Muscarinic M4 and M5 receptor subtypes in the ventral subiculum differentially modulate alcohol seeking vs consumption in male alcohol preferring rats.

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Muscarinic acetylcholine receptors (mAChRs) mediate alcohol consumption and seeking in rats, and while M4 and M5 mAChRs have recently been implicated to mediate these behaviours in the striatum, their role in other regions remain unknown. The ventral tegmental area (VTA) and ventral subiculum (vSub) both densely express M4 and M5 mAChRs and modulate alcohol seeking via their projections to the nucleus accumbens shell (AcbSh).In Indiana alcohol preferring (iP) male rats we examined Chrm4 (M4 ) and Chrm5 (M5 ) expression in the VTA and vSub following long-term alcohol consumption and abstinence using RT-qPCR. Next, 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 M4 and M5 mAChRs within the vSub in alcohol consumption, context-induced alcohol seeking, locomotor activity and food/water consumption.Long-term alcohol and abstinence dysregulated mAChR gene expression in the vSub, not VTA. Chrm4 was downregulated following long-term alcohol and abstinence, while Chrm5 was upregulated following long-term alcohol consumption. In line with these data, intra-vSub M4 positive allosteric modulator (VU0467154) reduced context-induced alcohol seeking, but not motivation for alcohol self-administration, while M5 negative allosteric modulator (ML375) reduced initial motivation for alcohol self-administration, but not context-induced alcohol seeking.Collectively our data highlight alcohol-induced cholinergic dysregulation in the vSub and distinct roles for M4 and M5 mAChR allosteric modulators to reduce alcohol consumption or seeking.

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Authors: Leigh C Walker, Kate L Huckstep, Nicola A Chen, Lexi J Hand, Craig W Lindsley, Christopher J Langmead, Andrew J Lawrence