Two are the sigma receptors

Two are the sigma receptors identified to date: the non-opioid receptor, σ1R, and σ2R, whose identity with the Progesterone Receptor Membrane Component 1 (PGRMC-1) protein is in doubt (Chu et al., 2015). Despite endogenous ligands have not been yet identified, drugs of abuse may interact with these two receptors at “physiologically” relevant concentrations. Recent studies have demonstrated that cocaine binding to σ1R regulates GPCR signaling, likely, by means of direct interaction between the σ1R and, among other, dopamine D1 (Navarro et al., 2010) (Moreno et al., 2014) and D2 (Navarro et al., 2013) and corticotropin-releasing factor CRF1 receptors (Navarro et al., 2015). Although its role as true receptor is not demonstrated, synthetic agonists and antagonists are available for σ1R. PRE-084 is considered a selective agonist due to its ability to dose-dependently dissociate σ1R from a binding immunoglobulin protein/78 kDa glucose-regulated protein (BiP/GPR-78) (Hayashi and Su, 2007). Once the agonist binds to σ1R, the receptor translocates to the plasma membrane and modulates cell responses via protein-protein-interaction events related to Phenformin pathway handling (Su et al., 2016; Wu and Bowen, 2008). Of special interest here is the regulation of GPCR functionality. σ1R not only binds cocaine but methamphetamine and, therefore, drugs of abuse use σ1R to mediate some of their effects (Lever et al., 2016; Nguyen et al., 2005; Shull, 2002; Skuza, 1999). Drugs impeding the interaction of cocaine with σ1R are proposed to reduce drug-seeking behavior (Matsumoto et al., 2001). There is evidence of σ2R involvement in amphetamine effect on dopamine transport (Izenwasser et al., 1998; Weatherspoon and Werling, 1999). In addition, treatment with σ2R antagonists counteracts cocaine-induced locomotor stimulation in mice (Guo and Zhen, 2015; Lever et al., 2014). Our results now point to a relevant role of σ2R on mediating effect of drugs of abuse and by mechanisms also involving interaction with GPCRs and modulation of their functionality. Remarkably, we here report that the effect of amphetamine on CRF2R was mediated by σ1R, whereas the effect of the drug on OX1R was, instead, mediated by σ2R. Although direct studies with amphetamine have not been reported, it is known that methamphetamine may bind to both sigma receptors although with more affinity to the σ1R (Nguyen et al., 2005). The results of microdialysis are relevant as they demonstrate that Orexin A leads in the VTA to increases in interstitial concentration of both dopamine and glutamate. The finding fits with hypocretin-mediated increased glutamatergic neurotransmission in this area (Borgland et al., 2008), with regulation of dopamine neuron activity driven by prefrontal cortex activation (Moorman and Aston-Jones, 2010), with fast scan cyclic voltammetry-based data on regulation of dopamine concentration in the nucleus accumbens shell (Patyal et al., 2012), and with regulation of synaptic plasticity elicited by morphine (Baimel and Borgland, 2015). Interestingly, CRF2 receptor is expressed in VTA terminals of neurons projecting from the hypothalamus (Slater et al., 2016). The effect of local administration of amphetamine on increasing VTA dopamine concentration was already reported in the nineties (Byrnes and Wallace, 1997; Pan et al., 1996). Later on, differential effects due to different administration regimes of amphetamine (and of cocaine) administration was reported (Zhang et al., 2001). In addition a review on the evidence of glutamatergic and dopaminergic neurotransmission involvement in the behavioral actions exerted by amphetamine was provided (Vanderschuren and Kalivas, 2000). The mediation of GABAB receptors on the alteration of glutamate and dopamine efflux after amphetamine administration was also suggested (Giorgetti et al., 2002). Interestingly, evidence points that metabotropic but not ionotropic receptors in the nucleus accumbens, are involved in the amphetamine-mediated increase in dopamine efflux/levels (Darracq et al., 2001). It is however intriguing that amphetamine may block “inhibitory glutamate transmission in dopamine neurons” (Paladini et al., 2001).