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

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Abstract

Rationale

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.

Materials and 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-HT1A 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.

Conclusion

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.

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Acknowledgment

This work was supported by a Merit Award (WAW) from the Department of Veteran’s Affairs and by PHS grant NS 36410 (WAW.). This research represents work carried out in partial fulfillment of the requirements for the degree of Doctor of Philosophy (LM).

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Authors and Affiliations

  1. Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA

    Laurence Mignon

  2. Research Service-151, Edward Hines Jr. VA Hospital, Hines, IL, 60141, USA

    William A. Wolf

  3. Department of Anatomy & Cell Biology, University of Illinois at Chicago, Chicago, IL, 60612, USA

    William A. Wolf

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  1. Laurence Mignon
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  2. William A. Wolf
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Correspondence to William A. Wolf.

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Mignon, L., Wolf, W.A. Postsynaptic 5-HT1A receptor stimulation increases motor activity in the 6-hydroxydopamine-lesioned rat: implications for treating Parkinson’s disease. Psychopharmacology 192, 49–59 (2007). https://doi.org/10.1007/s00213-006-0680-0

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  • DOI: https://doi.org/10.1007/s00213-006-0680-0

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