RUOLO DEI RECETTORI NICOTINICI CENTRALI NELL'ADDICTION' E NELLA 'DEPENDENCE' DA NICOTINA: POTENZIALE STRATEGIA FARMACOLOGICA DI NUOVI AGONISTI NICOTINICI PARZIALI
Tesi di Dottorato
Data di Pubblicazione:
2014
Citazione:
RUOLO DEI RECETTORI NICOTINICI CENTRALI NELL'ADDICTION' E NELLA 'DEPENDENCE' DA NICOTINA: POTENZIALE STRATEGIA FARMACOLOGICA DI NUOVI AGONISTI NICOTINICI PARZIALI / L. Ponzoni ; tutor: M. Sala ; direttore della scuola: A. Panerai. Università degli Studi di Milano, 2014 Dec 16. 27. ciclo, Anno Accademico 2014. [10.13130/l-ponzoni_phd2014-12-16].
Abstract:
Rationale 1: Cigarette smoking is one of the most serious health problems worldwide and people trying to stop smoking have high rates of relapse. Nicotine is the main psychoactive ingredient in cigarettes and its binding to neuronal nicotinic acetylcholine receptors (nAChRs) located in the mesolimbic areas induces reward (Picciotto and Kenney, 2013).
Current first-line pharmacotherapies aiming at encouraging people to stop smoking include nicotine replacement therapy, bupropion hydrochloride and varenicline tartrate. The atypical antidepressant bupropion reduces the severity of nicotine craving during withdrawal, but its long-term beneficial effects on relapse are not clear (Hughes et al., 2007). Cytisine-related varenicline tartrate is a partial agonist of α4β2 and α6β2 nAChR subtypes and a full agonist of α7 and α3β4 nAChRs. Clinical trials indicate that varenicline is effective in decreasing relapse to smoking in humans (Cahill et al., 2011; Gonzales et al., 2006; Joreby et al., 2006; Tonstad et al., 2006; Zierler-Brown and Kyle, 2007) but adverse cardiovascular effects and/or neuropsychiatric events have recently been reported including depression, suicidal ideation, suicide attempts and completed suicide (Freedman, 2007; Moore et al., 2011; Singh et al., 2011).
Aim 1: In search for new drugs that act on nicotine-induced dopamine release, firstly we tested the ability of new nicotinic partial agonists derivated from cytisine, 1,2-bis(cytisin-12-ul)ethane (CC4) and 1,4-bis(cytisin-12-yl)-2-butyne (CC26), compared to nicotine, cytisine and varenicline, to reduce nicotine-induced Conditioned Place Preference (CPP) in zebrafish, a promising animal model for rapidly screening new compounds to induce smoking cessation.
Results 1: Our results demonstrated that CC4, CC26, cytisine and varenicline induced per se CPP with an inverted U-shaped dose-response curve similar to that of nicotine. However, when co-administered with the maximally effective dose of nicotine, they blocked its reinforcing effect. Since very little is known about the pharmacology of the native nicotinic subtypes expressed in zebrafish, we used binding and pharmacological experiments to identify the native nicotinic receptors in adult zebrafish brain by means of subtypes-selective antagonists. The results demonstrated that zebrafish brain expresses two distinct classes of nicotinic receptors: one containing the α7 subunit that binds [125I]-αbungarotoxin with high affinity and another that binds [3H]-epibatidine. We used also three antagonists α-conotoxin MII, methyllycaconitine (MLA) and dihydro-β-erythroidine (DhβE), selective respectively for α6β2, α7 and β2. Mecamilamine, a non selective antagonist, DhβE and MLA blocked the nicotine rewarding effect, demonstrating that nicotine exerted its addictive properties acting on α7 and β2 nAChRs.
Since the results obtained in zebrafish looked promising, CC4 was also tested on rats, to verify if in this animal model it was effective in reducing nicotine rewarding effect. Our results demonstrated that CC4, like cytisine and nicotine, induced CPP and is ICV self-administered with an inverted-U dose response curve. Both models (CPP and ICV self-administration) showed that CC4 is per se slighty reinforcing, although to a lesser extent than nicotine. Moreover, in line with the fact that CC4 is a partial agonist, pre-treatment with non-reinforcing doses of CC4 significantly antagonized the rewarding effects induced by nicotine, both in CPP and in self administration task, without affecting motor functions. These findings indicate that this compound has a selective effect in reducing nicotine addiction-associated behaviours.
Conclusions 1: Our results, obtained in zebrafish and in rats, demonstrated
Tipologia IRIS:
Tesi di dottorato
Keywords:
CIGARETTE SMOKE; NICOTINE; ADDICTION; DEPENDENCE
Elenco autori:
L. Ponzoni
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