Glutamate Receptors and Drug Addiction

Glutamate is the primary excitatory amino acid transmitter in the brain and acts on various ionotropic and metabotropic receptor subtypes. Specific subtypes of glutamate receptors are not only molecular targets for some drugs of abuse, but also mediate many of the maladaptive neuroadaptations that occur as a result of chronic drug use. Glutamate receptors are also considered novel targets for improved pharmacotherapeutics for the treatment of addictive disorders as well as their underlying neuropathology. The existing body of literature on the topic of glutamate receptors and drug addiction is growing at an exponential rate, and a comprehensive review of this literature would be beyond the scope of this chapter. Therefore, what follows is a summary of selected well-characterized and consistent phenomena that have emerged in the addiction literature with respect to glutamate receptors and drugs of abuse. These phenomena include: (1) alcohol-induced upregulation of N-methyl-d-aspartate receptor function; (2) psychostimulant-induced α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor redistribution and impairment of type 2/3 metabotropic glutamate receptor function; and (3) blockade of opiate tolerance by antagonism of glutamatergic transmission. These phenomena are first described and then followed by a discussion of their potential clinical and translational relevance.