Nellie E. Byun1,
2, Robert L. Barry, 23, Michael D. Grannan4,
Stephen M. Damon5, Nathaniel D. Kelm, 26, Matthew J.
Mulder1, Amanda W. Huang1, Thomas M. Bridges1,
4, Malcolm J. Avison, 23, Craig W. Lindsley1,
7, Jeff Conn1, 4, John C. Gore2,
3, Carrie K. Jones1, 4
1Center
for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, United
States; 2Institute of Imaging Science, Vanderbilt University,
Nashville, TN, United States; 3Radiology & Radiological
Sciences, Vanderbilt University, Nashville, TN, United States; 4Pharmacology,
Vanderbilt University, Nashville, TN, United States; 5Neurology,
Vanderbilt University, Nashville, TN, United States; 6Biomedical
Engineering, Vanderbilt University, Nashville, TN, United States; 7Chemistry,
Vanderbilt University, Nashville, TN, United States
Pharmacological MRI was used to determine the effects of a selective M4 muscarinic acetylcholine receptor positive allosteric modulator, VU0152100, on amphetamine-evoked dopaminergic neurotransmission and functional connectivity in rats in vivo. VU0152100 blunted amphetamine-evoked activation in striatal regions, consistent with separate microdialysis results, as well as in thalamus and hippocampus. Functional connectivity analysis revealed multiple functional correlations in the amphetamine group and loss of correlations with VU0152100 pretreatment, notably for retrosplenial and accumbal connections. These findings support potentiation of endogenous cholinergic activity at M4 as a novel antipsychotic mechanism through which dopaminergic activity can be modulated without directly targeting dopamine receptors.