Brain Research, 410 (1987) 135-139 135 Elsevier BRE 22224 Upregulation of imipramine binding and serotonin uptake by estradiol in female rat brain Moshe Rehavi 1, Hagit Sepcuti 1 and Abraham Weizman 2 IDepartrnent of Physiology and Pharmacology and 2Geha Psychiatric Hospital, Sackler Faculty of Medicine, Tel-A viv University, Tel-A viv (Israel) (Accepted 20 January 1987) Key words: Imipramine binding; Serotonin uptake; Estradiol; Tricyclic antidepressant; Gonadal hormone; Platelet This report describes the effect of chronic estradiol treatment on the serotonin transporter in the female rat brain. Both [3H]imipra- mine binding and [3H]serotonin uptake increased by 20-30% in the frontal cortex and hypothalamus of ovariectomized rats after 12 days of 17fl-estradiol treatment. No differences were observed in the binding and uptake parameters as a function of the rats' estrous cycle or in untreated ovariectomized rats, as compared to controls. Estradiol in vitro, inhibits [3H}imipramine binding as well as sero- tonin uptake in rat brain and human platelets. Like serotonin, estradiol decreases the dissociation rate in vitro of [3H]imipramine from its binding site in a dose-dependent manner. Several lines of evidence suggest that sex steroid hormones are involved in the etiology of some types of depression. Behavioral changes are observed in women during the menstrual cycle, in the postpartum period and in the menopause 12. The use of oral con- traceptives was claimed to induce depression 9'11 and it is widely accepted that the incidence of affective disorders is more frequent in women than in men 28. High-affinity binding sites for [3H]imipramine have been demonstrated and characterized in rat and human brain 17'2° as well as in platelets derived from many species 28. Studies from several laboratories have shown that [3H]imipramine binding sites are functionally related to the presynaptic uptake or transport sites for serotonin and that these sites me- diate the well-known effects of tricyclic antidepres- sants in inhibiting biogenic amine uptake ~5. Several lines of evidence suggest that these binding sites are clinically relevant. Decreased [3H]imipramine bind- ing to platelets of affective patients has been re- ported by several groups 5't4. Decreased [3H]imipra- mine binding was also reported in patients with syn- dromes related to depression, such as anorexia ner- vosa 27 and obsessive compulsive disorder 26. The de- creased number of these binding sites in platelets of depressed patients, as well as in brain membranes from suicides 15'23, support earlier data 25 suggesting that a defect in serotonin transport is associated with the affective disorder. The metabolism of serotonin (5-HT) is influenced by estradiol. It was reported that estradiol treatment regulates 5-HT turnover in rat brain t°, as well as the 5-HT postsynaptic receptor in rat brain 3. Progesterone and estradiol treatments are reported to modify monoamine uptake in the hy- pothalamus 8. The sex steroid hormones as well as the seroton- ergic system probably both have a role in the patho- physiology of depression. In this study we investi- gated the in vitro and in vivo effects of estradiol on the high-affinity [3H]imipramine binding and [3H]se- rotonin uptake in female rat brain. These two presyn- aptic biochemical markers are known to be affected during depression and a possible regulation of these markers by estradiol could elucidate the involvement Correspondence: M. Rehavi, Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel- Aviv 69978, Israel.