There are at least 15 confirmed 5-hydroxytryptamine (5-HT) receptor subtypes, each encoded by their own distinct genes (Raymond et al., 2001). These subtypes are divided in to seven subfamilies; which are characterized by pharmacological, structural and functional features (Hoyer et al., 1994). The range of 5-HT receptors is further increased by post genomic modifications such as alternative splicing, which can give rise to 10 splice variants for the 5-HT4 receptor and mRNA editing in conjunction with 5-HT2C receptors (Bockaert et al., 2006). 5-HT1, 5-HT2, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 are metabotropic G-protein coupled receptors (GPCRs), whereas 5-HT3 is uniquely ionotropic, (Engleman et al., 2008) (see Fig. 1.)

Walstab, J., Rappold, G. and Niesler, B. (2010). 5-HT3 receptors: Role in disease and target of drugs. Pharmacology & Therapeutics, 128(1), pp.146-169.
Fig. 1. Schematic of a typical 5-HT3 receptor, showing the cation lumen after the removal of a subunit. Arrows point to reveal the agonistic, competitive, non-competitive antagonists and positive modulators. The orthosteric ligand binding site is magnified to show the binding loops of neighbouring subunits. An arrow also shows the transmembrane (TM) domains of an individual subunit, with TM2 lining the channel pore.

A pentemeric receptor consisting of four TM segments to form an intrinsic cation selective, water-filled channel (Barnes et al., 2009). A typical subunit exhibits a large extracellular N-terminus (Iversen, 2009) and a short extracellular C-terminus (Mukerji, Haghighi and Séguéla, 1996). As a member of the cys-loop family of ligand-gated ion channel receptors, 5-HT3 channel opening is a result of the extracellular connection of an agonist to a distinctive binding site on the channel protein. A conformational change occurs resulting in the opening of the central ion pore, where ion selectivity is determined by receptor structure, in and around the ion pore (Connolly and Wafford, 2004). The 5-HT receptors belonging to the GPCR family are classified by the presence of 7 transmembrane spanning domains and their ability to modify G-protein dependent processes. This group of GPCRs can be further divided into families based upon their amino acid sequence and secondary messengers (Iversen, 2009) (see Fig. 2.)

Raymond, J., Mukhin, Y., Gelasco, A., Turner, J., Collinsworth, G., Gettys, T., Grewal, J. and Garnovskaya, M. (2001). Multiplicity of mechanisms of serotonin receptor signal transduction. Pharmacology & Therapeutics, 92(2-3), pp.179-212.
Fig. 2. 5-HT1 receptors generally inhibit adenylyl cyclase (AC) through pertussis-toxin-sensitive G proteins of the Gi family. In contrast, 5-HT4, 5-HT6, and 5-HT7 receptors are a heterogeneous group and stimulate the AC pathway using Gs family G-proteins. AC activation results in Increased production of cAMP, leading to the activation of protein kinase A (PKA). 5-HT2 receptors stimulate arachidonic acid (AA) through PLA2 activity using G-proteins. 5-HT2 receptors through Gq/11 family of G-proteins, also activate PLC-, resulting in an increase of phosphatidylinositol 4, 5-bisphosphate (PIP2) to inositol triphosphate (IP3) and diacylglycerol (DAG). Accumulation of IP3 results in the increased concentration of intracellular calcium (Ca2+) levels. Alternatively, DAG activates Ca2+ and the phospholipid-dependent protein kinase C (PKC).

In addition to dopaminergic and glutamatergic circuits, serotonergic mechanisms play definitive roles in addictive behavior (Kirby, Zeeb and Winstanley, 2011) through receptors 5-HT1A, 5-HT1B, 5-HT2, 5-HT3A and 5-HT6. Studies have shown that 5-HT1A receptor agonist 8-OH-DPAT heightened cocaine reinforcement in response to a second-order schedule applied at low dosage, suggesting an increased efficacy of cocaine (Nader and Barrett, 1990). Equally, 5-HT1B receptor activation in the VTA induced GABA inhibition, subsequently producing a rise in DA release in the VTA and NAc, leading to increased alcohol intake (Sari, 2012). Low doses of 5-HT2A and 5-HT2c receptor antagonists ritanserin and ketanserin showed an increase in response using a second order schedule in squirrel monkeys (Howell and Byrd, 1995). Hodge et al., 2008, suggests that in 5-HT3AKO mice, the 5-HT3A-subunit is required for the induction of cocaine sensitization, highlighting a role in the regulation of neurobehavioral adaptions to repeat cocaine administration and ethanol consumption, underlining their role in drug addiction. 5-HT6 receptors at present are poorly understood. However, antagonist SB-258510A has been shown to increase amphetamine self-administration (Frantz et al., 2002).
References
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* Distribution of 5-HT3 receptors – both peripheral nervous system and central nervous system * 5-HT3 receptors (name of journal) (Thompson + Lummis)