Abstract

Although few medications have been approved by the U.S. Food and Drug Administration (FDA) to assist people to quit tobacco smoking, there are no FDA-approved medications to treat dependence on other psychostimulant drugs, such as cocaine. The motivation to maintain psychostimulant drug seeking and self-administration involves alterations in glutamatergic neurotransmission. Thus, medications that modulate glutamate transmission may be effective treatments for psychostimulant dependence. One presynaptic inhibitory glutamate receptor that critically regulates glutamate transmission is the metabotropic glutamate 7 receptor (mGluR7). This review summarizes nonhuman experimental animal data that indicate a critical role for mGluR7 in drug-taking and drug-seeking behaviors for the psychostimulants cocaine and nicotine. AMN082, the only commercially available allosteric receptor agonist, has been used to investigate the role of mGluR7 in psychostimulant dependence. Systemic administration or microinjection of AMN082 into brain sites within the mesocorticolimbic system decreased self-administration and reinstatement of both cocaine and nicotine seeking. In vivo microdialysis results indicated that a nucleus accumbens-ventral pallidum γ-aminobutyric acid-ergic mechanism may underlie AMN082-induced antagonism of the reinforcing effects of cocaine, whereas a glutamate mGlu2/3 receptor mechanism underlies the AMN082-induced blockade of cocaine seeking. These findings indicate an important role for mGluR7 in mesolimbic areas in modulating the reinforcing effects of psychostimulant drugs, such as nicotine and cocaine, and the conditioned behaviors associated with drugs of abuse. Thus, selective mGluR7 agonists or positive allosteric modulators may have the potential to treat psychostimulant dependence.

Keywords: Addiction, AMN082, cocaine, drug discovery, glutamate, mGluR7, nicotine.