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Amphetamine self-administration attenuates dopamine D2 autoreceptor function.

Erin S Calipari1, Haiguo Sun1, Khalil Eldeeb1

  • 1Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston Salem, NC, USA.

Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology
|February 12, 2014
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Summary
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Amphetamine (AMPH) disrupts dopamine D2 autoreceptor function by impairing its G-protein coupling in the midbrain. This dysfunction, linked to increased RGS2 activity, may drive addiction by enhancing dopamine signaling.

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • Dopamine D2 autoreceptors regulate dopamine neuron activity via negative feedback.
  • Dysfunctional autoreceptors after drug exposure can lead to aberrant dopamine signaling and addiction.

Purpose of the Study:

  • To investigate the molecular mechanisms of drug-induced changes in dopamine D2 autoreceptor function.
  • To identify the specific G-protein coupling and signaling pathways affected by amphetamine.

Main Methods:

  • Voltammetry to assess dopamine release in the nucleus accumbens.
  • Antibody-capture [(35)S]GTPγS scintillation proximity assay to determine receptor-G-protein coupling.
  • Analysis of Regulator of G-protein Signaling (RGS) protein expression and trafficking.

Main Results:

  • Amphetamine self-administration impaired D2 autoreceptor-mediated inhibition of dopamine release.
  • Midbrain D2/D3 receptors preferentially couple to Gαi2, while striatal receptors couple to Gαi2 and Gαo.
  • Amphetamine abolished the Gαi2 interaction with midbrain D2/D3 receptors, associated with increased RGS2 activity.
  • Amphetamine did not affect RGS4 or RGS8 in the midbrain.

Conclusions:

  • Midbrain D2/D3 receptors are particularly vulnerable to amphetamine-induced alterations in G-protein coupling.
  • Disrupted D2 autoreceptor function, potentially mediated by RGS2, contributes to enhanced dopamine signaling and addiction.
  • RGS2 represents a potential therapeutic target for addiction treatment.