Noradrenergic alpha1 receptors as a novel target for the treatment of nicotine addiction.
Nicotine is the main psychoactive ingredient in tobacco and its rewarding effects are considered primarily responsible for persistent tobacco smoking and relapse. Although dopamine has been extensively implicated in the rewarding effects of nicotine, noradrenergic systems may have a larger role than previously suspected. This study evaluated the role of noradrenergic alpha(1) receptors in nicotine and food self-administration and relapse, nicotine discrimination, and nicotine-induced dopamine release in the nucleus accumbens in rats. We found that the noradrenergic alpha(1) receptor antagonist prazosin (0.25-1 mg/kg) dose dependently reduced the self-administration of nicotine (0.03 mg/kg), an effect that was maintained over consecutive daily sessions; but did not reduce food self-administration. Prazosin also decreased reinstatement of extinguished nicotine seeking induced by either a nicotine prime (0.15 mg/kg) or nicotine-associated cues, but not food-induced reinstatement of food-seeking, and decreased nicotine-induced (0.15 mg/kg) dopamine release in the nucleus accumbens shell. However, prazosin did not have nicotine-like discriminative effects and did not alter the dose-response curve for nicotine discrimination. These findings suggest that stimulation of noradrenergic alpha(1) receptors is involved in nicotine self-administration and relapse, possibly via facilitation of nicotine-induced activation of the mesolimbic dopaminergic system. The findings point to alpha(1) adrenoceptor blockade as a potential new approach to the treatment of tobacco dependence in humans.
Forget
Benoit
B
Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, Toronto, Canada. benoit.forget@pasteur.fr
Wertheim
Carrie
C
Mascia
Paola
P
Pushparaj
Abhiram
A
Goldberg
Steven R
SR
Le Foll
Bernard
B
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D004192:Discrimination, Psychological / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005518:Food Preferences / Q000187:drug effects; D017551:Microdialysis / Q000379:methods; D009538:Nicotine / Q000008:administration & dosage; D018722:Nicotinic Agonists / Q000008:administration & dosage; D011224:Prazosin / Q000627:therapeutic use; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology; D012646:Self Administration / Q000379:methods; D014029:Tobacco Use Disorder / Q000188:drug therapy* / Q000378:metabolism* / Q000523:psychology
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D018722:Nicotinic Agonists; D018340:Receptors, Adrenergic, alpha-1; D009538:Nicotine; D011224:Prazosin