Role of Central Serotonin Receptors in Nicotine Addiction

Abstract

Regulation of normal or abnormal behaviour is critically controlled by the central serotonergic systems. Recent evidence has suggested that serotonin (5-HT) neurotransmission dysfunction contributes to a variety of pathological conditions, including depression, anxiety, schizophrenia and Parkinson's disorders. There is also a great amount of evidence indicating that 5-HT signalling may affect the reinforcing properties of drugs of abuse by the interaction and modulation of dopamine (DA) function. This chapter is focused on one of the more addictive drugs, nicotine. It is widely recognised that the effects of nicotine are strongly associated with the stimulatory action it exhibits on mesolimbic DAergic function. We outline the role of 5-HT and its plethora of receptors, focusing on 5-HT 2 subtypes with relation to their involvement in the neurobiology of nicotine addiction. We also explore the novel pharmacological approaches using 5-HT agents for the treatment of nicotine dependence. Compelling evidence shows that 5-HT 2C receptor agonists may be possible therapeutic targets for smoking cessation, although further investigation is required.

Acute and Chronic Nicotine Exposures Differentially Affect Central Serotonin 2A Receptor Function: Focus on the Lateral Habenula

“…Our data on the LHb further support the significant involvement of this small epithalamic area [28,29] and the 5-HT 2A R system [17,35] and their interaction in nicotine effects in the brain and, in general, in drug dependency. Nicotine's modulation is a complex phenomenon and, apart from the rewarding effect mediated by increasing DAergic transmission [7], this alkaloid modulates different neurotransmitter systems.…”

“…Nicotine's modulation is a complex phenomenon and, apart from the rewarding effect mediated by increasing DAergic transmission [7], this alkaloid modulates different neurotransmitter systems. Among them, nicotine affects 5-HT neurons and 5-HT-innervated brain areas [17,36]. For instance, the LHb receives a dense serotonergic innervation from the raphe nuclei [30], expresses several 5-HTR subtypes [30,31], the HT2A gene [37], and 5-HT 2A R protein, both on neurons and glial cells [34].…”

“…Moreover, 5-HT and its receptors may be a key to tobacco addiction. Extensive and compelling animal and human data have recently revealed an essential interaction between nicotine and 5-HT 2C receptors (5-HT 2C Rs) that might open new therapeutic avenues to smoking cessation [14][15][16][17]. On the other hand, the 5-HT 2A Rs have been less investigated, although it is known that the 5-HT 2A R exerts a distinct role compared to 5-HT 2C Rs concerning the regulation of midbrain DA neurons [18,19], ultimately leading to an opposite influence of the two 5-HTRs in nicotine addiction.…”

“…On the other hand, the 5-HT 2A Rs have been less investigated, although it is known that the 5-HT 2A R exerts a distinct role compared to 5-HT 2C Rs concerning the regulation of midbrain DA neurons [18,19], ultimately leading to an opposite influence of the two 5-HTRs in nicotine addiction. Indeed, their blockade is able to counteract nicotine self-administration, reinstatement, sensitization, conditioned hyperactivity, and withdrawal behaviors [17,20,21]. Even if 5-HT 2A Rs are expressed in brain areas involved in nicotine addiction [22,23], the effect of nicotine on their expression has not yet been thoroughly investigated.…”

A Metric Space Approach on the Molecular vs. Chemical Similarity of Some Analgesic and Euphoric Compounds

“…On that side, of the less structural similarity, are the results of both nicotine and caffeine. Nevertheless, it has been observed that nicotine exhibits an antistress activity [29,30,31], is causing illusions [32] as well as it causes or it could cause addiction [33], and is widely known that the vast majority of the studied compounds are causing similar effects. When the discussion comes to caffeine, that causes dopamine release in specific regions of the brain [33,34], a matching to cocaine that acts similar in the brain, or due to its calm down effect [35,36,37,38], connection to serotonin and endomorphines could have been observed, as well.…”