Activation of the 5-HT(6) receptor attenuates long-term potentiation and facilitates GABAergic neurotransmission in rat hippocampus.

The 5-HT(6) receptor is predominantly expressed in the CNS and has been implicated in the regulation of cognitive function. Antagonists of the 5-HT(6) 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-HT(6) antagonists increases the release of acetylcholine and glutamate in the frontal cortex and dorsal hippocampus. In contrast, the selective 5-HT(6) agonist, WAY-181187, can elicit robust increases in extracellular levels of GABA. The reported behavioral and neurochemical effects of 5-HT(6) receptor ligands raise the possibility that the 5-HT(6) receptor may modulate synaptic plasticity in the hippocampus. In the present study, selective pharmacological tools were employed to determine the effect of 5-HT(6) 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-HT(6) 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-HT(6) 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-HT(6) antagonist SB-399885 (300 nM). Taken together, these results suggest that the 5-HT(6) 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-HT(6) antagonists.