Antipsychotic drug-like effects of the selective M4 muscarinic acetylcholine receptor positive allosteric modulator VU0152100.
Accumulating evidence suggests that selective M4 muscarinic acetylcholine receptor (mAChR) activators may offer a novel strategy for the treatment of psychosis. However, previous efforts to develop selective M4 activators were unsuccessful because of the lack of M4 mAChR subtype specificity and off-target muscarinic adverse effects. We recently developed VU0152100, a highly selective M4 positive allosteric modulator (PAM) that exerts central effects after systemic administration. We now report that VU0152100 dose-dependently reverses amphetamine-induced hyperlocomotion in rats and wild-type mice, but not in M4 KO mice. VU0152100 also blocks amphetamine-induced disruption of the acquisition of contextual fear conditioning and prepulse inhibition of the acoustic startle reflex. These effects were observed at doses that do not produce catalepsy or peripheral adverse effects associated with non-selective mAChR agonists. To further understand the effects of selective potentiation of M4 on region-specific brain activation, VU0152100 alone and in combination with amphetamine were evaluated using pharmacologic magnetic resonance imaging (phMRI). Key neural substrates of M4-mediated modulation of the amphetamine response included the nucleus accumbens (NAS), caudate-putamen (CP), hippocampus, and medial thalamus. Functional connectivity analysis of phMRI data, specifically assessing correlations in activation between regions, revealed several brain networks involved in the M4 modulation of amphetamine-induced brain activation, including the NAS and retrosplenial cortex with motor cortex, hippocampus, and medial thalamus. Using in vivo microdialysis, we found that VU0152100 reversed amphetamine-induced increases in extracellular dopamine levels in NAS and CP. The present data are consistent with an antipsychotic drug-like profile of activity for VU0152100. Taken together, these data support the development of selective M4 PAMs as a new approach to the treatment of psychosis and cognitive impairments associated with psychiatric disorders such as schizophrenia.
1] Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA [3] Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, USA.
Nellie E
NE
Byun
1] Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
Michael
M
Grannan
1] Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
Michael
M
Bubser
1] Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
Robert L
RL
Barry
1] Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
Analisa
A
Thompson
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
John
J
Rosanelli
1] Neuroscience Graduate Program, Vanderbilt University, Nashville, TN, USA [2] Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA [3] Vanderbilt International Scholars Program, Vanderbilt University, Nashville, TN, USA.
Raajaram
R
Gowrishankar
1] Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.
Nathaniel D
ND
Kelm
Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, USA.
Stephen
S
Damon
1] Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA [3] Department of Chemistry, Vanderbilt University Medical Center, Nashville, TN, USA.
Thomas M
TM
Bridges
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
Bruce J
BJ
Melancon
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
James C
JC
Tarr
1] Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA [3] Department of Chemistry, Vanderbilt University Medical Center, Nashville, TN, USA.
John T
JT
Brogan
1] Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA [2] Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, USA [3] Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
Malcolm J
MJ
Avison
1] Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Psychiatry, Vanderbilt University Medical Center, Nashville, TN, USA.
Ariel Y
AY
Deutch
Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Jürgen
J
Wess
1] Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Chemistry, Vanderbilt University Medical Center, Nashville, TN, USA.
Michael R
MR
Wood
1] Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA [3] Department of Chemistry, Vanderbilt University Medical Center, Nashville, TN, USA.
Craig W
CW
Lindsley
1] Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA [3] Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.
John C
JC
Gore
1] Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
P Jeffrey
PJ
Conn
1] Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
Carrie K
CK
Jones
D000661:Amphetamine / Q000633:toxicity; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002461:Cell Line, Transformed; D000697:Central Nervous System Stimulants / Q000633:toxicity; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D005239:Fear / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006948:Hyperkinesis / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043588:Receptor, Muscarinic M4 / Q000819:agonists* / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics; D013216:Reflex, Startle / Q000187:drug effects; D013876:Thiophenes / Q000494:pharmacology*
C579414:3-amino-N-(4-methoxybenzyl)-4,6-dimethylthieno(2,3-b)pyridine-2-carboxamide; D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D011725:Pyridines; D043588:Receptor, Muscarinic M4; D013876:Thiophenes; D000661:Amphetamine