Abstract
5-HT plays a regulatory role in voluntary movements of the basal ganglia and has a major impact on disorders of the basal ganglia such as Parkinson's disease (PD). Clinical studies have suggested that 5-HT2 receptor antagonists may be useful in the treatment of the motor symptoms of PD. We hypothesized that 5-HT2A receptor antagonists may restore motor function by regulating glutamatergic activity in the striatum. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exhibited decreased performance on the beam-walking apparatus. Peripheral administration of the 5-HT2A receptor antagonist M100907 improved performance of MPTP-treated mice on the beam-walking apparatus. In vivo microdialysis revealed an increase in striatal extracellular glutamate in MPTP-treated mice and local perfusion of M100907 into the dorsal striatum significantly decreased extracellular glutamate levels in saline and MPTP-treated mice. Our studies suggest that blockade of 5-HT2A receptors may represent a novel therapeutic target for the motor symptoms of PD.
Highlights
Serotonin (5-HT) projections from the dorsal raphe nucleus innervate all components of the basal ganglia circuitry (Lavoie and Parent, 1990). 5-HT has been shown to modulate dopamine (DA) neurotransmission in the striatum, and GABA and glutamate transmission in the output regions of the basal ganglia via a number of 5-HT receptors (Nicholson and Brotchie, 2002)
We hypothesized that 5-HT2A receptors localized on cortico-striatal axons regulate glutamatergic activity in the striatum and that 5-HT2A receptor antagonists may restore motor function by normalizing the overactive glutamatergic drive resulting from DA depletion
Effects of 5-HT2A receptor antagonist M100907 on performance on the beam-walking apparatus 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine produced more than 10-fold increase in the number of footslips during beam traversal
Summary
Serotonin (5-HT) projections from the dorsal raphe nucleus innervate all components of the basal ganglia circuitry (Lavoie and Parent, 1990). 5-HT has been shown to modulate dopamine (DA) neurotransmission in the striatum, and GABA and glutamate transmission in the output regions of the basal ganglia via a number of 5-HT receptors (Nicholson and Brotchie, 2002). We assessed the effect of the 5-HT2A receptor antagonist M100907 on motor impairments in MPTP-treated mice. Effects of 5-HT2A receptor antagonist M100907 on performance on the beam-walking apparatus 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine produced more than 10-fold increase in the number of footslips during beam traversal (number of footslips/subject: Control 0.42 ± 0.12; MPTP 5.97 ± 0.58; n = 31/group).
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