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Preferential inhibition of dizocilpine-induced hyperlocomotion by olanzapine
1University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.
Abstract:
This study examined the putative inhibitory effect of the atypical antipsychotic, olanzapine, on dizocilpine (MK-801)-induced stereotypy and hyperlocomotion. Dizocilpine (0.1, 0.25 and 0.5 mg/kg) produced a dose-dependent increase in both stereotypy and hyperlocomotion. Pretreatment with olanzapine (0.25 and 0.5 mg/kg) inhibited the dizocilpine (0.5 mg/kg)-induced hyperlocomotion but not the stereotypy. At the higher doses (1, 2 and 4 mg/kg), olanzapine blocked both the stereotypy and hyperlocomotion induced by dizocilpine. Similarly, olanzapine, 0.25 and 0.5 mg/kg, did not inhibit apomorphine (3 mg/kg)-induced stereotypy, whereas the higher dose (1 mg/kg) blocked it. We also studied the effect of olanzapine on spontaneous locomotor activity and catalepsy. Olanzapine (0.25 and 0.5 mg/kg) did not induce a decrease in spontaneous locomotor activity but did so at the higher doses (1, 2 and 4 mg/kg). The lower doses (0.25, 0.5 and 1 mg/kg) did not induce catalepsy but higher doses (2 and 4 mg/kg) induced a significant catalepsy which lasted for more than 4 h. The results thus showed that, at lower doses, olanzapine selectively inhibited behaviours mediated by the mesolimbic/mesocortical system while at higher doses it inhibited behaviours mediated by both mesolimbic/mesocortical and nigrostriatal systems. Therefore, the minimal extrapyramidal side-effects produced by olanzapine at effective doses might be due to its preferential action at the mesolimbic/mesocortical area.
Insights
Olanzapine, an atypical antipsychotic, selectively inhibits certain behaviors at lower doses. Higher doses of olanzapine block both stereotypy and hyperlocomotion, potentially explaining its reduced side effects.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Atypical antipsychotics are used to treat psychosis.
- Olanzapine is an atypical antipsychotic with a complex mechanism of action.
- Dizocilpine (MK-801) is a NMDA receptor antagonist that induces psychotomimetic-like behaviors.
Purpose of the Study:
- To investigate the inhibitory effects of olanzapine on dizocilpine-induced stereotypy and hyperlocomotion.
- To determine the dose-dependent effects of olanzapine on behaviors mediated by different dopaminergic pathways.
- To explore the relationship between olanzapine's dose-dependent effects and its extrapyramidal side effect profile.
Main Methods:
- Administration of dizocilpine (0.1-0.5 mg/kg) to induce stereotypy and hyperlocomotion in rodents.
- Pretreatment with varying doses of olanzapine (0.25-4 mg/kg) to assess its inhibitory effects.
- Evaluation of olanzapine's impact on apomorphine-induced stereotypy.
- Assessment of olanzapine's effects on spontaneous locomotor activity and catalepsy.
Main Results:
- Dizocilpine induced a dose-dependent increase in stereotypy and hyperlocomotion.
- Low doses of olanzapine (0.25-0.5 mg/kg) inhibited dizocilpine-induced hyperlocomotion but not stereotypy.
- Higher doses of olanzapine (1-4 mg/kg) blocked both dizocilpine-induced stereotypy and hyperlocomotion.
- Olanzapine showed dose-dependent effects on spontaneous locomotor activity and catalepsy, with higher doses inducing catalepsy.
Conclusions:
- At lower doses, olanzapine selectively inhibits behaviors mediated by the mesolimbic/mesocortical system.
- At higher doses, olanzapine inhibits behaviors mediated by both mesolimbic/mesocortical and nigrostriatal systems.
- The preferential action of olanzapine at the mesolimbic/mesocortical area at effective doses may explain its minimal extrapyramidal side effects.