Molecular mechanisms of psychostimulant addiction

Drug addiction represents a pathological form of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry. The aberrant behavioral phenotypes can be assessed by an animal model of drug-induced behavioral sensitization, which is characterized by an initiation stage that is formed in the ventral tegmental area and a behavioral expression stage determined mainly in the nucleus accumbens. Numerous studies during past decades demonstrate that the mesocorticolimbic dopamine pathway plays an essential role in the development of behavioral sensitization. Moreover, a series of cellular signaling pathways and gene expression determine the severity of addictive behaviors. In addition to the well-characterized dopamine D₁ receptor-mediated cAMP/protein kinase A up-regulation in the nucleus accumbens, recent reports indicate the cellular mediator dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) and transcription regulator AFosB are associated with the accumbal PKA pathway to modulate the development of behavioral sensitization. The finding of cAMP-independent and dopamine D ₂ receptor-mediated Akt/GSK3 in activation in the nucleus accumbens of behaviorally sensitized animals implies that a signal cascade down-stream of both dopamine D₁ and D₂ receptors comprises the mainstay of the addiction network. This review outlines the cellular pathways that have been demonstrated to participate in psychostimulant addiction, focused particularly in the nucleus accumbens.