Ience | www.frontiersin.orgMay 2021 | Volume 15 | ArticleHersey et al.Modafinil for Psychostimulant Use DisorderDA and DAT, Their Role in Drug Abuse, Dependence, and as Potential Targets for Pharmacotherapy of PSUDDopamine’s part within the brain’s reward circuit has been extensively studied (Wise and Rompre, 1989; Di Chiara et al., 1993a, 1998; Sensible, 2008; Filovirus drug Arias-Carri et al., 2010; Taber et al., 2012), even so its role in drug abuse and dependence is still not totally clarified (Volkow et al., 2011; Wise and Robble, 2020). Following acute administration of drugs of abuse, including central stimulants and depressants, opiates, cannabinoids, and cholinergic agonists, elevated levels of extracellular DA happen to be reported in the brain regions that are the projection fields of dopaminergic neurons, especially the NAcc and caudate (Di Chiara and Imperato, 1988; Koob, 1992; Pontieri et al., 1995, 1996; Tanda et al., 1997a; Di Chiara et al., 1999). Acute administration of psychostimulants, in unique, has been shown to boost DA levels inside a dose dependent manner inside the NAcc shell and core, and within the striatum (Di Chiara et al., 1993b; Pontieri et al., 1995; Tanda et al., 1997b). These effects are probably related to the initial constructive experience of drug use that could also result in acquisition of drug-seeking behaviors and to the desire to repeat behaviors that lead to a pleasurable encounter (Pettit and Justice, 1989; Woolverton and Johnson, 1992; Koob et al., 1998), but do not account for all neurological elements of substance use disorder (Salamone et al., 2003; Robinson and Kolb, 2004; Russo et al., 2009; Golden and Russo, 2012). Repeated drug use has been shown to result in synaptic adjustments, enabling for thedevelopment of a unique regulation of neurotransmission and also other neuronal activities, which is believed to be the driving force behind drug addiction (Thomas et al., 2008; Luscher and Malenka, 2011). Certainly, addictive drugs regularly elicit neurological alterations which are indicative of prospective targets for greater understanding and treating the improvement of certain patterns of drug use and dependence. Regulation of expression and trafficking of presynaptic DATs by synaptic DA levels has been proposed as a pharmacological target involved within the improvement of PSUD (Zahniser and Sorkin, 2004). Indeed, each acute and chronic cocaine exposure increases DAT density within the NAcc and DS (Zahniser and Sorkin, 2004), although other psychostimulants including amphetamine and METH reduce DAT expression within the exact same regions (Saunders et al., 2000; Sandoval et al., 2001; Barr et al., 2006; Kahlig et al., 2006). Despite varying levels of transporter presence, a main outcome of psychostimulant use is an increase in synaptic DA levels by inhibiting its presynaptic neuronal reuptake or by interacting using the VMAT2, releasing DA into the cytoplasm and after that releasing DA into the synapse by reversing its transport path via DAT (Sulzer et al., 2005; Xie and Miller, 2009; Calipari et al., 2013). The regulation of DAT expression makes it Mineralocorticoid Receptor medchemexpress possible for the formation of a feedback loop amongst DAT abundance and psychostimulant presence within the brain (Verma, 2015). The resulting modifications in DAT density immediately after drug use perpetuates a need to have for consistent amounts on the drug to prevent withdrawal and to sustain substantial levels of DA and DAT expression.TABLE 2 | Neurochemical actions of MOD. Agent(s) MOD Dose(s), species 300 mg/kg, s.c. RAT 200 mg/kg, i.v. RAT 106 mg/k.