Serotonin receptors as potential targets for modulation of nicotine use and dependence
ABSTRACT Nicotine use carries considerable health risks and plays a major role in a variety of diseases. Current pharmacological treatments to aid in smoking cessation include nicotine-replacement therapy and non-nicotinic strategies such as bupropion and varenicline. While these treatments benefit some individuals there is still a need for better and more effective treatment strategies. Nicotine is the major psychoactive substance in tobacco. Some behavioural effects of nicotine, including its reinforcing efficacy result in part from activation of mesolimbic dopamine neurons. Modulation of dopamine function is one potential treatment strategy that could treat nicotine dependence. Serotonergic neurons modulate the functioning of dopamine neurons in a complex fashion. Much of this complexity arises from the fact that serotonin (5-HT) exerts its effects through multiple receptor subtypes, some of which even act in apparent functional opposition to each other. This article reviews evidence, primarily from animal experiments, using behavioural procedures relevant to nicotine use on the potential for 5-HT receptors as targets for treating nicotine dependence. The 5-HT(1A, 2A, 2C, 3, 4, 6) receptor subtypes have received most experimental attention, with the 5-HT(1A) and 5-HT(2C) receptors being the best studied. Several studies have now shown that 5-HT(1A) receptor antagonists alleviate some of the behavioural signs induced by nicotine withdrawal. Electrophysiological and neurochemical studies show that stimulation of 5-HT(2C) receptors reduces the function of the mesolimbic dopamine pathway. 5-HT(2C) receptor agonists block the stimulatory action of nicotine on midbrain dopamine function. They also reduce several behavioural effects of nicotine including its discriminative stimulus properties and reinforcing effects. Although more work remains to be done, 5-HT(2C) receptor agonists perhaps hold the most promise as potential therapies for smoking cessation.
SourceAvailable from: Darakhshan Haleem[Show abstract] [Hide abstract]
ABSTRACT: Apomorphine is a non-narcotic derivative of morphine, which acts as a dopamine agonist to produce psychostimulant like effects. Currently, apomorphine is used in patients with advanced Parkinson's disease, for the treatment of persistent and disabling motor fluctuations, but a constellation of addictive syndromes such as excessive over use of medication, compulsive behaviors, and disturbances of impulse control are noticed in certain patients. Research on rodent models using conditioned place preference (CPP) paradigm also shows that the drug is rewarding. Previously we have shown that repeated administration of apomorphine produces behavioral sensitization which is prevented in rats co-injected with a low (1.0 mg/kg) but not higher (2.0 mg/kg) dose of buspirone. The present study shows that rewarding effects of apomorphine (1.0 mg/kg) in a CPP paradigm are also blocked in rats co-injected with a low (1.0 mg/kg) but not higher (2.0 mg/kg) dose of buspirone. The levels of serotonin and its metabolite are decreased in the caudate as well as nucleus accumbens of rats exhibiting CPP and the decreases do not occur in animals co-injected with low or higher dose of buspirone. The levels of dopamine and its metabolites are not affected in animals exhibiting CPP; administration as well as co-administration of higher dose of buspirone decreased dopamine metabolism in the caudate as well as nucleus accumbens. The findings suggest a critical role of serotonin in the rewarding effects of apomorphine and imply that co-use of buspirone at low doses can help to control addictive syndromes in Parkinson's disease patients on apomorphine therapy.Brain Research 10/2014; 1586. DOI:10.1016/j.brainres.2014.06.022
[Show abstract] [Hide abstract]
ABSTRACT: 5-Hydroxytryptamine2C (5-HT2C) receptor agonists reduce the breakpoint in progressive ratio schedules of reinforcement, an effect that has been attributed to a decrease of the efficacy of positive reinforcers. However, a reduction of the breakpoint may also reflect motor impairment. Mathematical models can help to differentiate between these processes.Psychopharmacology 08/2014; 232(4). DOI:10.1007/s00213-014-3700-5
[Show abstract] [Hide abstract]
ABSTRACT: Smoking tobacco is highly addictive and a leading preventable cause of death. The main addictive constituent is nicotine; consequently it has been administered to laboratory animals to model tobacco dependence. Despite extensive use, this model might not best reflect the powerful nature of tobacco dependence because nicotine is a weak reinforcer, the pharmacology of smoke is complex and non-pharmacological factors have a critical role. These limitations have led researchers to expose animals to smoke via the inhalative route, or to administer aqueous smoke extracts to produce more representative models. The aim was to review the findings from molecular/behavioural studies comparing the effects of nicotine to tobacco/smoke extracts to determine whether the extracts produce a distinct model. Indeed, nicotine and tobacco extracts yielded differential effects, supporting the initiative to use extracts as a complement to nicotine. Of the behavioural tests, intravenous self-administration experiments most clearly revealed behavioural differences between nicotine and extracts. Thus, future applications for use of this behavioural model were proposed that could offer new insights into tobacco dependence.Neuroscience & Biobehavioral Reviews 07/2014; 47. DOI:10.1016/j.neubiorev.2014.07.014