The serotonin 2C receptor (5-HT2c-R) has been implicated in the control of reward related behaviours including drug misuse, sexual and feeding behaviour. This thesis describes experiments investigating the role of the 5-HT2c receptor in feeding and feeding-related behaviours. Using 5-HT2c receptor null mutant (KO) mice, the aims of this thesis are to explore the role of the 5-HT2c receptor in feeding and feeding related behaviours. Experiments reported in chapters 3 to 5 look specifically at pharmacologically induced hypophagia in wildtype and 5-HT2c KO mice as well as in wildtype mice pre-treated with the selective 5-HT2c-R antagonist SB 242084. Results suggest that hypophagia induced following administration of either the non-selective 5-HT agonist mCPP or the 5-HT2AnB2c, -Ra gonist Ro 60-0175 is mediatedp rimarily by activation of the 5-HT2c-R. Data from the behavioural satiety sequence also suggests that both compounds have effects beyond 5-HT2c-R activation which become apparent only when the 5-HT2c-R has been inactivated. Data from thesec haptersa lso suggestt hat the 5-HT2A2, c-Ra gonist DOI suppresses feeding as the result of 5-HT2c-R activation and that activation of 5-HT2Areceptors by this compound induces an increase in post-prandial activity that does not interfere with food intake. Data presented in this thesis also show that 5-HT2c KO mice are more sensitive to the hypophagic effects of 5-HTIB-R activation, indicating that 5-HTI. -induced hypophagia is not dependant on the presence of a population of functional 5-HT2c receptors. In addition to this, these data suggest a modulatory role for the 5-HT2c-R over the behavioural expression of activation of other 5-HT receptors. This modulatory role is further explored in chapter 6, which describes an in-depth pharmacological analysis of mCPP-induced hyperactivity in 5-HT2c KO mice as measured using simple forward locomotor activity. Results from these data suggest that, contrary to previous suggestions, mCPP-induced hyperactivity occurs as the result of a cumulative effect of 5-HTIBand 5-HT2A-R activation on mesolimbic dopamine efflux. Chapter 7 further investigates the role of 5-HT2c, 5-HTBand 5-HT2Areceptors in actvivity induced by the amphetamine derivative, MDMA. Results are discussed with reference to the possibility of at least two anatomically distinct populations of 5-HT2c receptors that have opposing roles in the modulation of mesolimbic doparnine and reward

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Nicotinic acetylcholine receptors (nAChRs) and 5-hydroxytryptamine type 3 receptors (5HT3R.S) are pentameric ligand-gated ion channels which form both heteromeric and homomeric complexes. Aspects of the assembly and pharmacological properties of the a 7 nAChR and 5HT3R were examined through three independent studies. The first study examined the mechanism by which the 5HT3B subunit, when expressed alone, is retained within the endoplasmic reticulum (ER). The 5HT3R forms both homomeric (composed of 5HT3A subunits) and heteromeric (composed of 5HT3A and 5HT3B subunits) complexes. In contrast to 5HT3A, the 5HT3B subunit cannot form a functional homomeric receptor. An ER retention motif (RAR) was identified in the 5HT3B subunit, which appears to be masked by the 5HT3A subunit. Evidence to support this conclusion was obtained from co-expression of the subunits, which resulted in the presence of 5HT3B on the cell surface. The a 7 nAChR and 5HT3R have similar N-terminal ligand binding domains and cross-reactivity of some ligands is observed. Both mouse 5HT3A and a 7 are potentiated by the aromatic moiety of 5-HT, 5-hydroxyindole (5-HI), whereas human 5HT3A is not. In an attempt to define the 5-HI binding site, human/mouse 5HT3A subunit chimeras were constructed. Studies using the chimeras suggest that the action of 5-HI may be mediated by both the N- and C-terminal domains of 5HT3A. In the final study, the effects of the putative chaperone protein, RIC3, on ct7 receptor expression were examined. The efficient functional expression of the cc7 nAChR has been shown to be critically dependent on host-cell type, unlike the 5HT3R. RIC3 was shown to facilitate the efficient cell-surface expression of al in a mammalian cell line, where functional expression was not previously observed. The RIC3 protein has been identified as an a7-interacting protein which promotes the efficient assembly and folding of the subunit. RIC3 was also shown to promote 5HT3aR assembly.

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