Muscarinic M₄ and M₅ receptors in the ventral subiculum differentially modulate alcohol seeking versus consumption in male alcohol‐preferring rats

Abstract

Background and Purpose: Muscarinic acetylcholine receptors mediate alcohol consumption and seeking in rats. While M 4 and M 5 receptors have recently been implicated to mediate these behaviours in the striatum, their role in other brain regions remain unknown. The ventral tegmental area (VTA) and ventral subiculum (vSub) both densely express M 4 and M 5 receptors and modulate alcohol-seeking, via their projections to the nucleus accumbens shell (AcbSh). Experimental Approach: In Indiana alcohol-preferring (iP) male rats, we examined Chrm4 (M 4 ) and Chrm5 (M 5 ) expression in the VTA and vSub following long-term alcohol consumption and abstinence using RT-qPCR. Using a combination of retrograde tracing and RNAscope, we examined the localisation of Chrm4 and Chrm5 on vSub cells that project to the AcbSh. Using selective allosteric modulators, we examined the functional role of M 4 and M 5 receptors within the vSub in alcohol consumption, context-induced alcohol-seeking, locomotor activity, and food/water consumption.

M1 muscarinic receptor activation decreases alcohol consumption via a reduction in consummatory behavior

“…We have previously shown that allosteric modulation of the M 4 and M 5 receptors specifically reduces alcohol consumption in male iP rats. 4,5,7 Further, we show similar striatal M 4 mAChR dysregulation across human and rodent species following chronic alcohol consumption. 5 Whether the same alcohol-induced dysregulation is observed in outbred strains has not been thoroughly examined, however, iP rats are a strain that voluntarily consumes enough alcohol to achieve intoxication and dependence.…”

“…Operant self‐administration was conducted as per our previous reports 7,35,36 . Standard operant chambers (Med Associates) located in ventilated cubicles fitted with sound‐proofing were used.…”

“…Operant self-administration was conducted as per our previous reports. 7,35,36 Standard operant chambers (Med Associates) located in ventilated cubicles fitted with sound-proofing were used. Individual chambers were equipped with two retractable levers, located on opposite sides of the chamber.…”

“…Recently, we have implicated both the M 4 and M 5 muscarinic acetylcholine receptors (mAChRs) in alcohol consumption and seeking. [4][5][6][7] However, little research has focused on M 1 mAChRs in drug and alcohol use disorders (AUD), with a primary focus surrounding cognition, including in Alzheimer's disease (AD), Parkinson's disease (PD), and schizophrenia. [8][9][10] M 1 mAChRs are expressed in reward circuitry, including the amygdala, striatum, and hippocampus.…”

“…Given that acetylcholine (ACh) mediates reward, 1,2 learning, memory, and other higher‐order cognitive processes, 3 the cholinergic system is an appealing pathway to target for the treatment of neuropsychiatric disorders, including addiction. Recently, we have implicated both the M 4 and M 5 muscarinic acetylcholine receptors (mAChRs) in alcohol consumption and seeking 4‐7 . However, little research has focused on M 1 mAChRs in drug and alcohol use disorders (AUD), with a primary focus surrounding cognition, including in Alzheimer's disease (AD), Parkinson's disease (PD), and schizophrenia 8‐10 …”