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 DeltaFosB are associated with the accumbal PKA pathway to modulate the development of behavioral sensitization. The finding of cAMP-independent and dopamine D2 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.
Chen
Jin-Chung
JC
Neuropharmacology Laboratory, Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan, Taiwan. Jinchen@mail.cgu.edu.tw
Chen
Pei-Chun
PC
Chiang
Yao-Chang
YC
D019969:Amphetamine-Related Disorders / Q000188:drug therapy / Q000209:etiology*; D000818:Animals; D000697:Central Nervous System Stimulants / Q000009:adverse effects*; D019970:Cocaine-Related Disorders / Q000188:drug therapy / Q000209:etiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004298:Dopamine / Q000502:physiology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000502:physiology; D018698:Glutamic Acid / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D006801:Humans; D008694:Methamphetamine / Q000009:adverse effects*; D015398:Signal Transduction; D017557:Ventral Tegmental Area / Q000502:physiology
D000697:Central Nervous System Stimulants; D017362:Cyclic AMP Response Element-Binding Protein; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D018698:Glutamic Acid; D008694:Methamphetamine; D017868:Cyclic AMP-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D004298:Dopamine