Mechanisms of Antiparkinsonian Anticholinergic Therapy Revisited

•Anticholinergics are effective to manage PD, but their side effects limit their utility.•Targeting SCIN has antiparkinsonian and antidyskinetic effects, avoiding side effects.•SCIN burst-pause firing can reveal the mechanisms of anticholinergics in PD and LID.•Restoring normal SCIN activity might maximize the therapeutic effects.•Dopamine D5 receptors in SCIN emerge as a promising target to restore SCIN activity. Before the advent of L-DOPA, the gold standard symptomatic therapy for Parkinson’s disease (PD), anticholinergic drugs (muscarinic receptor antagonists) were the preferred antiparkinsonian therapy, but their unwanted side effects associated with impaired extrastriatal cholinergic function limited their clinical utility. Since most patients treated with L-DOPA also develop unwanted side effects such as L-DOPA-induced dyskinesia (LID), better therapies are needed. Recent studies in animal models demonstrate that optogenetic and chemogenetic manipulation of striatal cholinergic interneurons (SCIN), the main source of striatal acetylcholine, modulate parkinsonism and LID, suggesting that restoring SCIN function might serve as a therapeutic option that avoids extrastriatal anticholinergics’ side effects. However, it is still unclear how the altered SCIN activity in PD and LID affects the striatal circuit, whereas the mechanisms of action of anticholinergic drugs are still not fully understood. Recent animal model studies showing that SCINs undergo profound changes in their tonic discharge pattern after chronic L-DOPA administration call for a reexamination of classical views of how SCINs contribute to PD symptoms and LID. Here, we review the recent advances on the circuit implications of aberrant striatal cholinergic signaling in PD and LID in an effort to provide a comprehensive framework to understand the effects of anticholinergic drugs and with the aim of shedding light into future perspectives of cholinergic circuit-based therapies.