Neurochemical effects of 8-hydroxy-2-di-n-propylamino tetralin in rats treated with haloperidol.

In view of a possible role of presynaptic serotonin (5-hydroxytryptamine, 5-HT) receptors in the precipitation of extrapyramidal side effects (EPS), the present study was designed to investigate the neurochemical effects of a selective 5-HT1A ligand, 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPAT) in rats following single (5 mg/kg) and repeated (two-times a day for 9 days at dosage of 5mg/kg) haloperidol administration. Haloperidol plus 8-OH-DPAT injected animals exhibited a decrease in dopamine (DA) and an increase in DA metabolite homovanillic acid (HVA) levels in the striatum and rest of the brain. The two groups of animals exhibited comparable levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the striatum and rest of the brain. Animals injected with haloperidol and killed 24 hrs after the last injection of haloperidol exhibited higher DA and HVA levels in the striatum but not in the rest of the brain. Conversely, dihydroxyphenylacetic acid (DOPAC), the other metabolite of DA, decreased in the rest of the brain. 5-HIAA concentrations increased in the striatum but not in the rest of the brain. Administration of 8-OH-DPAT significantly decreased 5-HT and 5-HIAA levels in the rest of brain and did not alter 5-HIAA in the striatum of repeated saline injected rats. Conversely, same dose of 8-OH-DPAT injected to repeatedly haloperidol injected animals did not decrease 5-HT and 5-HIAA concentrations in the rest of the brain but decreased 5-HIAA levels in the striatum. No effect of 8-OH-DPAT injections occurred on striatal or rest of the brain DA metabolism in repeatedly saline injected animals except that DOPAC decreased in the striatum of both groups. The results are discussed in the context of a role of somatodendritic 5-HT1A receptors in the regulation of DA metabolism following single and repeated administration of haloperidol. It is suggested that an increase in the responsiveness of these receptors may be involved in the precipitation of EPS observed in patients on haloperidol therapy.