Effects of coincident 5-HT sub(1A) receptor stimulation and NMDA receptor antagonism on l-DOPA-induced dyskinesia and rotational behaviors in the hemi-parkinsonian rat

• Published in: Psychopharmacology 2008-07, Vol.199 (1), p.99-108
• Main Authors: Dupre, Kristin B, Eskow, Karen L, Steiniger, Aimee, Klioueva, Anna, Negron, Giselle E, Lormand, Lydia, Park, John Y, Bishop, Christopher
• Format: Article
• Language: English
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-008-1135-6

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-HT sub(1A) receptors and glutamate, the current study examined the effects of the 5-HT sub(1A)R agonist, plus or minus 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: plus or minus 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 plus or minus 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 plus or minus 8-OH-DPAT (0.03 mg/kg, i.p.) + MK-801 (0.1 mg/kg, i.p.) were administered to l-DOPA-naive hemiparkinsonian rats before the forepaw adjusting steps test. Results: Individually, both plus or minus 8-OH-DPAT and MK-801 dose-dependently decreased l-DOPA-induced AIMs without affecting rotations. Combined subthreshold doses of plus or minus 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-HT sub(1A)R and NMDAR that may improve pharmacological treatment of PD patients.