Effects of acute and chronic administration of olanzapine in comparison toclozapine and haloperidol on extracellular recordings of substantia nigra reticulata neurons in the rat brain

Rationale : Previously, we have shown that the atypical antipsychotics cloz apine and risperidone, unlike haloperidol, decreased the firing rate of sub stantia nigra reticulata (SNR) neurons. As the SNR receives substantial inp ut from the striatum, an area where motoric side-effects of antipsychotics are thought to be mediated, the SNR might be an interesting brain structure with regard to motor side-effects. Objective: : The newly developed atypic al antipsychotic olanzapine was studied for its effects on the firing rate of SNR cells. In addition, to gain insight in the implications of our exper imental setup for clinical use, responses upon clozapine, olanzapine and ha loperidol were studied after chronic treatment. Methods: In chloralhydrate- anaesthetized male Wistar rats, extracellular recordings were made from SNR neurons upon intravenously (IV) administered cumulative doses of the antip sychotics. Naive rats and rats that were subcutaneously (SC) injected for 2 1 days with an antipsychotic were used. Results: Olanzapine (50-100 mg/kg; IV), significantly inhibited the firing rate of the SNR neurons. Upon 21 da ys of treatment with a daily SC injection of 20 mg/kg clozapine, the challe nge on day 22 with cumulative injections of clozapine (200-6400 mg/kg; IV) significantly inhibited the firing rate of the SNR neurons. Olanzapine (50- 1600 mg/kg; IV) also significantly inhibited the SNR activity when pretreat ed with olanzapine in an SC administered dose of 1 mg/kg, but not 5 mg/kg. Haloperidol (12.5-800 mu g/kg; IV) did not significantly affect the SNR act ivity in rats pretreated with SC administered 0.5 mg/kg haloperidol. Conclu sions: Upon acute and chronic administration of clozapine and olanzapine ve rsus haloperidol, differential effects on SNR neuronal firing could be obta ined. The experimental setup seem to be valid for further studies into the mechanism of action of typical versus (relatively low doses of) atypical an tipsychotics. The implications of the inhibitory effect of atypical antipsy chotics on the SNR firing rate are presently unknown, but could be associat ed with the lower propensity to induced motoric side-effects. On the other hand, the SNR activity might also reflect non-motoric activity possibly rel ated to negative symptoms.