Dopaminergic and cholinergic involvement in the discriminative stimulus effects of nicotine and cocaine in rats.
BACKGROUND
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.
Desai
Rajeev I
RI
School of Psychology, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK. rdesai@intra.nida.nih.gov
Barber
David J
DJ
Terry
Philip
P
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D018679:Cholinergic Agonists / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005475:Flupenthixol / Q000494:pharmacology; D005795:Generalization, Stimulus; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D018721:Muscarinic Agonists / Q000494:pharmacology; D009538:Nicotine / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010862:Pilocarpine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D018679:Cholinergic Agonists; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D018721:Muscarinic Agonists; D018733:Nicotinic Antagonists; D010862:Pilocarpine; D008464:Mecamylamine; D009538:Nicotine; D005475:Flupenthixol; D003042:Cocaine; D000109:Acetylcholine; D004298:Dopamine