Extrapyramidal Side Effects with Chronic Atypical Antipsychotic Can Be Predicted by Labeling Pattern of FosB and phosphoThr34-DARPP-32 in Nucleus Accumbens.

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.

Cross-tolerance between nitric oxide synthase inhibition and atypical antipsychotics modify nicotinamide-adenine-dinucleotide phosphate-diaphorase activity in mouse lateral striatum.

Previous research indicates that the subchronic administration of NG-nitro-L-arginine (L-NOARG) produces tolerance to haloperidol-induced catalepsy in Swiss mice. The present study aimed to further investigate whether intermittent subchronic systemic administration of L-NOARG induces tolerance to the cataleptic effects of haloperidol as well as olanzapine or clozapine (Clz) in C57Bl mice after subchronic administration for 5 consecutive days. Striatal FosB protein expression was measured in an attempt to gain further insights into striatal mechanisms in antipsychotic-induced extrapyramidal symptoms side effects. An nicotinamide-adenine-dinucleotide phosphate-diaphorase histochemical reaction was also used to investigate whether tolerance could induce changes in the number of nitric oxide synthase-active neurons. Subchronic administration of all antipsychotics produced catalepsy, but cross-tolerance was observed only between L-NOARG (15 mg/kg, intraperitoneally) and Clz (20 mg/kg, intraperitoneally). This cross-tolerance effect was accompanied by decreased FosB protein expression in the dorsal striatum and the nucleus accumbens shell region, and reduced icotinamide-adenine-dinucleotide phosphate-diaphorase activity in the dorsal and ventral lateral striatum. Overall, these results suggest that interference with the formation of nitric oxide, mainly in the dorsal and ventral lateral-striatal regions, appears to improve the cataleptic effects induced by antipsychotics acting as antagonists of low-affinity dopamine D2 receptor, such as Clz.