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Delighted that our collaborative study on the role of M4 muscarinic receptors in alcohol addiction is finally out in Biological Psychiatry ( @els_psychiatry). Major effort by teams at @TheFlorey and @MIPS_Australia. What did we find? #scicomm https://www.biologicalpsychiatryjournal.com/article/S0006-3223(20)30131-1/fulltext
We ran genome-wide RNA sequencing on post-mortem caudate-putamen brain samples from age and gender matched non-smoking individuals with alcohol use disorder (AUD) and non-drinkers.
Using qPCR & radioligand binding (old school), we showed that M4 mAChR was down-regulated in putamen in AUD vs. control; no difference in caudate.
Why is this important? Long-term alcohol consumption is thought to result in a shift/switch in engagement from caudate to putamen.
Why is this important? Long-term alcohol consumption is thought to result in a shift/switch in engagement from caudate to putamen.
Putting rats on long term alcohol gives the same result - down-regulation of M4 mAChR only in the dorsolateral striatum (not dorsomedial).
For RNAscope fans, we see this specifically on dopamine D1 positive spiny projection neurons (rather than ChAT-positive interneurons).
For RNAscope fans, we see this specifically on dopamine D1 positive spiny projection neurons (rather than ChAT-positive interneurons).
So, a reduction in dorsolateral M4 mAChR in both human & rats on long-term alcohol? What do they need?
A positive allosteric modulator (PAM), of course
Here we used VU0467154, which markedly and selectively potentiates the affinity (and hence potency) of ACh at the M4 mAChR.
A positive allosteric modulator (PAM), of course
Here we used VU0467154, which markedly and selectively potentiates the affinity (and hence potency) of ACh at the M4 mAChR.
Thanks to Craig Lindsley at @VCNDD_TN for the generous gift of enough compound for these studies!
Systemic administration of VU0467154 to rats on long-term alcohol reduced alcohol self-administration, motivation to obtain alcohol, and cue-induced reinstatement of alcohol seeking, without motor side effects.
And in an elegant twist, microinjections directly into the dorsolateral striatum did the same.
(not dissimilar to our study of the M5 mAChR negative allosteric modulator ML375, which reduced alcohol self-admin after dorsolateral, but not dorsomedial microinjection @NPP_Journal).
(not dissimilar to our study of the M5 mAChR negative allosteric modulator ML375, which reduced alcohol self-admin after dorsolateral, but not dorsomedial microinjection @NPP_Journal).
So, a new(-ish) indication for an old target (M4 is of long standing interest to many in the schizophrenia field); let's hope it moves us towards better therapeutics for #addiction /end
P.S. Kudos to @LeighWalkerPhD for driving this study - a complete star.
