Noradrenergic α1 Receptors as a Novel Target for the Treatment of Nicotine Addiction

Abstract

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.

Effects of risperidone on the acquisition and reinstatement of the conditioned place preference induced by MDMA

“…The action of risperidone on adrenergic alpha1 and alpha2 receptors (Leysen et al, 1988) could contribute to the effects of MDMA + risperidone on reinstatement, since drugs acting at both receptors modify reinstatement of cocaine and nicotine seeking. In particular, alpha2 receptor agonists (Smith and Aston-Jones, 2011) and alpha1 antagonists (Forget et al, 2010;Zhang and Kosten, 2005) block reinstatement of drug-seeking. The potentiation of the reinstating effects of MDMA priming by risperidone observed in our study was probably due to the complex biochemical profile of this antipsychotic, which affects multiple receptor subtypes of several neurotransmitters.…”

Dyskinesias and impulse control disorders in Parkinson's disease: From pathogenesis to potential therapeutic approaches

“…Prazosin successfully diminished nicotine-induced DA release in the NAc shell (Forget et al, 2010), and may therefore be a useful drug to prevent the enhanced dopaminergic neurotransmission observed in the NAc in substance addictions (Willuhn et al, 2010). In the case of drugs that act on ␤-type receptors, propanolol was able to decrease methylphenidate-induced impulsivity (Milstein et al, 2010), prevent retrieval of cocaine-associated conditioned place preference (Otis and Mueller, 2011) and reduce ethanol seeking in rats (Gilpin and Koob, 2010).…”

Dopamine D3 Receptors in the Basolateral Amygdala and the Lateral Habenula Modulate Cue-Induced Reinstatement of Nicotine Seeking

“…Methods are as previously reported (Forget et al, 2010;Gamaleddin et al, 2011;Khaled et al, 2010). Briefly, rats were trained to lever press for food such that each lever press resulted in a 45 mg food pellet (Bioserv, Frenchtown, NJ, USA).…”