MODULATION OF NERVE TERMINAL 5-HT-1B AUTORECEPTORS BY CHRONIC ANTIDEPRESSANT AND CORTICOSTERONE ADMINISTRATION IN THE RAT: IN VIVO MICRODIALYSIS STUDIES

MODULATION OF NERVE TERMINAL 5-HT-1B AUTORECEPTORS BY CHRONIC ANTIDEPRESSANT AND CORTICOSTERONE ADMINISTRATION IN THE RAT: IN VIVO MICRODIALYSIS STUDIES.

M.E. Newman*, E. Gur, E. Dremencov, B. Lerer,
Biological Psychiatry Laboratory, Hadassah University Hospital, Jerusalem, Israel.

Much attention has been given to desensitization of somatodendritic presynaptic 5-HT-1A autoreceptors and sensitization of post-synaptic 5-HT-1A receptors as mechanisms involved in mediating the actions of antidepressant drugs. Recent evidence suggests that desensitization of the presynaptic 5-HT-1B autoreceptors situated at the nerve terminals may also be an important mechanism in the action of tricyclic drugs such as desipramine as well as SSRIs such as paroxetine. We investigated the sensitivity of nerve terminal 5-HT-1B autoreceptors by measuring the increase in 5-HT levels induced by peripheral injection of the 5-HT1B/1D antagonist GR 127935 (5 mg/kg s.c.), using in vivo microdialysis. In the presence of 10 mM citalopram in the perfusion medium, this agent induced a 2- to 3-fold rise in 5-HT levels. Animals which had received subchronic treatment with fluoxetine (10 mg/kg i.p. for 6 days) showed a significantly reduced response to GR 127935 in the hippocampus, while animals which had received chronic clomipramine (10 mg/kg for 28 days by osmotic minipump) showed a significantly reduced response in hypothalamus. Animals which had received corticosterone (50 mg/kg s.c. twice daily for 10 days) showed a significant increase in the response to GR 127935 in the hypothalamus. Since cortisol levels are elevated in depressed patients and some animal models of depression are characterized by an elevated 5-HT-1B receptor number, we suggest that administration of corticosterone may constitute a "biochemical model of depression" and that activity at presynaptic 5-HT-1B autoreceptors, leading to changes in 5-HT release, may play an important role in mediating depression and in the action of antidepressant drugs. Supported by the U.S.-Israel Binational Science Foundation.