Overcoming the effects of stress on synaptic plasticity in the intact hippocampus: rapid actions of serotonergic and antidepressant agents

Abstract

Acute inescapable stress dramatically affects the inducibility of plasticity at glutamatergic synapses in the intact hippocampus. The present study examined the involvement of serotonergic mechanisms in mediating and modulating the block of long-term potentiation (LTP) in the CA1 area of anesthetized rats after exposure to an elevated platform stress. Fluoxetine and fenfluramine, agents that raise hippocampal extracellular 5-HT concentration, blocked the induction of LTP in nonstressed animals, thus mimicking the effect of stress. In contrast, (+/-)-tianeptine, a drug that decreases 5-HT levels, had no effect on LTP induction in nonstressed animals. Remarkably, (+/-) administration of tianeptine after the stress rapidly overcame the block of LTP induction without affecting baseline excitatory transmission. Consistent with a reduction of 5-HT levels being responsible for this effect of tianeptine, the (-) enantiomer, which is associated with the 5-HT uptake enhancing action of (+/-)-tianeptine, also caused a recovery of the induction of LTP in previously stressed animals, whereas the relatively inactive (+) enantiomer had no effect. Furthermore, fluoxetine prevented the effect of tianeptine in stressed animals. These findings show that antidepressants have rapid and powerful interactions with the mechanisms controlling the persistence of the block of LTP by inescapable stress.

Fig. 1.

Block of LTP induction in the CA1 area of nonstressed anesthetized rats by agents that raise hippocampal 5-HT levels. A, Application of high-frequency stimulation (arrow) after the intraperitoneal injection (inj) of water vehicle (n = 5) induced stable LTP of the field EPSP. B,C, The same tetanus after injection of either fenfluramine (5 mg/kg; n = 5; B) or fluoxetine (10 mg/kg; n = 5; C) failed to induce LTP. D, Pretreatment with the 5-HT uptake enhancer tianeptine (1 mg/kg; n = 5) did not affect the induction of LTP. Values are the mean ± SEM percentage of baseline EPSP amplitude. Insets show typical traces of EPSPs at the times indicated.

Fig. 2.

The 5-HT uptake enhancer tianeptine overcomes the stress-induced block of LTP. A, In animals that had been stressed by placing them on an elevated platform for 30 min before anesthesia, high-frequency stimulation (arrows) failed to induce LTP either before or after intraperitoneal injection (inj) of water vehicle (n = 5).B, Injection of (±)-tianeptine (1 mg/kg;n = 6) before the second tetanus enabled the induction of LTP in stressed animals. Values are the mean ± SEM percentage of baseline EPSP amplitude. Insets show typical traces of EPSPs at the times indicated.

Fig. 3.

Enantiomer selectivity and fluoxetine sensitivity of the effect of tianeptine. A,B, Pretreatment with the uptake-enhancing (−)-enantiomer (A, open circles) but not the (+)-enantiomer (B, closed squares) of tianeptine (0.5 mg/kg; n = 5 per group) enabled the recovery of the ability to induce LTP in stressed rats. C, Dual injection of both fluoxetine (10 mg/kg) and (±)-tianeptine (1 mg/kg;n = 5) failed to overcome the block of LTP by stress. Values are the mean ± SEM percentage of baseline EPSP amplitude. Insets show typical traces of EPSPs at the times indicated.