Accumbens Mechanisms for Cued Sucrose Seeking

Area of Science:

• Neuroscience
• Addiction Research
• Neuropharmacology

Background:

• Addictive drugs and natural rewards activate similar brain circuits, particularly dopamine pathways.
• Relapse to drug seeking involves glutamate spillover in the nucleus accumbens core (NAcore), activating metabotropic glutamate receptor 5 (mGluR5) on neuronal nitric oxide synthase (nNOS) interneurons.
• Unlike drug seeking, sucrose seeking does not typically involve glutamate spillover.

Purpose of the Study:

• To investigate if promoting glutamate spillover in the NAcore could mimic cocaine-induced adaptations and enhance cue-induced reinstatement of sucrose seeking.
• To explore the role of presynaptic metabotropic glutamate receptor 2/3 (mGluR2/3) and mGluR5 in regulating glutamate release and its impact on seeking behaviors.

Main Methods:

• Blocking astroglial glutamate transporters (GLT-1) to induce glutamate spillover.
• Administering antagonists for mGluR2/3 and mGluR5.
• Stimulating mGluR5 and activating nNOS interneurons chemogenetically.
• Utilizing animal models of relapse to drug and sucrose seeking.

Main Results:

• Blocking GLT-1 to induce glutamate spillover did not affect reinstated sucrose seeking.
• Blocking mGluR2/3 potentiated cue-induced sucrose seeking, an effect reversed by mGluR5 antagonism.
• mGluR5 stimulation did not promote sucrose seeking, and blocking nNOS did not reduce potentiated sucrose seeking after mGluR2/3 blockade.
• Chemogenetic activation of nNOS interneurons reinstated sucrose seeking.

Conclusions:

• Dysregulated presynaptic mGluR2/3 signaling, rather than glutamate spillover activating nNOS, appears to be a shared signaling mechanism in drug seeking and potentiated sucrose seeking.
• These findings differentiate the neurobiological pathways underlying drug addiction and natural reward seeking.