Haloperidol (but not ziprasidone) withdrawal potentiates sensitization to the hyperlocomotor effect of cocaine in mice.

One important contributing factor in the high prevalence of drug abuse disorders seen among schizophrenic patients seems to be related to chronic treatment with typical neuroleptics. We have previously demonstrated that withdrawal from long-term treatment with the typical neuroleptic haloperidol, but not the atypical neuroleptic ziprasidone, potentiated the hyperlocomotor effect induced by a single cocaine injection and cocaine-induced conditioned place preference in mice. In the present study we investigated whether withdrawal from long-term treatment with these same neuroleptics would also modify cocaine-induced hyperlocomotion sensitization, which has been proposed as an animal model for the intensification of drug craving in cocaine addiction. Swiss male mice were i.p. treated with haloperidol (1.0 mg/kg) or ziprasidone (4.0 mg/kg) for 15 days. Twenty-four hours after the last injection, animals received an i.p. injection of cocaine (10 mg/kg) for 5 consecutive days, being placed after each injection in the open-field apparatus in order to perform a drug-environment conditioning. Seven days after the last drug-environment conditioning procedure, the animals were challenged with an i.p. injection of cocaine (10 mg/kg), placed in the open-field apparatus and had their locomotor activity quantified. Withdrawal from haloperidol (but not ziprasidone) potentiated cocaine-induced behavioral sensitization. These results are suggested to be a consequence of the development of the dopaminergic supersensitivity phenomenon by long-term treatment with the typical compound. Our findings provide additional support for the use of atypical agents like ziprasidone in the treatment of schizophrenic patients with comorbid substance abuse disorder.

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.