PROJECT SUMMARY / ABSTRACT
Our proposal investigates in the nonhuman primate (NHP) how muscarinic modulation enhances cognition,
motivation and behavioral regulation and which neurochemical and cell-type specific mechanisms underlie these
positive effects. We specifically will benchmark a positive allosteric modulator (PAM) for the centrally expressed
muscarinic M1 receptor, developed at the Vanderbilt Center for Drug Discovery. M1-PAMs promise to overcome
dose-limiting side effects and avoid agonist overstimulation that limit compliance, efficacy, and tolerability of
existing compounds. M1 selective modulation can be antipsychotic, reduce negative symptoms (e.g. reduce lack
of motivation) and ameliorate cognitive deficits in patients with schizophrenia. M1-PAMs may achieve this by
gating intrinsic cholinergic signaling which is believed to regulate glutamatergic and dopaminergic release in the
prefrontal cortex and striatum. We test these hypothesized working mechanisms by determining the
neurochemical and electrophysiological consequences of M1 PAM action.
First, we will determine the dose-response efficacy of M1 PAMs to enhance cognition, motivation, and behavioral
regulation, comparing their effects to the agonist Xanomeline and the non-selective cholinergic drug Donepezil.
We will assess primary cognitive functions (attention, working memory), primary motivational functions (effort
control, resilience to loss), cognitive flexibility (set shifting, perseveration, reward learning), visuospatial problem
solving, and the regulation of behavior video-captured when NHPs engage with the touchscreen assessment
Kiosk in their home cages. The behavioral metrics evaluate five RDoC domains, tested in single sessions using
a novel Multi-Task Test Battery for NHP. We will determine dose-response efficacy for each RDoC domain
separately which clarifies how broad M1 PAMs enhance cognitive-motivational-behavioral functions and which
domains suffer from dose-limiting side effects with a conventional agonist and a nonselective cholinergic drug.
Second, we will determine the drug-dose dependent changes of extracellular concentrations of Acetylcholine,
Dopamine, Serotonin, Glutamate, GABA, and of the systemically administered drug itself. We achieve this in
NHPs in parallel in three brain areas that load differently on the five RDoC domains to determine the dose-
response efficacy for each brain area separately. The dorsolateral prefrontal cortex is assessed to understand
how M1 PAMs regulate glutamate and acetylcholine implicated to support cognitive RDoC constructs. The
Striatum is assessed to understand how M1 PAMs regulate dopamine to support reward learning and cognitive
flexibility. The anterior cingulate cortex is assessed to determine dose-efficacy for modulating serotonin and
glutamate to mediate effort-control and motivation. Simultaneously, neural spiking activity is recorded to
understand how M1 PAMs alter firing and synchronization of different interneuron types that we distinguish
electrophysiologically. Together, the proposed studies elucidate the working mechanisms and strength of M1
PAMs relative to existing dose-limited drug regime and thereby inform treatment strategies for schizophrenia.