Local modulation of striatal glutamate efflux by serotonin 1A receptor stimulation in dyskinetic, hemiparkinsonian rats

Abstract

Serotonin 1A receptor (5-HT 1A R) agonists reduce both L-DOPA-and D1 receptor (D1R) agonistmediated dyskinesia, but their anti-dyskinetic mechanism of action is not fully understood. Given that 5-HT 1A R stimulation reduces glutamatergic neurotransmission in the dopamine-depleted striatum, 5-HT 1A R agonists may diminish dyskinesia in part through modulation of pro-dyskinetic striatal glutamate levels. To test this, rats with unilateral medial forebrain bundle dopamine or sham lesions were primed with L-DOPA (12 mg/kg + benserazide, 15 mg/kg, sc) or the D1R agonist SKF81297 (0.8 mg/kg, sc) until abnormal involuntary movements (AIMs) stabilized. On subsequent test days, rats were treated with vehicle or the 5-HT 1A R agonist ±8-OH-DPAT (1.0 mg/kg, sc), followed by L-DOPA or SKF81297, or intrastriatal ±8-OH-DPAT (7.5 or 15 mM), followed by L-DOPA. In some cases, the 5-HT 1A R antagonist WAY100635 was employed to determine receptor-specific effects. In vivo microdialysis was used to collect striatal samples for analysis of extracellular glutamate levels during AIMs assessment. Systemic and striatal ±8-OH-DPAT attenuated L-DOPA-induced dyskinesia and striatal glutamate efflux while WAY100635 reversed ±8-OH-DPAT's effects. Interestingly, systemic ±8-OH-DPAT diminished D1R-mediated AIMs without affecting glutamate. These findings indicate a novel anti-dyskinetic mechanism of action for 5-HT 1A R agonists with implications for the improved treatment of Parkinson's disease.

Effects of 5-HT1A Receptor Stimulation on D1 Receptor Agonist-Induced Striatonigral Activity and Dyskinesia in Hemiparkinsonian Rats

“…17 However, whether D1R agonists directly induce glutamate release is less studied. In agreement with our previous work, 20 despite significant dyskinesia, treatment with the D1R agonist SKF81297 in hemiparkinsonian rats did not modify striatal glutamate levels ( Figure 5). However, striatal 5-HT 1A R stimulation alone diminished local glutamate (by ∼25%) and reduced it further (by ∼40%) when given with the D1R agonist.…”

“…1,16,65,66 However, the decrease in D1R agonist-induced AIMs by 5-HT 1B receptor agonism was moderate and rotational activity was not modified. 65 Importantly, in previous studies 7,20,37 and the current one (see Figures 4−6), the effects on AIMs and rotations were reversed with coadministration of the 5-HT 1A R antagonist WAY100635, further proposing the participation of this receptor subtype in our molecular and neurochemical effects. Nonetheless, future studies may wish to utilize lower concentrations of ±8-OH-DPAT in order to improve receptor specificity.…”

“…Importantly, the effects of striatal 5-HT 1A R stimulation alone or in combination with D1R stimulation reflect the systemic effects displayed in Experiment 1 and are commensurate with previous findings. 8,9,20,36,37 Striatal ±8-OH-DPAT Alone and with SKF81297 Reduces Local Glutamate Levels. Enhanced activity of the glutamatergic corticostriatal pathway is believed to be a contributing mechanism of LID.…”

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

“…In agreement with overactive glutamatergic transmission in LID and the antidyskinetic effect of various glutamate receptor antagonists, studies have demonstrated increased levels of glutamate in the striatum and increased levels of the GLT1 glutamate transporter in the basal ganglia of the dyskinetic 6-OHDAlesioned rat (Jonkers et al, 2002;Robelet et al, 2004;Dupre et al, 2011). Accordingly, decreasing glutamate release was proposed to be an effective way to alleviate dyskinesia.…”

2.12.2 the Serotonin System: A Potential Target for Anti-Dyskinetic Treatments and Biomarker Discovery

“…Stimulating the 5-HT autoreceptors has shown to reduce the activity of the raphe-striatal neurons, blunt the extracellular dopamine release in the striatum and attenuate the expression of LID in animal models of PD [7,8]. Stimulation of 5-HT1A and/or 5-HT1B receptors is also able to reduce D1-agonist-induced dyskinesia through a postsynaptic mechanism, (although, this require higher doses than those for attenuating LID) [14][15][16]. In line with this, recent data points to a role of 5-HT1A receptors expressed in primary motor cortex in the modulation of LID [17].…”