Stress impairs 5-HT_2A receptor-mediated serotonergic facilitation of GABA release in juvenile rat basolateral amygdala

The occurrence of stress and anxiety disorders has been closely associated with alterations of the amygdala GABAergic system. In these disorders, dysregulation of the serotonergic system, a very important modulator of the amygdala GABAergic system, is also well recognized. The present study, utilizing a learned helplessness stress rat model, was designed to determine whether stress is capable of altering serotonergic modulation of the amygdala GABAergic system. In control rats, administration of 5-HT or α-methyl-5-HT, a 5-HT₂ receptor agonist, to basolateral amygdala (BLA) slices dramatically enhanced frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs). This effect was blocked by selective 5-HT _2A receptor antagonists while a selective 5-HT_2B receptor agonist and a selective 5-HT_2C receptor agonist were without effect on sIPSCs. Double immunofluorescence labeling demonstrated that the 5-HT _2A receptor is primarily localized to parvalbumin-containing BLA interneurons. Thus, serotonin primarily acts via 5-HT_2A receptors to facilitate BLA GABAergic inhibition. In stressed rats, the 5-HT_2A receptor-mediated facilitative actions were severely impaired. Quantitative RT-PCR and western blot analysis showed that the impairment of 5-HT_2A receptor signaling primarily resulted from receptor downregulation. The stress-induced effect appeared to be specific to 5-HT_2A receptors because stress had no significant impact on other serotonin receptors, as well as histamine H₃ receptor and α₂ adrenoceptor signaling in the BLA. This severe impairment of 5-HT_2A receptor-mediated facilitation of BLA GABAergic inhibition might result in an amygdala circuitry with hyperexcitability, and a lower threshold of activation, and thus be an important mechanism underlying the emergence of stress-associated psychiatric symptoms.