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Noradrenergic alpha1 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.

SUBMITTER: Forget B

PROVIDER: S-EPMC3055474 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Noradrenergic alpha1 receptors as a novel target for the treatment of nicotine addiction.

Forget Benoit B Wertheim Carrie C Mascia Paola P Pushparaj Abhiram A Goldberg Steven R SR Le Foll Bernard B

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20100331 8

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 re ...[more]

PMID: 20357760

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Project description:The mammalian main olfactory bulb (MOB) receives a dense noradrenergic innervation from the pontine nucleus locus coeruleus that is important for neonatal odor preference learning and odor processing in mature animals. Modulation of GABAergic granule cells (GCs) is thought to play a key role in the net functional impact of norepinephrine (NE) release in the MOB, yet there are few direct studies of the influence of NE on these cells. In the present study we investigated noradrenergic modulation of GC excitability using electrophysiological approaches in rat MOB slices. A moderate concentration of NE (10 microM) and the alpha1 receptor agonist phenylephrine (10 microM) depolarized and increased spontaneous or current injection-evoked spiking in GCs. By contrast, low NE concentrations (0.1-1.0 microM) or the alpha2 receptor agonist clonidine (Clon, 10 microM) hyperpolarized and decreased the discharge of GCs. The effects of NE (10 microM) were blocked by antagonism of alpha1 and alpha2 receptors. Inhibitory effects of low NE concentrations were blocked or converted to excitatory responses by alpha2 receptor blockade, whereas excitatory effects of the moderate NE concentration were converted to inhibitory responses after alpha1 receptor blockade. NE (10 microM) and phenylephrine elicited inward currents that reversed near the potassium equilibrium potential. The effects of NE and phenylephrine were associated with increased membrane input resistance. Clonidine elicited an outward current associated with decreased membrane input resistance that reversed near the potassium equilibrium potential. These results indicate that alpha1 and alpha2 receptor activation exert opposing effects on GC excitability. Low concentrations of NE acting via alpha2 receptors suppress GC excitability, while higher concentrations of NE acting at alpha1 receptors increase GC excitability. These findings are consistent with recent findings that alpha1 and alpha2 receptor activation increase and decrease, respectively, GABAergic inhibition of mitral cells. The differential affinities of alpha1 and alpha2 noradrenergic receptor subtypes may allow for differential modulation of GABA release and olfactory processing as a function of the level of NE release, which in turn, is regulated by behavioral state.

Project description:BACKGROUND:Smoking and tobacco use continue to be the largest preventable causes of death globally. A novel therapeutic approach has recently been proposed: administration of an enzyme that degrades nicotine, the main addictive component of tobacco, minimizing brain exposure and reducing its reinforcing effects. Pre-clinical proof of concept has been previously established through dosing the amine oxidase NicA2 from Pseudomonas putida in rat nicotine self-administration models of addiction. RESULTS:This paper describes efforts towards optimizing NicA2 for potential therapeutic use: enhancing potency, improving its pharmacokinetic profile, and attenuating immunogenicity. Libraries randomizing residues located in all 22 active site positions of NicA2 were screened. 58 single mutations with 2- to 19-fold enhanced catalytic activity compared to wt at 10??M nicotine were identified. A novel nicotine biosensor assay allowed efficient screening of the many primary hits for activity at nicotine concentrations typically found in smokers. 10 mutants with improved activity in rat serum at or below 250?nM were identified. These catalytic improvements translated to increased potency in vivo in the form of further lowering of nicotine blood levels and nicotine accumulation in the brains of Sprague-Dawley rats. Examination of the X-ray crystal structure suggests that these mutants may accelerate the rate limiting re-oxidation of the flavin adenine dinucleotide cofactor by enhancing molecular oxygen's access. PEGylation of NicA2 led to prolonged serum half-life and lowered immunogenicity observed in a human HLA DR4 transgenic mouse model, without impacting nicotine degrading activity. CONCLUSIONS:Systematic mutational analysis of the active site of the nicotine-degrading enzyme NicA2 has yielded 10 variants that increase the catalytic activity and its effects on nicotine distribution in vivo at nicotine plasma concentrations found in smokers. In addition, PEGylation substantially increases circulating half-life and reduces the enzyme's immunogenic potential. Taken together, these results provide a viable path towards generation of a drug candidate suitable for human therapeutic use in treating nicotine addiction.

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Noradrenergic alpha1 receptors as a novel target for the treatment of nicotine addiction.

Publications

Noradrenergic alpha1 receptors as a novel target for the treatment of nicotine addiction.

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