Disrupting D1-NMDA or D2-NMDA receptor heteromerization prevents cocaine’s rewarding effects but preserves natural reward processing

Abstract

D2R-NMDAR receptor heteromers are potential therapeutic targets in drug addiction.

Cell-Type-Specific Adaptions in Striatal Medium-Sized Spiny Neurons and Their Roles in Behavioral Responses to Drugs of Abuse

“…Notably, we found a sharp decrease of D2R protein contents in samples from individuals with psychostimulant use disorder, which could partly explain the diminished bioavailability of D2R described in psychostimulant-dependent subjects by PET-imaging ( Volkow et al, 1999 ; Koob and Volkow, 2016 ; Trifilieff et al, 2017 ). However, despite this decreased D2R expression, the remaining pool of D2R forming D2R-NMDAR heteromers was threefold higher in subjects with psychostimulant misuse when compared to matched controls ( Andrianarivelo et al, 2021 ), therefore reinforcing that targeting D2R-NMDAR heteromers may be a strategy to pursue in order alleviate addiction symptoms in human.…”

“…To address this issue, the impact of repeated exposures to psychostimulant on DAR-NMDAR interactions has been studies in both MSN subtypes. We observed that cocaine-induced locomotor sensitization is associated with an increased heteromerization of both D1R-NMDAR and D2R-NMDAR in the NAc ( Andrianarivelo et al, 2021 ). However, the dynamics of these receptor interactions differs since cocaine-evoked D1R-NMDAR heteromerization appears as a transient phenomenon, whereas D2R-NMDAR heteromerization in the NAc core subdivision outlasts a one-week abstinence period.…”

“…At the behavioral level, inhibiting D1R-NMDAR selectively blocks the development of cocaine-induced locomotor sensitization and CPP but preserves the maintenance of these behaviors. By contrast, inhibiting D2R-NMDAR complexes alters the maintenance of cocaine’s sensitizing effects as well as the reinstatement of cocaine-induced CPP ( Andrianarivelo et al, 2021 ), therefore showing that DAR-NMDAR heteromerization in both MSN subtypes shapes distinct components of psychostimulant-adaptive behaviors. Notably, the implication of these heteromers depends on the nature of the reward since disrupting either heteromer subtype in the NAc preserves food reward processing ( Andrianarivelo et al, 2021 ).…”

“…By contrast, inhibiting D2R-NMDAR complexes alters the maintenance of cocaine’s sensitizing effects as well as the reinstatement of cocaine-induced CPP ( Andrianarivelo et al, 2021 ), therefore showing that DAR-NMDAR heteromerization in both MSN subtypes shapes distinct components of psychostimulant-adaptive behaviors. Notably, the implication of these heteromers depends on the nature of the reward since disrupting either heteromer subtype in the NAc preserves food reward processing ( Andrianarivelo et al, 2021 ). The involvement of D2R-NMDAR heteromerization in controlling the maintenance of the sensitizing and rewarding effects of cocaine without impacting on natural reward processing points those heteromers as targets of potential therapeutic value.…”

“…The involvement of D2R-NMDAR heteromerization in controlling the maintenance of the sensitizing and rewarding effects of cocaine without impacting on natural reward processing points those heteromers as targets of potential therapeutic value. This assumption is reinforced by the fact that such heteromers are also detected in human post-mortem caudate putamen samples from subjects with psychostimulant use disorder and matched controls ( Andrianarivelo et al, 2021 ). Notably, we found a sharp decrease of D2R protein contents in samples from individuals with psychostimulant use disorder, which could partly explain the diminished bioavailability of D2R described in psychostimulant-dependent subjects by PET-imaging ( Volkow et al, 1999 ; Koob and Volkow, 2016 ; Trifilieff et al, 2017 ).…”