Nicotinic acetylcholine receptors in the ventral tegmental area mediate the dopamine activating and reinforcing properties of ethanol cues

Psychopharmacology (Berl). 2007 Dec;195(3):333-43. doi: 10.1007/s00213-007-0899-4. Epub 2007 Aug 17.

Abstract

Rationale: Cues associated with alcohol can elicit craving, support drug-seeking and precipitate relapse.

Objectives: We investigated the possible involvement of nicotinic acetylcholine receptors (nAChRs) in the ventral tegmental area (VTA) in the conditioned reinforcing properties of ethanol-associated stimuli in the rat.

Materials and methods: First, using in vivo microdialysis, we analyzed the effect of VTA perfusion of the nonselective nAChR antagonist mecamylamine (MEC) or the selective alpha4beta2* nAChR antagonist dihydro-beta-erythroidine (DHbetaE) on the nucleus accumbens (nAc) dopaminergic response to the presentation of an ethanol-associated conditioned stimulus (CS). Second, rats were trained to associate a tone+light CS with the presentation of 10% ethanol and were subsequently tested on the acquisition of a new instrumental response with conditioned reinforcement (CR) after local VTA infusion of MEC, DHbetaE, or alpha-Conotoxin MII (alpha-CtxMII, a selective alpha3beta2* and alpha6* nAChR antagonist).

Results: The ethanol-associated CS elevated nAc dopamine, an effect that was blocked by VTA perfusion of MEC but not DHbetaE. Systemic administration of MEC or local VTA infusion of MEC or alpha-CtxMII selectively blocked ethanol-associated CR, whereas systemic DHbetaE had no effect.

Conclusions: We hypothesize a novel mechanism by which alcohol-associated cues promote drug-seeking behavior via activation of dopamine-stimulating alpha-CtxMII-sensitive nAChRs in the VTA. Pharmacological manipulations of selective nAChRs may thus be possible treatment strategies to prevent cue-induced relapse.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Conditioning, Operant / drug effects*
  • Conotoxins / pharmacology
  • Cues
  • Dihydro-beta-Erythroidine / pharmacology
  • Dopamine / metabolism*
  • Ethanol / pharmacology*
  • Male
  • Mecamylamine / pharmacology
  • Microdialysis
  • Nicotinic Agonists / pharmacology
  • Nicotinic Antagonists / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Receptors, Nicotinic / physiology*
  • Reinforcement, Psychology*
  • Self Administration
  • Ventral Tegmental Area / drug effects*
  • Ventral Tegmental Area / metabolism

Substances

  • Conotoxins
  • Nicotinic Agonists
  • Nicotinic Antagonists
  • Receptors, Nicotinic
  • alpha-conotoxin MII
  • Dihydro-beta-Erythroidine
  • Ethanol
  • Mecamylamine
  • Dopamine