Effects of 5-HT1A Receptor Stimulationon D1 Receptor Agonist-Induced Striatonigral Activity and Dyskinesiain Hemiparkinsonian Rats

摘要

Accumulating evidence supports the value of 5-HT1A receptor (5-HT1AR) agonists for dyskinesias that arise with long-term L-DOPA therapy in Parkinson’s disease (PD). Yet, how 5-HT1AR stimulation directly influences the dyskinetogenic D1 receptor (D1R)-expressing striatonigral pathway remains largely unknown. To directly examine this, one cohort of hemiparkinsonian rats received systemic injections of Vehicle + Vehicle, Vehicle + the D1R agonist (0.8 mg/kg), or the 5-HT1AR agonist ±8-OH-DPAT (1.0 mg/kg) + . Rats were examined for changes in abnormal involuntary movements (AIMs), rotations, striatal preprodynorphin (PPD), and glutamic acid decarboxylase (GAD; 65 and 67) mRNA via RT-PCR. In the second experiment, hemiparkinsonian rats received intrastriatal pretreatments of Vehicle (aCSF), ±8-OH-DPAT (7.5 mM), or ±8-OH-DPAT + the 5-HT1AR antagonist WAY100635 (4.6 mM), followed by systemic Vehicle or after which AIMs, rotations, and extracellular striatal glutamate and nigral GABA efflux were measured by in vivo microdialysis. Results revealed D1R agonist-induced AIMs were reducedby systemic and intrastriatal 5-HT1AR stimulation whilerotations were enhanced. Although ±8-OH-DPAT did not modify D1Ragonist-induced increases in striatal PPD mRNA, the D1R/5-HT1AR agonist combination enhanced GAD65 and GAD67 mRNA. When appliedlocally, ±8-OH-DPAT alone diminished striatal glutamate levelswhile the agonist combination increased nigral GABA efflux. Thus,presynaptic 5-HT1AR stimulation may attenuate striatalglutamate levels, resulting in diminished D1R-mediated dyskineticbehaviors, but maintain or enhance striatal postsynaptic factors ultimatelyincreasing nigral GABA levels and rotational activity. The currentfindings offer a novel mechanistic explanation for previous resultsconcerning 5-HT1AR agonists for the treatment of dyskinesia.