Postsynaptic 5-HT1A receptor stimulation increases motor activity in the 6-hydroxydopamine-lesioned rat: implications for treating Parkinson’s disease

Abstract

We have shown that the 5-HT1A agonist R-(+)-hydroxy-2-(di-n-propylamino)tetralin [R-(+)-8-OHDPAT] enhances motor activity in the monoamine-depleted rat, an acute model of Parkinson's disease. The present work extends these findings by investigating motor effects of R-(+)-8-OHDPAT in the unilateral 6-hydroxydopamine-lesioned rat, a chronic model of Parkinson's disease. The objectives of the present study were to assess the motor response to R-(+)-8-OHDPAT in rats with unilateral destruction of the nigrostriatal dopamine system and to determine the involvement of postsynaptic 5-HT1A receptors in this response. Rotational behavior after R-(+)-8-OHDPAT was investigated in rats that received 6-hydroxydopamine unilaterally into the median forebrain bundle 2 weeks before testing. A dose of 0.3 mg/kg subcutaneously (s.c.) R-(+)-8-OHDPAT induced significant ipsilateral turning in unilateral 6-OHDA-lesioned rats. Pretreatment with the selective 5-HT(1A) antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclohexanecarboxiamide maleate (WAY-100635, 0.1 mg/kg, s.c.) blocked turning. Blockade of 5-HT synthesis and 5-HT depletion caused by the tryptophan hydroxylase inhibitor DL: -p-chlorophenylalanine did not decrease R-(+)-8-OHDPAT-induced turning. Finally, a subset of animals were tested for their turning response to the dopamine agonist apomorphine after tests with R-(+)-8-OHDPAT had been completed. Correlation analysis indicated no relationship existed between the turning response to apomorphine and the turning response to R-(+)-8-OHDPAT. R-(+)-8-OHDPAT induces ipsilateral turning in unilateral 6-OHDA lesioned rats by stimulating postsynaptic 5-HT1A receptors, not by altering 5-HT synthesis and release. The mechanism underlying the motor effects of R-(+)-8-OHDPAT appears to differ from classic dopaminergic anti-parkinsonian agents suggesting that 5-HT1A agonists might prove useful adjunctive therapy in the treatment of Parkinson's disease.