Antagonism of Muscarinic Acetylcholine Receptors Alters Synaptic ERK Phosphorylation in the Rat Forebrain

Abstract

Acetylcholine (ACh) is a key transmitter in the mesocorticolimbic circuit. By interacting with muscarinic ACh receptors (mAChR) enriched in the circuit, ACh actively regulates various neuronal and synaptic activities. The extracellular signal-regulated kinase (ERK) is one of members of the mitogen-activated protein kinase family and is subject to the regulation by dopamine receptors, although the regulation of ERKs by limbic mAChRs is poorly understood. In this study, we investigated the role of mAChRs in the regulation of ERK phosphorylation (activation) in the mesocorticolimbic system of adult rat brains in vivo. We targeted a sub-pool of ERKs at synaptic sites. We found that a systemic injection of the mAChR antagonist scopolamine increased phosphorylation of synaptic ERKs in the striatum (caudate putamen and nucleus accumbens) and medial prefrontal cortex (mPFC). Increases in ERK phosphorylation in both forebrain regions were rapid and transient. Notably, pretreatment with a dopamine D1 receptor (D1R) antagonist SCH23390 blocked the scopolamine-stimulated ERK phosphorylation in these brain regions, while a dopamine D2 receptor antagonist eticlopride did not. Scopolamine and SCH23390 did not change the amount of total ERK proteins. These results demonstrate that mAChRs inhibit synaptic ERK phosphorylation in striatal and mPFC neurons under normal conditions. Blockade of this inhibitory mAChR tone leads to the upregulation of ERK phosphorylation likely through a mechanism involving the level of D1R activity.

Intrastriatal administration of botulinum neurotoxin A normalizes striatal D2R binding and reduces striatal D1R binding in male hemiparkinsonian rats

“…We therefore hypothesize that, in the present study, the reduction in D 1 R concentrations is attributable to BoNT‐A instead of 6‐OHDA intervention. On the other hand, no change in striatal D 1 R expression was observed in mice lacking the muscarinic M 4 AChR (M 4 mAChR) (Schmidt et al, ), despite the reciprocal involvement of both transmitter targets in striatonigral signaling (Mao, Wang, & Wang, ) and transmitter release (Tzavara et al, ). Thus, whether M 4 mAChRs are directly involved in the effect of BoNT‐A on striatal D 1 Rs needs to be proven.…”

Na+, K+-ATPase Signaling and Bipolar Disorder

“…It is well established that alterations in these intracellular signaling have profound effects on synaptic transmission and plasticity. This was documented repeatedly for ERK [ 110 , 111 , 112 ], AKT [ 113 , 114 , 115 ], and NFκB [ 116 , 117 , 118 ] activations.…”

Muscarinic Acetylcholine Receptors Inhibit Fyn Activity in the Rat Striatum In Vivo

“…Scopolamine was administered at a dose of 5 mg/kg. Selection of this dose was due to the fact that scopolamine injected at this dose increased immediate early gene expression and phosphorylation of extracellular signal-regulated kinases in the rat striatum in vivo (Wang and McGinty, 1996a; Mao et al, 2017). Atropine was injected at 5 mg/kg (i.p.).…”