Cholinergic Modulation of Neostriatal Output: A Functional Antagonism between Different Types of Muscarinic Receptors

Abstract

It is demonstrated that acetylcholine released from cholinergic interneurons modulates the excitability of neostriatal projection neurons. Physostigmine and neostigmine increase input resistance (RN) and enhance evoked discharge of spiny projection neurons in a manner similar to muscarine. Muscarinic RN increase occurs in the whole subthreshold voltage range (-100 to -45 mV), remains in the presence of TTX and Cd2+, and can be blocked by the relatively selective M1,4 muscarinic receptor antagonist pirenzepine but not by M2 or M3 selective antagonists. Cs+ occludes muscarinic effects at potentials more negative than -80 mV. A Na+ reduction in the bath occludes muscarinic effects at potentials more positive than -70 mV. Thus, muscarinic effects involve different ionic conductances: inward rectifying and cationic. The relatively selective M2 receptor antagonist AF-DX 116 does not block muscarinic effects on the projection neuron but, surprisingly, has the ability to mimic agonistic actions increasing RN and firing. Both effects are blocked by pirenzepine. HPLC measurements of acetylcholine demonstrate that AF-DX 116 but not pirenzepine greatly increases endogenous acetylcholine release in brain slices. Therefore, the effects of the M2 antagonist on the projection neurons were attributable to autoreceptor block on cholinergic interneurons. These experiments show distinct opposite functions of muscarinic M1- and M2-type receptors in neostriatal output, i.e., the firing of projection neurons. The results suggest that the use of more selective antimuscarinics may be more profitable for the treatment of motor deficits.

Roles of the M1 Muscarinic Acetylcholine Receptor Subtype in the Regulation of Basal Ganglia Function and Implications for the Treatment of Parkinson's Disease

“…For instance, mAChR activation inhibits various K ϩ currents, including KCNQ channel currents in MSNs, and this effect was lost in M1 KO mice (Shen et al, 2005). Another type of K ϩ channels that regulate MSN excitability and also are modulated by mAChR signaling is inwardly rectifying potassium (Kir2) channels (Galarraga et al, 1999;Shen et al, 2007). Unlike KCNQ channels, which are inhibited uniformly by mAChR activation in MSNs that reside in both direct and indirect pathways (Shen et al, 2005), Kir2 currents are inhibited differentially by muscarinic activation in MSNs depending on their projection targets; specifically, it preferentially reduces Kir2 channel currents in striatopallidal MSNs but has little effect on striatonigral MSNs (Shen et al, 2005).…”

The scientific and clinical basis for the treatment of Parkinson disease (2009)

“…453 Cholinergic interneurons in the striatum bear D1 and D5 dopamine receptors 454 and exert powerful effects on the excitability of MSNs and dopaminergic function. [455][456][457] The precise mechanism of action of anticholinergic drugs in PD is not known, and it is possible that enhanced benefits with a better safety profile could be obtained with antagonists of muscarinic cholinergic receptor subtypes.…”

Functional roles of neurotransmitters and neuromodulators in the dorsal striatum

“…Potassium currents through A-type K v 4, Kir2, and KCNQ potassium channels are reduced by M1 receptor activation (Galarraga et al 1999;Shen et al 2005) and are accompanied by a shift in voltage-dependent activation and inactivation (Akins et al 1990;Nakamura et al 1997). Also, M1 negatively regulates Ca v 1.3 channels by activating phospholipase C and protein phosphatase 2B (PP-2B), and inhibits Ca v 2.1 channels (Perez-Rosello et al 2005;Perez-Burgos et al 2010).…”