The ability to induce long-term potentiation (LTP) in the intact hippocampus has been shown to be greatly impaired following exposure to an inescapable elevated platform stress (Xu et al. 1997). Recently a role for the serotonergic system in the mediation/modulation of the effects of stress on LTP has been suggested (Shakesby et al. 2002). In the present study we investigated the ability of serotonergic agents to overcome the block of LTP by stress.
Male Wistar rats (240-360 g) had electrodes implanted into the stratum radiatum of the CA1 region of the dorsal hippocampus under urethane anaesthesia (1.5 g kg-1, I.P.). Test field EPSP amplitude was 50 % of the maximum and was increased to 75 % maximum during high frequency stimulation (HFS). The Department of Health, Republic of Ireland licenced the experimental protocol including the humane method of killing. HFS (10 trains of 20 stimuli at 200 Hz) induced stable LTP of the field EPSP in non-stressed rats (n = 5; 136 ± 6 % of baseline 60 min after HFS; P < 0.001, compared with pre-HFS baseline: mean ± S.E.M., Student’s paired t test). In contrast, in animals that were immediately anaesthetised after being exposed to the elevated platform stress for 30 min, HFS failed to induce LTP (n = 5; 102 ± 5% P > 0.05). (±)Fenfluramine (5 mg kg-1, I.P.), a 5-HT releaser and 5-HT uptake inhibitor, was found to reverse the stress-induced block of LTP (n = 7; 140 ± 9% P < 0.005). The effect of (±)fenfluramine was prevented by pre-treatment with (±)tianeptine (2 mg kg-1, I.P.), an agent that promotes 5-HT uptake (n = 7; 109 ± 10% P > 0.1). This provides evidence that the recovery of LTP was due to the ability of (±)fenfluramine to raise brain 5-HT levels. Consistent with this, the 5-HT2 receptor antagonist cinanserin (30 mg kg-1, I.P.) also prevented the effect of (±)fenfluramine (n = 5; 107 ± 13% P > 0.5). Further evidence for the involvement of 5-HT2 receptors was the recovery of LTP in stressed rats treated with the 5-HT2B/2C receptor agonist mCPP (1-(3-chlorophenyl)piperazine, 10 mg kg-1, I.P.) (n = 5; 154 ± 15% P < 0.01).
It is concluded that raising brain 5-HT levels can overcome the effects of inescapable stress on synaptic plasticity by activation of 5-HT2 receptors.
This work was supported by Science Foundation Ireland and the Irish Higher Education Authority.