Muscarinic M 4 and M 5 receptors in the ventral subiculum differentially modulate alcohol seeking versus consumption in male alcohol-preferring rats.

Autor: Walker LC; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.; Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia., Huckstep KL; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.; Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia., Chen NA; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.; Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia., Hand LJ; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.; Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia., Lindsley CW; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA., Langmead CJ; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia., Lawrence AJ; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.; Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2021 Sep; Vol. 178 (18), pp. 3730-3746. Date of Electronic Publication: 2021 Jun 03.
DOI: 10.1111/bph.15513
Abstrakt: 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.
Key Results: Long-term alcohol and abstinence dysregulated the expression of genes for muscarinic receptors in the vSub, not in the VTA. Chrm4 was down-regulated following long-term alcohol and abstinence, while Chrm5 was up-regulated following long-term alcohol consumption. Consistent with these data, a positive allosteric modulator (VU0467154) of intra-vSub M 4 receptors reduced context-induced alcohol-seeking, but not motivation for alcohol self-administration, while M 5 receptor negative allosteric modulator (ML375) reduced initial motivation for alcohol self-administration, but not context-induced alcohol-seeking.
Conclusion and Implications: Collectively, our data highlight alcohol-induced cholinergic dysregulation in the vSub and distinct roles for M 4 and M 5 receptor allosteric modulators to reduce alcohol consumption or seeking.
(© 2021 The British Pharmacological Society.)
Databáze: MEDLINE
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