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  • In summary we hypothesize that targeting

    2019-07-31

    In summary, we hypothesize that targeting the A1R–D1R heterotetramer with heteromer-selective drugs might improve safety and efficacy of the pharmacological therapy for RLS and other motor diseases, resulting in fewer side effects than classical drugs developed for targeting monomeric A1R or D1R.
    Introduction Drug addiction is a chronic and relapsing disorder that results from protracted drug consumption by vulnerable individuals, leading to compulsive drug intake despite deleterious consequences. Drug-evoked neuronal activity changes within the so-called Formoterol Hemifumarate reward circuit are fundamental for the instatement of the enduring behavioral alterations that are characteristic of addiction (Lüscher and Malenka, 2011). Such modulations of synaptic efficacy are translated into specific patterns of signaling pathway activation and gene expression driving a long-lasting remodeling of neural circuits, likely involved in the transition from casual to compulsive drug intake and addiction (Nestler, 2001, 2014). Despite their distinct targets, all drugs of abuse hijack the natural reward system by increasing dopamine (DA) concentration in the mesolimbic system, especially in the striatum (Di Chiara and Imperato, 1988), resulting in alterations in glutamate transmission-dependent plasticity (Lüscher and Malenka, 2011). The striatum is considered a key target structure of drugs of abuse within the reward circuit because it is at the crossroad of converging glutamate signals arising from limbic, thalamic and cortical regions, which encode components of drug-associated stimuli and environment, along with DA transmission that mediates reward prediction error and incentive values. This integration of DA and glutamate inputs is mainly accomplished by the Medium-sized Spiny GABAergic Neurons (MSN), which receive glutamate axon terminals and DA afferences converging on MSN dendritic spines (Moss and Bolam, 2008; Doig et al., 2010). MSN form primarily two segregated populations based on the expression of either DA D1 (D1R) or DA D2 (D2R) receptors, which are G protein-coupled receptors (GPCR) positively and negatively coupled to adenylyl cyclase though their respective coupling to Gs/olf and Gi/o subtypes (Felder et al., 1991; Corvol et al., 2001), although a fraction of MSN in the ventral striatum (i.e. nucleus accumbens; NAcc) express both receptors (Bertran-Gonzalez et al., 2008). These two sub-populations of MSN also display distinct projections within the cortico-basal ganglia network with the D1R-MSN and D2R-MSN forming the direct pathway (dMSN) and the indirect pathway (iMSN), respectively. In the dorsal part of the striatum, dMSN and iMSN exert opposite functions regarding the control of motor behavior. Optogenetic stimulations of dorsal dMSN and iMSN has been shown to promote and inhibit locomotion, respectively (Kravitz et al., 2010). Within the NAcc, this functional dichotomy also applies to reward-dependent learning since the activation of the direct pathway neurons promotes reward whereas the stimulation of indirect pathway neurons is associated with punishment (Hikida et al., 2010; Lobo et al., 2010; Kravitz et al., 2012). The surge of DA induced by drugs of abuse thus triggers a stimulation of D1R that activates dMSN and promotes reiforcement, whereas the D2R-mediated inhibition iMSN opposes to aversion, explaining why a high rewarding value of a stimuli is set when both D1R and D2R are stimulated. Based on these observations, it has been proposed that the imbalance between the activity of dMSN and iMSN evoked by drugs of abuse may drive towards compulsive drug intake and addiction (Lobo and Nestler, 2011; Volkow and Morales, 2015). We and others have started to identify the underlying cellular and molecular mechanisms (Girault et al., 2007; Cahill et al., 2014a; Pascoli et al., 2014a). We found that a single cocaine administration triggers a D1R-mediated facilitation of N-methyl-d-aspartate glutamate receptors (NMDAR) that activates in dMSN the extracellular signal-regulated kinase1/2 (ERK1/2), which controls epigenetic and genic responses that are mandatory for the development of long-term behavioral alterations (Pascoli et al., 2011a, 2014a,b).