Neuropharmacological studies of 5-HT â‚‚c receptor mutant mice

• Main Author: Dalton, Gemma Louise
• Published: University of Sussex 2004
• Subjects: 615.78
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404303

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