Methamphetamine dependence: medication development efforts based on the dual deficit model of stimulant addiction

Converging lines of evidence indicate that withdrawal from prolonged exposure to stimulants and alcohol results in synaptic deficits of both dopamine (DA) and serotonin (5-HT). According to the dual deficit model proposed by the authors, DA dysfunction during cocaine or alcohol withdrawal underlies anhedonia and psychomotor retardation, whereas 5-HT dysfunction gives rise to depressed mood, obsessional thoughts, and lack of impulse control. This model predicts that pharmacotherapies which correct only one of the two neurochemical deficits will not be effective. On the other hand, pharmacotherapies which "correct" both of the proposed DA and 5-HT abnormalities should be effective in treating stimulant and alcohol dependence. This paper reviews two approaches, based on the dual deficit model, taken by our laboratory to develop medications to treat stimulant abuse.