Transcripts encoding GPCRs, heterotrimeric G-protein subunits, regulators of G-protein signaling (RGS), GPCR kinases (GRK) and adenylate cyclases (Adcy) responded differently to cocaine and withdrawal. Genes encoding GPCRs and RGSs were identified in all five clusters. Particularly striking was the prevalence of GPCRs for neuropeptides, with different receptor subtypes in different clusters (e.g., Wnt, galanin, somatostatin, and opioid receptors). The μ-opioid (Oprm1) receptor, associated with increased sensations of reward and pleasure, showed a sustained increase in expression in response to cocaine, as expected (Di Chiara and Imperato, 1988; Wee and Koob, 2010), as did the endocannabinoid (Cnr1) receptor (Adamczyk et al., 2012a; Adamczyk et al., 2012b). The σ-opioid receptor (Oprd1), also involved in positive reinforcement of drugs of abuse (Le Merrer et al., 2009), increased expression only in Withdrawal. The κ-opioid receptor (Oprk1), crucial to the negative emotional state of withdrawal (Wee and Koob, 2010), showed a sustained increase, as also observed in postmortem tissue from cocaine overdose victims (Mash and Staley, 1999). Transcripts encoding several neuropeptides were substantially down-regulated by cocaine: Pomc (proopiomelanocortin),Tac1 (tachykinin), Oxt (oxytocin) and Cartpt (CART; cocaine and amphetamine regulated peptide).
