The motivational valence of nicotine in the rat ventral tegmental area is switched from rewarding to aversive following blockade of the alpha7-subunit-containing nicotinic acetylcholine receptor

Psychopharmacology (Berl). 2003 Mar;166(3):306-13. doi: 10.1007/s00213-002-1317-6. Epub 2003 Feb 5.


Rationale: Within the mammalian ventral tegmental area (VTA), nicotine produces both aversive and rewarding motivational effects. However, the specific neuronal nicotinic acetylcholine receptor (nAChR) subtypes responsible for these effects are not clearly understood.

Objectives: In the present study, we challenged the motivational effects of nicotine directly in the VTA with nAChR subunit specific antagonists.

Methods: Using an unbiased place-conditioning procedure as a behavioural assay, we performed bilateral microinfusions of nicotine over a wide range of concentrations (0.008, 8, 24 and 48 nmol/0.5 microl) and challenged the aversive and reinforcing behavioural effects of these nicotine doses with co-administration of di-hydro-beta-erythroidine (DHbetaE) (5 or 50 nmol/0.5 microl), a nAChR antagonist with higher relative affinity for the alpha4beta2 nAChR subunit, methyllycaconitine citrate (MLA) (0.4 or 4 nmol/0.5 microl), a nAChR antagonist that displays greater relative affinity for the alpha7 nAChR, and the NMDA receptor antagonist, d-2-amino-7-phosphoheptanoic acid (AP-7; 18 nmol/0.5 microl).

Results: The alpha4beta2 antagonist DHbetaE blocked both the rewarding and aversive properties of intra-VTA nicotine. However, the alpha7 antagonist MLA blocked nicotine reward and switched the motivational valence of higher doses of nicotine (8-48 nmol/0.5 microl) from rewarding to aversive. The NMDA antagonist AP-7 blocked both the aversive and rewarding effects of intra-VTA nicotine.

Conclusions: These results suggest a functional dissociation between nAChR neural substrates within the VTA that mediate the bivalent motivational properties of nicotine and further suggest that nicotine may produce its motivational effects through a glutamatergic mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Amino-5-phosphonovalerate / analogs & derivatives*
  • 2-Amino-5-phosphonovalerate / pharmacology
  • Aconitine / analogs & derivatives*
  • Aconitine / pharmacology
  • Animals
  • Conditioning, Operant / drug effects
  • Dihydro-beta-Erythroidine / pharmacology
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Antagonists / pharmacology
  • Male
  • Microinjections
  • Motivation*
  • Nicotine / pharmacology*
  • Nicotinic Agonists / pharmacology*
  • Nicotinic Antagonists / pharmacology*
  • Rats
  • Rats, Wistar
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, Nicotinic / drug effects*
  • Reinforcement, Psychology
  • Reward
  • Ventral Tegmental Area / anatomy & histology
  • Ventral Tegmental Area / physiology*
  • alpha7 Nicotinic Acetylcholine Receptor


  • Chrna7 protein, rat
  • Excitatory Amino Acid Antagonists
  • Nicotinic Agonists
  • Nicotinic Antagonists
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Nicotinic
  • alpha7 Nicotinic Acetylcholine Receptor
  • methyllycaconitine
  • Dihydro-beta-Erythroidine
  • Nicotine
  • 2-Amino-5-phosphonovalerate
  • 2-amino-7-phosphonoheptanoic acid
  • Aconitine