Clozapine, ziprasidone and aripiprazole but not haloperidol protect against kainic acid-induced lesion of the striatum in mice, in vivo: Role of 5-HT1A receptor activation

Excessive activation of non-NMDA receptors, AMPA and kainate, contributes to neuronal degeneration in acute and progressive pathologies, possibly including schizophrenia. Because 5-HT1A receptor agonists have neuroprotective properties (e.g., against NMDA-induced neurotoxicity), we compared the effects of the antipsychotics, clozapine, ziprasidone and aripiprazole, that are partial agonists at 5-HT1A receptor, with those of haloperidol, which is devoid of 5-HT1A agonist properties, on kainic acid (KA)-induced striatal lesion volumes, in C57Bl/6N mice. The involvement of 5-HT1A receptors was determined by antagonist studies with WAY100635, and data were compared with those obtained using the potent and high efficacy 5-HT1A receptor agonist, F13714. Intra-striatal KA lesioning and measurement of lesion volumes using cresyl violet staining were carried out at 48 h after surgery. F13714, antipsychotics or vehicle were administered ip twice, 30 min before and 3 1/2 h after KA injection. WAY100635 (0.63 mg/kg) or vehicle were given sc 30 min before each drug injection. Clozapine (2 × 10 mg/kg), ziprasidone (2 × 20 mg/kg) and aripiprazole (2 × 10 mg/kg) decreased lesion volume by 61%, 59% and 73%, respectively. WAY100635 antagonized the effect of ziprasidone and of aripiprazole but only slightly attenuated that of clozapine. In contrast, haloperidol (2 × 0.16 mg/kg) did not affect KA-induced lesion volume. F13714 dose-dependently decreased lesion volume. The 61% decrease of lesion volume obtained with F13714 (2 × 0.63 mg/kg) was antagonized by WAY100635. WAY100635 alone did not affect lesion volume. These results show that 5-HT1A receptor activation protects against KA-induced striatal lesions and indicate that some atypical antipsychotic agents with 5-HT1A agonist properties may protect against excitotoxic injury, in vivo.