Fletcher PJ, Le AD, Higgins GA. Serotonin receptors as potential targets for modulation of nicotine use and dependence. Prog Brain Res 172: 361-383

Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Progress in brain research (Impact Factor: 2.83). 02/2008; 172:361-83. DOI: 10.1016/S0079-6123(08)00918-7
Source: PubMed


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.

9 Reads
  • Source
    • "A role of serotonin in behavioral sensitization and drug addiction (Ikram and Haleem, 2011; Fletcher et al., 2008; Fig. 4 – The levels of dopamine, DOPAC and HVA in the caudate (A) and nucleus accumbens (B) of repeated apomorphine, buspirone and co-treated groups. Values are mean7SD (n ¼8). "
    [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 · 2.84 Impact Factor
    • "However, a similar shared neural circuit may not mediate the effects of 5-HT acting on 5-HT 2A and 5-HT 2C receptors on other psychostimulant-induced behaviours, such as cocaine and nicotine self-administration, given that M100907 and Ro60-0175 differentially affect these behaviours as shown in previous studies [26] [27]. Regardless, these receptors are promising targets for treatment of drug addiction [12] [13] although a better understanding of the mechanisms and circuitry of 5-HT 2A and 5-HT 2C receptor modulation of DA is important in the development of those treatments. Expanding the results in the present study to other drugs of abuse such as nicotine would provide valuable information into the viability of these receptors as pharmaceutical targets in the treatment of addic- tion. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Serotonin (5-HT) plays a role in several psychiatric disorders including drug addiction. The 5-HT system modulates the activity of midbrain dopamine (DA) systems, and the behavioural effects of psychostimulants mediated by these systems. The direction of this modulation depends upon the 5-HT receptor subtypes involved, with 5-HT2A and 5-HT2C receptors having opposing effects. For example the 5-HT2A receptor antagonist M100907 and the 5-HT2C receptor agonist Ro60-0175 both attenuate several cocaine-induced behavioural and neurochemical effects. To investigate the possible brain regions involved in the interactions between 5-HT2A or 5-HT2C receptor ligands and cocaine-induced behaviour, we examined the effects of M100907 or Ro60-0175 on cocaine-induced locomotion and mRNA expression of the immediate early gene zif268. Sprague-Dawley rats were pre-treated with M100907 (0.5 mg/kg), Ro60-0175 (1.0 mg/kg) or vehicle, and then injected with cocaine (15 mg/kg) or vehicle. Locomotor activity was monitored for 60 min before rats were sacrificed for zif268 mRNA in situ hybridization mapping. Cocaine increased locomotor activity and zif268 mRNA expression consistently in the nucleus accumbens core, the orbitofrontal cortex and the caudate. M100907 attenuated cocaine-induced locomotion and zif268 mRNA expression in these brain regions in a defined subset of rats but failed to alter any effects of cocaine in another defined subset of rats. Ro60-0175 blocked cocaine-induced locomotion and zif268 mRNA expression in similar brain regions. Our results suggest that despite the opposing actions of 5-HT at 5-HT2A and 5-HT2C receptors, ligands acting on these receptors likely modulate cocaine-induced locomotion via a common mechanism to influence DA-dependent circuitry.
    Behavioural brain research 11/2012; 240(1):171–181. DOI:10.1016/j.bbr.2012.11.030 · 3.03 Impact Factor
  • Source
    • "It has been suggested that 5-HT 2C receptor agonists and 5-HT 2A receptor antagonists may have potential as treatments for cocaine abuse (Bubar and Cunningham, 2006; Higgins and Fletcher, 2003). This potential may extend to other addictive drugs, particularly nicotine (Fletcher et al., 2008). Many of the effects of nicotine are mediated in part by interactions between nicotinic acetylcholine receptors (nAChRs), GABA, glutamate and dopamine in the ventral tegmental area (VTA) (Di Matteo et al., 2007; Markou, 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The reinforcing effects of nicotine are mediated in part by brain dopamine systems. Serotonin, acting via 5-HT(2A) and 5-HT(2C) receptors, modulates dopamine function. In these experiments we examined the effects of the 5-HT(2C) receptor agonist Ro60-0175 and the 5-HT(2A) receptor antagonist (M100907, volinanserin) on nicotine self-administration and reinstatement of nicotine-seeking. Male Long-Evans rats self-administered nicotine (0.03 mg/kg/infusion, IV) on either a FR5 or a progressive ratio schedule of reinforcement. Ro60-0175 reduced responding for nicotine on both schedules. While Ro60-0175 also reduced responding for food reinforcement, response rates under drug treatment were several-fold higher than in animals responding for nicotine. M100907 did not alter responding for nicotine, or food, on either schedule. In tests of reinstatement of nicotine-seeking, rats were first trained to lever press for IV infusions of nicotine; each infusion was also accompanied by a compound cue consisting of a light and tone. This response was then extinguished over multiple sessions. Injecting rats with a nicotine prime (0.15 mg/kg) reinstated responding; reinstatement was also observed when responses were accompanied by the nicotine associated cue. Ro60-0175 attenuated reinstatement of responding induced by nicotine and by the cue. The effects of Ro60-0175 on both forms of reinstatement were blocked by the 5-HT(2C) receptor antagonist SB242084. M100907 also reduced reinstatement induced by either the nicotine prime or by the nicotine associated cue. The results indicate that 5-HT(2C) and 5-HT(2A) receptors may be potential targets for therapies to treat some aspects of nicotine dependence.
    Neuropharmacology 02/2012; 62(7):2288-98. DOI:10.1016/j.neuropharm.2012.01.023 · 5.11 Impact Factor
Show more