Serotonin receptors as potential targets for modulation of nicotine use and dependence

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

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.

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    • "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). "
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    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
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    • "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). "
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    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
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    • "Preclinical research has shown that modulating activity at these receptors may prevent relapse following withdrawal, and may also decrease the amount of drug intake (see above). Targeting the 5-HT system may therefore prove to be an effective strategy in developing treatments for substance abuse (see Fletcher et al., 2008a for review in relation to nicotine addiction), partially due to its importance in regulating impulsivity. Furthermore, abnormally high levels of either impulsive choice or action may also be a potential risk factor for the development of an addictive phenotype. "
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    ABSTRACT: The serotonin (5-hydroxytryptamine; 5-HT) system has long been associated with mood and its dysregulation implicated in the pathophysiology of mood and anxiety disorders. While modulation of 5-HT neurotransmission by drugs of abuse is also recognized, its role in drug addiction and vulnerability to drug relapse is a more recent focus of investigation. First, we review preclinical data supporting the serotonergic raphe nuclei and their forebrain projections as targets of drugs of abuse, with emphasis on the effects of psychostimulants, opioids and ethanol. Next, we examine the role of 5-HT receptors in impulsivity, a core behavior that contributes to the vulnerability to addiction and relapse. Finally, we discuss evidence for serotonergic dysregulation in comorbid mood and addictive disorders and suggest novel serotonergic targets for the treatment of addiction and the prevention of drug relapse.
    Neuropharmacology 04/2011; 61(3):421-32. DOI:10.1016/j.neuropharm.2011.03.022 · 5.11 Impact Factor
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