RESUMO
Extrapyramidal side effects (EPS) can be induced by neuroleptics that regulate the expression of transcription factor FosB and dopaminergic mediator DARPP-32 in the striatum. However, the long-term neurobiological changes in striatal projection neurons resulting from a cumulative dosage of typical and atypical antipsychotics are poorly understood. The present study aimed to determine the differential and long-lasting changes in FosB distribution and DARPP-32 phosphorylation in the striatum and nucleus accumbens (NAc) associated with chronic antipsychotic-induced EPS. Male C57Bl/6J mice received daily injections of Olanzapine (Olz, 15 mg/kg), Clozapine (Clz, 20 mg/kg), or Haloperidol (Hal, 1 mg/kg), for a period of 11 weeks with a 4-day withdrawal period before the last dosage. Catalepsy for detection of EPS, along with open-field and rotarod tests, were assessed as behavioral correlates of motor responses. Additionally, FosB and phosphorylated-DARPP-32 immunohistochemistry were examined in striatal regions after treatment. All antipsychotics produced catalepsy and reduced open-field exploration, such as impaired rota-rod performance after Olz and Hal. The washout period was critical for Clz-induced side effects reduction. Both Olz and Clz increased FosB in NAc Shell-region, and phosphoThr34-DARPP-32 in NAc. Only Clz reduced phosphoThr75-DARPP-32 in the dorsal striatum and showed FosB/phosphoThr34-Darpp-32-ir in the NAc Core region. This study provides evidence that atypical antipsychotics such as Olz and Clz also give rise to EPS effects frequently associated with a cumulative dosage of typical neuroleptics such as Hal. Nevertheless, FosB/phosphoThr34-Darpp-32-ir in the NAc Core region is associated with hypokinetic movements inhibition.
RESUMO
Stimulation of the hippocampal formation can modulate nociceptive mechanisms, whereas painful stimuli can activate this structure. Stress exposure can produce plastic changes in the hippocampus. Nitric oxide (NO) is an important neuroregulatory agent present in the hippocampus. The objective of the present study was to investigate the effects of intrahippocampal administration of N(omega)-nitro-L-arginine methyl ester hydrochloride (L-NAME), an inhibitor of NO synthase (NOS), on nociceptive processes in stressed and nonstressed rats. Male Wistar rats (n=6-11/group) received unilateral microinjection of L-NAME (50-300 nmol/0.2 microl) into the dentate gyrus (DG) of the dorsal hippocampus. Immediately after the injection tail-flick reflex latency was measured. Stressed animals were submitted to 2 h of restraint and tested immediately or 1, 2, 5 or 10 days later. L-NAME failed to modify nociception in nonstressed rats. However, 5 days after, restraint L-NAME, at all doses tested, produced an antinociceptive effect (ANOVA, P<.05). The dose-response curve had an inverted U shape. L-NAME antinociceptive effect was antagonized by previous treatment with L-arginine (150 nmol/0.2 microl, P<.05). The results suggest that the modulation of nociceptive processes by NO in the dorsal hippocampus is dependent on previous stress exposure and on poststress interval.