Effects of coincident 5-HT1A receptor stimulation and NMDA receptor antagonism on L-DOPA-induced dyskinesia and rotational behaviors in the hemi-parkinsonian rat

Abstract

Rationale: Serotonin 1A receptor (5-HT1AR) agonists reduce L-DOPA-induced dyskinesia and enhance motor function in experimental and clinical investigations of Parkinson's disease (PD). While the mechanism(s) by which these effects occur are unclear, recent research suggests that modulation of glutamate neurotransmission contributes.

Objective: To further delineate the relationship between 5-HT1A receptors and glutamate, the current study examined the effects of the 5-HT1AR agonist, +/-8-OH-DPAT and the N-methyl-D-aspartic acid receptor (NMDAR) antagonist, MK-801, on L-DOPA-induced motor behavior.

Materials and methods: Unilateral 6-hydroxydopamine lesioned male Sprague-Dawley rats were rendered dyskinetic with 1 week of daily L-DOPA (12 mg/kg, i.p.) + benserazide (15 mg/kg, i.p.). On test days, one group of rats received pretreatments of: +/-8-OH-DPAT (0, 0.03, 0.1, 0.3 mg/kg, i.p.) or MK-801 (0, 0.03, 0.1, 0.3 mg/kg, i.p.). A second group was administered combined +/-8-OH-DPAT (0, 0.03 or 0.1 mg/kg, i.p.) + MK-801 (0, 0.1 mg/kg, i.p.). Pretreatments were followed by L-DOPA administration, after which, abnormal involuntary movements (AIMs) and rotations were monitored. To investigate effects on motor performance, subthreshold doses of +/-8-OH-DPAT (0.03 mg/kg, i.p.) + MK-801 (0.1 mg/kg, i.p.) were administered to L-DOPA-naïve hemiparkinsonian rats before the forepaw adjusting steps test.

Results: Individually, both +/-8-OH-DPAT and MK-801 dose-dependently decreased L-DOPA-induced AIMs without affecting rotations. Combined subthreshold doses of +/-8-OH-DPAT+MK-801 reduced L-DOPA-induced AIMs and potently enhanced contralateral rotations without altering L-DOPA-induced motor improvements.

Conclusions: The current results indicate a functional interaction between 5-HT1AR and NMDAR that may improve pharmacological treatment of PD patients.