Haloperidol (but not ziprasidone) withdrawal enhances cocaine-induced locomotor activation and conditioned place preference in mice.

It has been empirically suggested that the high incidence of drug abuse in schizophrenic patients is related to chronic neuroleptic treatment. We investigated the effects of withdrawal from long-term administration of the typical neuroleptic haloperidol and/or the atypical agent ziprasidone on the acute locomotor stimulant effect of cocaine as well as on cocaine-induced conditioned place preference (CPP). In the first experiment, mice were i.p. treated with haloperidol (1.0 mg/kg) and/or ziprasidone (4.0 mg/kg) for 15 days. At 72 h after the last injection, animals received an i.p. injection of cocaine (10 mg/kg) and their locomotor activity was quantified. In the second experiment, mice were withdrawn from the same haloperidol or ziprasidone treatment schedule and submitted to CPP. Withdrawal from haloperidol (but not ziprasidone or ziprasidone plus haloperidol) increased both cocaine-induced hyperactivity and CPP. These findings indicate that withdrawal from long-term treatment with typical neuroleptic drugs such as haloperidol (but not the atypical compound ziprasidone) may enhance some behavioral effects of cocaine in mice which have been related to drug dependence in humans.

Amphetamine-induced rapid-onset sensitization: role of novelty, conditioning and behavioral parameters.

BACKGROUND: Environmental factors may modulate sensitization to the locomotor-activating effects of psychostimulants. In addition, some parameters of locomotor activity seem to be more sensitive to detect cocaine-induced behavioral sensitization. We examined how novelty and conditioning can modulate a previously described rapid-onset type of behavioral sensitization to amphetamine (AMP) in mice, using total, peripheral and central open-field locomotion frequencies as experimental parameters. METHODS: In the first experiment, mice received an ip injection of saline (SAL) or 5.0 mg/kg AMP paired or not with the open-field or in their home-cages. Four hours later, all the animals received an ip SAL challenge injection and, 15 min later, were observed in the open-field for quantification of total, peripheral and central locomotion frequencies. The second experiment had a similar protocol, except that mice received a challenge injection of 1.5 mg/kg AMP. RESULTS: The priming AMP injection significantly increased all the parameters of locomotion of SAL-challenged mice firstly exposed to or previously paired (but not unpaired) with the open-field. AMP priming injection enhanced total and peripheral locomotion of all AMP-challenged mice but only increased central locomotion of mice submitted to novelty or environmental conditioning. CONCLUSION: Our results showed: 1) the development of an AMP-induced rapid-onset sensitization to novelty and rapid-onset environmental conditioning in mice, 2) the potentiation of the AMP-induced rapid-onset sensitization to an AMP challenge injection by novelty and environmental conditioning and 3) the importance of measuring different locomotor activity parameters in behavioral sensitization experiments.