Drugs of abuse also adversely affect astrocytes, providing potential pathophysiological mechanisms for initiation, maintenance, and relapse (see Table I). As in alcohol use disorders, astrocytic glutamate transporters play a pivotal role in the development and maintenance of cocaine misuse. In rodents, cocaine self-administration decreases glutamate in the nucleus accumbens (NAcc) core, which temporally coincides with decreased expression of EAAT2/ GLT-1 and xCT, the catalytic subunit of the glutamate antiporter system xC− which exchanges extracellular cysteine for intracellular glutamate (Knackstedt et al. 2010). Ceftriaxone prevents cocaine-induced reductions in the expression of both transporters and normalizes extracellular glutamate levels, which provides a viable mechanism to reverse cocaine-induced synaptic potentiation, e.g., decreased spontaneous excitatory postsynaptic currents, in the NAcc core and reduce cue- and cocaine-mediated reinstatement (Knackstedt et al. 2010; Trantham-Davidson et al. 2012). N-Acetylcysteine, a cystine prodrug that also stimulates xCT and GLT-1 expression (Knackstedt et al. 2010), decreases rodent cocaine seeking and other cocaine-related behaviours and reduces cravings in non-treatment-seeking cocaine-dependent subjects (Baker et al. 2003; Madayag et al. 2007; Amen et al. 2011). Diffuse astrogliosis has also been linked to methamphetamines (Pubill et al. 2003).
