Selective action of an atypical neuroleptic on the mechanisms related to the development of cocaine addiction: a pre-clinical behavioural study

An increased function in the mesolimbic dopaminergic system has been extensively associated with the rewarding effects of both natural stimuli and drugs of abuse. Thus, dopamine receptor blockers, such as neuroleptic drugs, can be proposed as candidates for potential therapeutic approaches to treat drug dependence. Notwithstanding, this therapeutic potential of neuroleptics critically depends on a selective action on the specific mechanisms related to the development of addiction. We compared the effects of different doses of haloperidol, ziprasidone and aripiprazole (first-, second- and third-generation neuroleptics, respectively) on spontaneous locomotor activity of mice in a novel environment, hyperlocomotion induced by acute cocaine administration and cocaine-induced locomotor sensitization by a two-injection protocol. Whereas high doses of haloperidol abolished the three behavioural paradigms without selectivity, low doses of ziprasidone selectively abolished the development of the behavioural sensitization phenomenon. Finally, low doses of aripiprazole inhibited acute cocaine-induced hyperlocomotion and behavioural sensitization without modifying spontaneous locomotor activity. Thus, aripiprazole at lower doses was the most selective antipsychotic drug concerning the inhibition of the development of behavioural sensitization to cocaine. Because locomotor sensitization in rodents has been proposed to share plastic mechanisms with drug addiction in humans, our data provide relevant suggestions to the clinical practice.