ACTIVATION OF THE 5-HT6 RECEPTOR ATTENUATES LONG-TERM POTENTIATION AND FACILITATES GABAergic NEUROTRANSMISSION IN RAT HIPPOCAMPUS

The 5-HT6 receptor is predominantly expressed in the CNS and has been implicated in the regulation of cognitive function. Antagonists of the 5-HT6 receptor improve cognitive performance in a number of preclinical models and have recently been found to be effective in Alzheimer's disease patients. Systemic administration of 5-HT6 antagonists increases the release of acetylcholine and glutamate in the frontal cortex and dorsal hippocampus. In contrast, the selective 5-HT6 agonist, WAY-181187, can elicit robust increases in extracellular levels of GABA. The reported behavioral and neurochemical effects of 5-HT6 receptor ligands raise the possibility that the 5-HT6 receptor may modulate synaptic plasticity in the hippocampus. In the present study, selective pharmacological tools were employed to determine the effect of 5-HT6 receptor activation on long-term potentiation (LTP) in brain slices containing area CA1 of the hippocampus. While having no effect on baseline synaptic transmission, the results demonstrate that the selective 5-HT6 agonist, WAY-181187, attenuated LTP over a narrow dose range (100-300 nM). The increase in the slope of the field excitatory post synaptic potential (fEPSP) caused by theta burst stimulation in brain slices treated with the most efficacious dose of WAY-181187 (200 nM) was 80.1+/-4.0% of that observed in controls. This effect was dose-dependently blocked by the selective 5-HT6 antagonist, SB-399885. WAY-181187 also increased the frequency of spontaneous GABA release in area CA1. As assessed by measuring and evaluating spontaneous inhibitory postsynaptic currents (sIPSCs), 200 nM WAY-181187 increased sIPSC frequency by 3.4+/-0.9 Hz. This increase in GABA sIPSCs was prevented by the selective 5-HT6 antagonist SB-399885 (300 nM). Taken together, these results suggest that the 5-HT6 receptor plays a role in the modulation of synaptic plasticity in hippocampal area CA1 and that the regulation of GABAergic interneuron activity may underlie the cognition enhancing effects of 5-HT6 antagonists. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.