Involvement of alpha1-adrenergic receptors in tranylcypromine enhancement of nicotine self-administration in rat.
BACKGROUND
The mechanisms mediating tobacco addiction remain elusive. Nicotine, the psychoactive component in tobacco, is generally believed to be the main cause of reward and addiction. However, tobacco smoke contains thousands of constituents, some of which may interact with nicotine to enhance reward. It has previously been shown that monoamine oxidase (MAO) inhibition, known to result from smoking, can enhance nicotine self-administration. The aim of the present study was to evaluate the role of noradrenergic systems in mediating this enhancement of nicotine reward.


OBJECTIVE
The objective of this study was to test the hypothesis that MAO inhibitor pretreatment enhances nicotine self-administration by activation of noradrenergic pathways that regulate dopamine release in the nucleus accumbens (NAc).


METHODS
The effect of prazosin (0.0625-0.5 mg/kg, i.p.), a specific alpha1-adrenergic receptor antagonist, was examined on male rats pretreated with tranylcypromine (3 mg/kg), an irreversible inhibitor of MAO A and B. Acquisition of nicotine (10 mug kg(-1) inj(-1), i.v.) self-administration behavior was examined over a 5-day period. Nicotine (60 mug kg(-1) inj(-1), i.v.)-induced increase in NAc extracellular dopamine levels was examined by in vivo microdialysis in non-self-administering animals.


RESULTS
We have shown that (1) tranylcypromine enhances nicotine self-administration, (2) prazosin pretreatment blocks both the acquisition and the expression of nicotine self-administration, and (3) prazosin pretreatment diminishes nicotine-induced dopamine release in the NAc.


CONCLUSIONS
These data indicate that the stimulation of alpha1-adrenergic receptors is critical for tranylcypromine enhancement of nicotine reward and suggest a critical interplay between the noradrenergic and dopaminergic systems in tobacco addiction.
Villégier
Anne-Sophie
AS
Department of Pharmacology, School of Medicine, University of California, Room 360, MS2, Irvine, CA 92697, USA. avillegi@uci.edu
Lotfipour
Shahrdad
S
Belluzzi
James D
JD
Leslie
Frances M
FM
D000818:Animals; D001522:Behavior, Animal; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011224:Prazosin; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects* / Q000378:metabolism; D012201:Reward; D012646:Self Administration; D014191:Tranylcypromine / Q000494:pharmacology*
D008996:Monoamine Oxidase Inhibitors; D018722:Nicotinic Agonists; D018340:Receptors, Adrenergic, alpha-1; D014191:Tranylcypromine; D009538:Nicotine; D004298:Dopamine; D011224:Prazosin