5-HT2 receptor-mediated reversal of the inhibition of hippocampal long-term potentiation by acute inescapable stress

The serotonergic system is known to modulate and mediate many of the central nervous system effects of stress. Here we investigated the ability of serotonergic agents to reverse the inhibition of the induction of hippocampal long-term potentiation (LTP) caused by prior exposure to inescapable stress. Elevated platform stress prevented the induction of LTP in the CA1 area of anaesthetized rats. An agent that increases extracellular 5-HT concentration, fenfluramine (5 mg/kg, i.p.) enabled the induction of LTP in previously stressed animals. Consistent with a role for enhanced activation of 5-HT2 receptors, the facilitatory effect of fenfluramine was prevented by the 5-HT2 receptor antagonist cinanserin (30 mg/kg). Agents that directly activate 5-HT2 receptors, including the 5-HT2B receptor agonist BW 723C86 (30 mg/kg) and the 5-HT2C receptor agonist MK-212 (3 mg/kg), mimicked the restorative effect of fenfluramine. Fenfluramine also opposed inhibition of LTP caused by the NMDA-receptor antagonist D-AP5 (100 nmol, i.c.v.) which suggests that the facilitatory action of serotonergic agents is not restricted to stress-mediated inhibition of LTP. These findings support an important role for activation of 5-HT2 receptors by systemically applied agents to enable recovery from the inhibition of LTP by stress.