In contrast to these results, activation of 5-HT1A receptors inhibits neuronal excitation through enhancement of potassium currents and inhibition of calcium channels (Araneda and Andrade, 1991). 5-HT receptors also appear to directly influence GABA and NMDA-mediated conductances with 5-HT2A/C receptors inhibiting GABA-induced currents via a PKC-dependent pathway (Liu et al., 2006). NMDA receptor currents are inhibited by 5-HT1A receptors whereas 5-HT2A activation enhances NMDA function. These effects appear to result from changes in NMDA receptor trafficking with inhibition and activation, respectively, of ERK phosphorylation of the MAP kinase pathway (Yuen et al., 2008). Although PFC neurons express both 5-HT1A and 5-HT2A receptors, these subtypes have a differential affinity for serotonin suggesting that activation of raphe serotonin neurons may initiate opposing changes in NMDA function in the PFC that depends on the extent and rate of firing. 5-HT also influences glutamatergic plasticity of PFC pyramidal neurons. Activation of 5-HT2A/C receptors during tetanic stimulation of deep-layer pyramidal neurons led to long-term depression of AMPA-mediated synaptic EPSCs (Zhong et al., 2008). This effect was NMDA independent but was blocked by antagonists of group I metabotropic glutamate receptors as well as inhibitors of P38 MAP kinase.
