Cocaine Self-Administration Elevates GluN2B within dmPFC Mediating Heightened Cue-Elicited Operant Responding

Area of Science:

• Neuroscience
• Addiction Research
• Pharmacology

Background:

• Cue-elicited drug craving is linked to prefrontal cortex (PFC) hyperactivity, suggesting altered excitatory neurotransmission.
• NMDA glutamate receptors, particularly GluN2 subunits, are crucial in addiction-related neuroplasticity.

Purpose of the Study:

• To investigate the relationship between cue-elicited cocaine seeking and GluN2A/B NMDA receptor subunit expression in the PFC.
• To examine these changes during early and late withdrawal phases after extended cocaine self-administration.
• To assess the functional impact of targeting GluN2B receptors in the PFC on drug-seeking behavior.

Main Methods:

• Rats underwent extended access to intravenous cocaine self-administration.
• Expression of GluN2A/B subunits in PFC subregions was measured during early (3 days) and late (30 days) withdrawal.
• The GluN2B-selective antagonist ifenprodil was infused into the dorsomedial PFC (dmPFC) to assess its effect on cue-elicited cocaine and sucrose seeking.

Main Results:

• Cocaine-seeking rats showed increased GluN2B expression in the dmPFC at both 3 and 30 days of withdrawal.
• This elevation was independent of withdrawal duration or prior extinction testing.
• Intra-dmPFC ifenprodil reduced cue-elicited cocaine seeking but potentiated cue-elicited sucrose seeking.

Conclusions:

• Elevated dmPFC GluN2B expression is a persistent pharmacodynamic response to excessive cocaine intake.
• Targeting GluN2B-containing NMDA receptors in the dmPFC can selectively reduce reactivity to drug-associated cues.
• This approach holds potential for treating addiction by diminishing drug seeking while preserving motivation for natural rewards.