicited a slight, transient depolarization, further converted to a greatly enhanced, prolonged response, by cocaine coinjection. The cocaine-triggered augmentation was a-IR-dependent, TRPC-mediated and contingent on [Ca2+](i) elevation. ATP-induced depolarization was similarly enhanced by cocaine. Thus, we identify a novel mechanism by which cocaine promotes activation of D-1-expressing nAcc neurons: enhancement of IP3R-mediated responses via sigma R-1 activation at the endoplasmic reticulum, resulting in augmented Ca2+ release and amplified depolarization due to subsequent stimulation of TRPC. In vivo, intra-accumbal blockade of sigma R-1 or TRPC significantly diminished cocaine-induced hyperlocomotion and locomotor sensitization, endorsing a physio-pathological significance of the pathway identified in vitro. (C) 2015 Elsevier Ltd. All rights reserved.