Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100

被引：101

作者：

Byun, Nellie E. ^{[1
,2
,3
]}

Grannan, Michael ^{[1
,2
]}

Bubser, Michael ^{[1
,2
]}

Barry, Robert L. ^{[3
,4
]}

Thompson, Analisa ^{[1
,2
]}

Rosanelli, John ^{[1
]}

Gowrishankar, Raajaram ^{[5
,6
,7
]}

Kelm, Nathaniel D. ^{[3
,8
]}

Damon, Stephen ^{[3
]}

Bridges, Thomas M. ^{[1
,2
,9
]}

Melancon, Bruce J. ^{[1
]}

Tarr, James C. ^{[1
]}

Brogan, John T. ^{[1
,2
,9
]}

Avison, Malcolm J. ^{[2
,3
,4
]}

Deutch, Ariel Y. ^{[2
,10
]}

Wess, Juergen ^{[11
]}

Wood, Michael R. ^{[1
,9
]}

Lindsley, Craig W. ^{[1
,2
,9
]}

Gore, John C. ^{[3
,8
]}

Conn, P. Jeffrey ^{[1
,2
]}

Jones, Carrie K. ^{[1
,2
]}

机构：

[1] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Med Ctr, Vanderbilt Univ Inst Imaging Sci, Nashville, TN 37232 USA

[4] Vanderbilt Univ, Med Ctr, Dept Radiol & Radiol Sci, Nashville, TN 37232 USA

[5] Vanderbilt Univ, Grad Program Neurosci, Nashville, TN 37232 USA

[6] Vanderbilt Univ, Vanderbilt Brain Inst, Nashville, TN 37232 USA

[7] Vanderbilt Univ, Vanderbilt Int Scholars Program, Nashville, TN 37232 USA

[8] Vanderbilt Univ, Dept Biomed Engn, Nashville, TN 37232 USA

[9] Vanderbilt Univ, Med Ctr, Dept Chem, Nashville, TN 37232 USA

[10] Vanderbilt Univ, Med Ctr, Dept Psychiat, Nashville, TN 37232 USA

[11] Natl Inst Diabet & Digest & Kidney Dis, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD USA

来源：

NEUROPSYCHOPHARMACOLOGY | 2014年 / 39卷 / 07期

基金：

美国国家卫生研究院;

关键词：

M-4; muscarinic; antipsychotic; allosteric; phMRI; VU0152100; IN-VIVO VALIDATION; AGONIST XANOMELINE; CHOLINERGIC INTERNEURONS; FUNCTIONAL CONNECTIVITY; KNOCKOUT MICE; DOPAMINE; RAT; ACTIVATION; EXPRESSION; IDENTIFICATION;

D O I：

10.1038/npp.2014.2

中图分类号：

Q189 [神经科学];

学科分类号：

071006 [神经生物学];

摘要：

Accumulating evidence suggests that selective M-4 muscarinic acetylcholine receptor (mAChR) activators may offer a novel strategy for the treatment of psychosis. However, previous efforts to develop selective M-4 activators were unsuccessful because of the lack of M-4 mAChR subtype specificity and off-target muscarinic adverse effects. We recently developed VU0152100, a highly selective M-4 positive allosteric modulator (PAM) that exerts central effects after systemic administration. We now report that VU01521 00 dose-dependently reverses amphetamine-induced hyperlocomotion in rats and wild-type mice, but not in M-4 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 M-4 on region-specific brain activation, VU0152100 alone and in combination with amphetamine were evaluated using pharmacologic magnetic resonance imaging (phMRI). Key neural substrates of M-4-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 M-4 PAMs as a new approach to the treatment of psychosis and cognitive impairments associated with psychiatric disorders such as schizophrenia.

引用

页码：1578 / 1593

页数：16

共 70 条

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The muscarinic M1/M4 receptor agonist xanomeline exhibits antipsychotic-like activity in Cebus apella monkeys [J].