Role of 5-HT6 receptor in conditioned learning and memory

The recently discovered 5-HT6 receptor has generated interest due to increasing evidence for its role in feeding, obesity, anxiety, depression and cognition. Initial studies utilising selective 5-HT6 receptor antagonists found pro-cognitive effects in various cognitive paradigms. In the last three years selective 5-HT6 receptor agonists have been developed and initial reports suggested they impaired cognition as predicted, but more recent reports have found paradoxical pro-cognitive effects in learning and memory tasks. The main aim of the current thesis was to determine the role of the 5-HT6 receptor in a conditioned emotion response (CER) task in rats. Both the effects of 5-HT6 receptor antagonists and agonists given alone, and their abilities to reverse a cholinergic- or glutamatergic-induced memory impairment were analysed. Secondly, to analyse the intracellular mechanisms involved in the behavioural effects exerted following treatment with 5-HT6 receptor ligands by examining changes in hippocampal protein expression. Pre-treatment with either the muscarinic receptor antagonist, scopolamine, or the NMDA receptor antagonist, MK-801, induced memory impairment in the 24 hour retention trial. Post-training administration of 5-HT6 receptor antagonist, SB-271046, and agonists, EMD 386088 and E-6801, had little effect on CER-induced behaviour when given alone, but both reversed the cholinergic- and glutamatergic-induced deficits. Western blot analysis revealed no significant difference between hippocampal BDNF and 5-HT6 receptor protein levels following any drug or shock treatment, but some interesting trends were observed. CER slightly increased BDNF expression, this was reduced by scopolamine and MK-801 which in turn was reversed with SB-271046 and EMD 386088. CER decreased 5-HT6 receptor expression, scopolamine caused further reduction, SB-271046 and EMD 386088 increased the expression following scopolamine. MK-801 increased 5-HT6 receptor expression, whilst SB-271046 further enhanced this expression, EMD 386088 reduced it. No significant results were observed in the proteomic studies. These findings provide further evidence for the exciting potential therapeutic use of 5-HT6 receptor compounds in the treatment of cognitive dysfunction.EThOS - Electronic Theses Online ServiceGBUnited Kingdo