Dopamine and glutamate interaction mediates reinstatement of drug-seeking behavior by stimulation of the ventral subiculum

Int J Neuropsychopharmacol. 2014 Oct 31;18(1):pyu008. doi: 10.1093/ijnp/pyu008.

Abstract

Background: Drug addiction is a chronic brain disease characterized by recurrent episodes of relapse to drug-seeking/-taking behaviors. The ventral subiculum, the primary output of the hippocampus, plays a critical role in mediating drug-seeking behavior.

Methods: A d-amphetamine intravenous self-administration rat model was employed along with focal electrical stimulation of the ventral subiculum (20 Hz/200 pulses) to examine its role in reinstatement of drug-seeking behavior. Dopamine efflux in the nucleus accumbens was measured by in vivo microdialysis and subsequent HPLC-ED analyses. Pharmacological antagonism of dopamine and ionotropic glutamate receptors locally within the nucleus accumbens was employed to assess the role of glutamate and dopamine in reinstatement of drug-seeking behavior induced by stimulation of the ventral subiculum.

Results: Here, we demonstrate that reinstatement of drug-seeking behavior following extinction of d-amphetamine self-administration by rats was induced by electrical stimulation in the ventral subiculum but not the cortex. This reinstatement was accompanied by a significant increase in dopamine efflux in the nucleus accumbens and was disrupted by microinfusion of a dopamine D1 or D2 antagonist into the nucleus accumbens. Inhibition of N-methyl-D-aspartate or non- N-methyl-D-aspartate receptors had no effect on the reinstatement induced by ventral subiculum stimulation, whereas co-infusion of D1 and N-methyl-D-aspartate antagonists at formerly ineffective doses prevented drug-seeking behavior.

Conclusions: These data support the hypothesis that dopamine/glutamate interactions within the ventral striatum related to memory processes are involved in relapse to addictive behavior.

Keywords: deep brain-stimulation; dopamine amphetamine-reinstatement; nucleus accumbens; ventral subiculum.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3,4-Dihydroxyphenylacetic Acid / metabolism
  • Amphetamine-Related Disorders / physiopathology*
  • Animals
  • Central Nervous System Stimulants / administration & dosage
  • Dextroamphetamine / administration & dosage
  • Dopamine / metabolism*
  • Dopamine Antagonists / pharmacology
  • Drug-Seeking Behavior / physiology*
  • Electric Stimulation
  • Extinction, Psychological / physiology
  • Glutamic Acid / metabolism*
  • Hippocampus / drug effects
  • Hippocampus / physiopathology*
  • Homovanillic Acid / metabolism
  • Male
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / physiopathology
  • Rats, Long-Evans
  • Receptors, Dopamine / metabolism
  • Receptors, Ionotropic Glutamate / antagonists & inhibitors
  • Receptors, Ionotropic Glutamate / metabolism
  • Self Administration
  • Visual Cortex / drug effects
  • Visual Cortex / physiopathology

Substances

  • Central Nervous System Stimulants
  • Dopamine Antagonists
  • Receptors, Dopamine
  • Receptors, Ionotropic Glutamate
  • 3,4-Dihydroxyphenylacetic Acid
  • Glutamic Acid
  • Dextroamphetamine
  • Dopamine
  • Homovanillic Acid