Genetic factors involved in neuroplasticity have been implicated in major psychiatric illnesses such as schizophrenia, depression, and substance abuse. Given its extended interactome, variants in the Disrupted-In-Schizophrenia-1 (DISC1) gene could contribute to drug addiction and psychiatric diseases. Thus, we evaluated how dominant-negative mutant DISC1 influenced the neurobehavioral and molecular effects of methamphetamine (METH). Control and mutant DISC1 mice were studied before or after treatment with non-toxic escalating dose (ED) of METH. In naive mice, we assessed METH-induced conditioned place preference (CPP), dopamine (DA) D2 receptor density and the basal and METH-induced activity of DISC1 partners, AKT and GSK-3 beta in the ventral striatum. In ED-treated mice, 4 weeks after METH treatment, we evaluated fear conditioning, depression-like responses in forced swim test, and the basal and METH-induced activity of AKT and GSK-3 beta in the ventral striatum. We found impairment in METH-induced CPP, decreased DA D2 receptor density and altered METH-induced phosphorylation of AKT and GSK-3 beta in naive DISC1 female mice. The ED regimen was not neurotoxic as evidenced by unaltered brain regional monoamine tissue content. Mutant DISC1 significantly delayed METH ED-produced sensitization and affected drug-induced phosphorylation of AKT and GSK-3 beta in female mice. Our results suggest that perturbations in DISC1 functions in the ventral striatum may impact the molecular mechanisms of reward and sensitization, contributing to comorbidity between drug abuse and major mental diseases. This article is part of a Special Issue entitled 'Schizophrenia'. (C) 2011 Elsevier Ltd. All rights reserved.