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


OBJECTIVE
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.


METHODS
Rotational behavior after R-(+)-8-OHDPAT was investigated in rats that received 6-hydroxydopamine unilaterally into the median forebrain bundle 2 weeks before testing.


RESULTS
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.


CONCLUSIONS
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.
Mignon
Laurence
L
Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Wolf
William A
WA
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D016627:Oxidopamine; D010300:Parkinson Disease / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D012701:Serotonin / Q000096:biosynthesis / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D018698:Glutamic Acid; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D016627:Oxidopamine