Effects of chronic antidepressants and electroconvulsive shock on serotonergic neurotransmission in the rat hippocampus : microdialysis studies in vivo .

Eliyahu Dremencov, Eitan Gur, Michael E. Newman and Bernard Lerer
Biological Psychiatry Lab., Dept. of Psychiatry, Hadassah - Hebrew University Medical Center, P.O.B. 12000 Jerusalem 91120 Israel.

The aim of this work was to examine the effects of chronic treatment with the tricyclic antidepressant, chlomipramine, and electroconvulsive shock (ECS) on serotonergic neurotransmission in the hippocampus. Previous studies reported that selective serotonin reuptake inhibitors (SSRIs) decrease presynaptic 5-HT autoreceptors mediated inhibition of serotonin release, while tricyclic antidepressants (TCAs) increase postsynaptic 5-HT1A activity (Mongeau et al, Brain Research Reviews 23: 145-195, 1997). Other studies postulated that chronic administration of the antidepressants and ECS activate cAMP formation in hippocampal neurones (Duman , Biol. Psychiatry 44: 324-335, 1998 ) . We determined the effects of chronic administration of clomipramine and ECS on 5-HT1B autoreceptor mediated control of 5-HT release and on cAMP formation in response to postsynaptic 5-HT1A receptor activation and activation of the catalytic unit of adenylate cyclase (AC). Previous microdialysis studies have found that 5-HT release in the hippocampus is mostly regulated by presynaptic nerve terminal 5-HT1B autoreceptor activation (Invernizzi et al., Brain Res. 696: 62-66, 1991), and that the postsynaptic 5-HT1A receptor, although it is a Gi protein coupled receptor and inhibits cAMP synthesis in vitro, elevates cAMP formation in the hipocampus of the living rat (Cadogan et al., J.Neurochem. 62: 1816-1821, 1994, Sijbesma et al., Neuropharmacology 30 : 967-975, 1991).
Methods. Clomipramine was given by miniosmotic pumps at 10 mg/kg/day for 28 days. ECS was given via ear clip electrodes daily for 10 days. Microdialysis probes were implanted into the hippocampus and perfused with Ringer's solution at 0.5 ml/min. 5-HT levels were determined by HPLC. cAMP levels were determined by radioimmunoassay .
Results. Chronic treatment with clomipramine increased the cAMP response to systemic administration of 0.2 mg/kg of the 5-HT1A receptor agonist 8-OH-DPAT but did not affect the cAMP response to the direct AC activator forskolin, administered for 30 min. via the probe at 50 mM,nor the 5-HT response to the 5-HT1B autoreceptor antagonist GR 127935 . Chronic ECS administration did not change the 5-HT response to GR 127935 and the cAMP response to 8-OH-DPAT, but decreased the cAMP response to forskolin. Conclusion. Chronic treatment with clomipramine increased postsynaptic 5-HT1A receptor activity reflected as increased 5-HT1A receptor mediated cAMP formation. Chronic ECS decreased AC activity (reduced cAMP formation in response to forskolin). Because cAMP formation in response to 8-OH-DPAT was not changed by ECS, we concluded that chronic treatment with ECS increased postsynaptic 5-HT1A receptor activity.