Abstract
Antagonists of the muscarinic acetylcholine receptors (mAChRs), were among the first treatments for Parkinson's disease (PD). However, the clinical utility of mAChR antagonists is limited by adverse effects associated with blockade of multiple mAChR subtypes. Understanding of the roles of specific mAChR subtypes in regulating basal ganglia and motor function could lead to development of novel agents that have antiparkinsonian activity with fewer adverse effects. Using novel, highly selective M1 antagonist, VU0255035, and M1 positive allosteric modulator (PAM), BQCA, we investigated roles of M1 receptors in cholinergic excitation and regulation of synaptic transmission in striatal medium spiny neurons (MSNs) and neurons in the subthalamic nucleus (STN) and substantia nigra par reticulata (SNr). Electrophysiological studies demonstrate that M1 activation has excitatory effects on MSNs but plays little or no role in mAChR-mediated increases in firing frequency or regulation of synaptic transmission in STN and SNr neurons. Based on this profile, M1-selective antagonists may have weak antiparkinsonian activity but would not have the full efficacy observed in non-selective mAChR antagonists. Consistent with this, the M1-selective antagonist VU0255035 partially reversed reserpine-induced akinesia and decreased haloperidol-induced catalepsy in rats, but did not have the full efficacy observed with the nonselective mAChR antagonist scopolamine. These results suggest that the M1 receptor participates in the overall regulation of basal ganglia function and antiparkinsonian effects of mAChR antagonists but that other mAChR subtype(s) also play important roles at multiple levels of the basal ganglia motor circuit.
- Received September 15, 2011.
- Revision received November 30, 2011.
- Accepted November 30, 2011.
- The American Society for Pharmacology and Experimental Therapeutics