A Subpopulation of Neuronal M₄Muscarinic Acetylcholine Receptors Plays a Critical Role in Modulating Dopamine-Dependent Behaviors

Involvement of a Subpopulation of Neuronal M4Muscarinic Acetylcholine Receptors in the Antipsychotic-like Effects of the M1/M4Preferring Muscarinic Receptor Agonist Xanomeline

“…The reported overall effects of xanomeline are in accordance with previous studies (Shannon et al, 2000;Woolley et al, 2009). We previously found that 2 mg/kg amphetamine induced a significantly larger increase in locomotor activity in D1-M4-KO mice relative to wild-type (Jeon et al, 2010). In the present study, D1-M4-KO mice similarly showed a trend toward an increased hyperlocomotor response to amphetamine compared with wild-type controls, although this did not reach significance.…”

“…D1-M4-KO mice were generated as previously described (Jeon et al, 2010). Knock-out mice and their wild-type littermates were bred at the animal facility at the Panum Institute, University of Copenhagen (Copenhagen, Denmark).…”

“…The M 4 mAChR subtype is the major mAChR expressed in the striatum (Levey, 1993), where the receptor is expressed on cholinergic interneurons, as well as on GABAergic projection neurons, where it is coexpressed with D 1 dopamine receptors (Weiner et al, 1990;Bernard et al, 1992). We have recently created a line of mice in which the M 4 mAChR is selectively abrogated in D 1 dopamine receptor-expressing neurons (D1-M4-KO) and shown that this specific subpopulation of M 4 mAChRs is critically involved in the regulation of dopaminergic neurotransmission (Jeon et al, 2010). Here we describe the effects of xanomeline on amphetamine-induced hyperactivity and apomorphine-induced climbing behavior in D1-M4-KO and wild-type mice to investigate the role of this receptor subpopulation in antipsychotic-like effects.…”

Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100

“…Interestingly, muscarinic agonist-induced reductions in accumbal and striatal DA release are absent in M 4 KO mice, suggesting that M 4 negatively regulates dopaminergic tone in these regions (Threlfell et al, 2010). M 4 KO mice also exhibit deficits in PPI and social interaction and enhanced dopamine D1 receptor-mediated effects on locomotor activity, which are recapitulated in D1-M 4 KO mice (Gomeza et al, 1999;Jeon et al, 2010;Koshimizu et al, 2012;Thomsen et al, 2010). Importantly, the APD-like effects of xanomeline are also abolished in both M 4 KO and D1-M 4 KO mice (Woolley et al, 2009;Dencker et al, 2011).…”

“…Both M 4 KO and D1-M 4 KO mice display attenuated antipsychotic-induced catalepsy (Jeon et al, 2010;FinkJensen et al, 2011). Our data showed that VU0152100 did not induce catalepsy over the dose range that produced APD-like activity, consistent with the lack of induction in Fos-li expression in the CP.…”