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The st r iatum i s the pr imar y input structure of the basal ganglia, which participates in motivational and goaldirected behaviors (Pisani et al., 2007). In physiological conditions, local cholinergic interneurons (ChIs) and dopaminergic afferents modulate basal ganglia output through striatal projection neurons, a l so ca l led medium sp iny neurons (MSNs). In general, the release of the neurotransmitters dopamine (DA) and acetylcholine (ACh) elicits contradictory effects on MSNs, which express their corresponding DA receptors (DARs) and muscarinic acetylcholine receptors (mAChRs) , respect ively (Ztaou and Amalric, 2019). Recently, we discovered a novel receptor-receptor interaction (i.e., heteromerization) between the dopamine D2 receptor (D2R) and the muscarinic acetylcholine M1 receptor (M1R), both expressed at striatopallidal MSNs (Crans et al., 2020). The putative striatal D2RM1R complex coordinates a sophisticated interplay between the dopaminergic and chol inergic neurotransmiss ion systems. Fuxe et al. (2012) foresaw that the existence of this heteromer within the str iatum would mechanist ical ly justify the use of anticholinergics in Parkinson’s disease (PD) treatment, thus opening up the development of novel pharmacotherapeutic strategies for PD management. As a proof of concept, we demonstrated that an M1R-selective antagonist (i.e., VU0255035, 10 mg/kg, i.p.) potentiated the antiparkinsonianlike efficacy of an ineffective D2R-selective agonist dose (i.e., sumanirole, 3 mg/kg, i.p.) in a rodent model of experimental Parkinsonism (Crans et al., 2020). Overall, the novel D2R-M1R heteromer could serve as a specific drug target to alleviate motor deficits in PD, whereas it may avoid major adverse effects associated with traditional pharmacotherapies.

neural regeneration research/neural regeneration research

Dopaminergic-cholinergic imbalance in movement disorders: a role for the novel striatal dopamine D<sub>2</sub>- muscarinic acetylcholine M<sub>1</sub> receptor heteromer

Dopaminergic-cholinergic imbalance in movement disorders: a role for the novel striatal dopamine D2- muscarinic acetylcholine M1 receptor heteromer

Dopaminergic-cholinergic imbalance in movement disorders: a role for the novel striatal dopamine D₂- muscarinic acetylcholine M₁ receptor heteromer