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.