Glutamate homeostasis and dopamine signaling: Implications for psychostimulant addiction behavior

Cocaine, amphetamine, and methamphetamine abuse disorders are serious worldwide health problems. To date, there are no FDA-approved medications for the treatment of these disorders. Elucidation of the biochemical underpinnings contributing to psychostimulant addiction is critical for the development of effective therapies. Excitatory signaling and glutamate homeostasis are well known pathophysiological substrates underlying addiction-related behaviors spanning multiple types of psychostimulants. To alleviate relapse behavior to psychostimulants, considerable interest has focused on GLT-1, the major glutamate transporter in the brain. While many brain regions are implicated in addiction behavior, this review focuses on two regions well known for their role in mediating the effects of cocaine and amphetamines, namely the nucleus accumbens (NAc) and the ventral tegmental area (VTA). In addition, because many investigators have utilized Cre-driver lines to selectively control gene expression in defined cell populations relevant for psychostimulant addiction, we discuss potential off-target effects of Cre-recombinase that should be considered in the design and interpretation of such experiments.