Modulating inhibitory response control through potentiation of GluN2D subunit-containing NMDA receptors

• Published in: Neuropharmacology 2020-08, Vol.173, p.107994-107994, Article 107994
• Main Authors: Callahan, Patrick M., Terry, Alvin V., Nelson, Frederick R., Volkmann, Robert A., Vinod, A.B., Zainuddin, Mohd, Menniti, Frank S.
• Format: Article
• Language: English
• Subjects: Basal ganglia; Executive function; GluN2D positive allosteric modulators; Inhibitory response control; NMDA receptors
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2020.107994

NMDA receptors containing GluN2D subunits are expressed in the subthalamic nucleus and external globus pallidus, key nuclei of the indirect and hyperdirect pathways of the basal ganglia. This circuitry integrates cortical input with dopaminergic signaling to select advantageous behaviors among available choices. In the experiments described here, we characterized the effects of PTC-174, a novel positive allosteric modulator (PAM) of GluN2D subunit-containing NMDA receptors, on response control regulated by this circuitry. The indirect pathway suppresses less advantageous behavioral choices, a manifestation of which is suppression of locomotor activity in rats. Systemic administration of PTC-174 produced a dose-dependent reduction in activity in rats placed in a novel open field or administered the stimulants MK-801 or amphetamine. The hyperdirect pathway controls release of decisions from the basal ganglia to the cortex to optimize choice processing. Such response control was modeled in rats as premature responding in the 5-choice serial reaction time (5-CSRT) task. PTC-174 produced a dose-dependent reduction in premature responding in this task. These data suggest that potentiation of GluN2D receptor activity by PTC-174 facilitates the complex basal ganglia information processing that underlies response control. The behavioral effects occurred at estimated free PTC-174 brain concentrations predicted to induce 10–50% increases in GluN2D activity. The present findings suggest the potential of GluN2D PAMs to modulate basal ganglia function and to treat neurological disorders related to dysfunctional response control. [Display omitted] •PTC-174 is a novel positive allosteric modulator of GluN2D subunit-containing NMDA receptors.•PTC-174 reduced spontaneous activity in a novel open field and hyperactivity produced by the stimulants amphetamine or MK-801 in rats.•PTC-174 improved inhibitory response control without degrading choice accuracy in a 5-CSRT task in adult rats.•Effects of PTC-174 may be accounted for by potentiation of activity in the indirect/hypredirect basal ganglia pathways.