Inhibitory regulation of the prefrontal cortex following behavioral sensitization to amphetamine and/or methamphetamine psychostimulants: A review of GABAergic mechanisms

Abstract

Behavioral sensitization to repeated psychostimulant administration has been proposed to reflect many of the neurochemical and behavioral changes that are characteristic of a range of disorders, including drug addiction and psychoses. While previous studies have examined the role of dopamine and glutamate neurotransmission in mediating sensitization, particularly within the prefrontal cortex (PFC), the role of inhibitory GABAergic processing of the PFC in the expression of sensitization is not well understood. Recent research, however, has proposed an emerging role of GABA synthesis, reuptake, ionotropic and metabotropic receptor regulation, and interneuronal changes following sensitization to methamphetamine and/or amphetamine within the PFC. The aim of this review, therefore, is to synthesize research findings on changes to the GABAergic network following sensitization induced by amphetamines (i.e., amphetamine and/or methamphetamine) in the PFC. In addition to providing an overview of global PFC changes, we also provide evidence of regional specific inhibitory influences on sensitized circuitry, focusing on the prelimbic and orbitofrontal cortices. We propose a neural circuit through which inhibitory PFC GABA changes mediate sensitized disease states, focusing on the interaction between the prelimbic and orbitofrontal cortices with subcortical brain structures and the mesolimbic system. Methodological considerations and avenues for future research are also discussed.

Keywords: Amphetamine; GABA; Inhibition; Methamphetamine; Prefrontal cortex; Psychostimulants; Sensitization.