Dopaminergic and cholinergic involvement in the discriminative stimulus effects of nicotine and cocaine in rats

Psychopharmacology (Berl). 2003 Jun;167(4):335-43. doi: 10.1007/s00213-003-1426-x. Epub 2003 Apr 9.


Rationale: Previous work has demonstrated asymmetrical cross-generalization between the discriminative stimulus effects of nicotine and cocaine: nicotine fully substitutes for cocaine, whereas cocaine only partially substitutes for nicotine. The factors responsible for the similarities and differences between the two drugs remain unclear.

Objective: The study tested the involvement of dopaminergic and/or cholinergic mechanisms in the discriminative stimulus effects of nicotine and cocaine.

Methods: One set of rats was trained to discriminate cocaine (8.9 mg/kg) from saline, and two other sets of rats were trained to discriminate nicotine (0.1 mg/kg) from saline.

Results: In cocaine-trained rats, among the cholinergic agonists studied only nicotine (0.01-0.56 mg/kg) produced full, dose-related substitution; nornicotine (1-5.6 mg/kg) substituted only partially, and lobeline (2.71-15.34 mg/kg) and pilocarpine (0.26-2.55 mg/kg) failed to engender any cocaine-appropriate responding. The nicotinic antagonist mecamylamine (1-5.6 mg/kg) failed to block cocaine's discriminative stimulus effects. The dopamine antagonist cis-flupentixol (0.48 mg/kg) blocked the substitution of nicotine for cocaine. In nicotine-trained rats, the dopamine uptake blockers cocaine, bupropion and nomifensine (0.2-26.1 mg/kg) each substituted only partially for nicotine, and cis-flupentixol (0.48-0.86 mg/kg) antagonized the discriminative stimulus effects of nicotine.

Conclusions: Nicotine fully substitutes for cocaine because of its effects on dopamine transmission, and not because the discriminative stimulus effects of cocaine incorporate a cholinergic component. Substitution of nicotine for cocaine may depend more on nicotine-induced dopamine release than does the nicotine-trained discriminative stimulus; there may be differential dopaminergic involvement after acute and repeated treatment with nicotine or cocaine.

Publication types

  • Comparative Study

MeSH terms

  • Acetylcholine / metabolism
  • Animals
  • Cholinergic Agonists / pharmacology*
  • Cocaine / pharmacology*
  • Conditioning, Operant / drug effects
  • Discrimination, Psychological / drug effects*
  • Dopamine / metabolism
  • Dopamine Antagonists / pharmacology
  • Dopamine Uptake Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Flupenthixol / pharmacology
  • Generalization, Stimulus
  • Male
  • Mecamylamine / pharmacology
  • Muscarinic Agonists / pharmacology
  • Nicotine / pharmacology*
  • Nicotinic Antagonists / pharmacology
  • Pilocarpine / pharmacology
  • Rats
  • Rats, Sprague-Dawley


  • Cholinergic Agonists
  • Dopamine Antagonists
  • Dopamine Uptake Inhibitors
  • Muscarinic Agonists
  • Nicotinic Antagonists
  • Pilocarpine
  • Mecamylamine
  • Nicotine
  • Flupenthixol
  • Cocaine
  • Acetylcholine
  • Dopamine