Sex hormone‐dependent desensitization of 5‐HT 1A autoreceptors in knockout mice deficient in the 5‐HT transporter

The serotonin transporter (5‐HTT) is the target of most antidepressant drugs, whose therapeutic action is related to their facilitatory influence on 5‐HT neurotransmission. In this study, we investigated the functional adaptive properties of 5‐HT 1A autoreceptors, which regulate serotonergic neuronal firing, in knockout mice deficient in 5‐HTT. Neurons of the dorsal raphe nucleus (DRN) were recorded extracellularly under chloral hydrate anaesthesia in male and female knockout 5‐HTT mice and their wild‐type counterparts. The inhibitory response of DRN neurons to intravenous injection of the 5‐HT 1A agonist 8‐OH‐DPAT was dramatically reduced in knockout 5‐HTT compared with wild‐type mice, especially in females. Changes in 8‐OH‐DPAT‐induced hypothermia and autoradiographic labelling of 5‐HT 1A sites in the DRN confirmed a greater level of desensitization/down‐regulation of 5‐HT 1A autoreceptors in female than in male knockout 5‐HTT mice. After gonadectomy, the functional status of 5‐HT 1A autoreceptors was unchanged in wild‐type mice, whereas in knockout 5‐HTT, castrated males exhibited a down‐regulation, and ovariectomized females an up‐regulation of these receptors, as shown by electrophysiological recording and autoradiographic labelling in the DRN, as well as by changes in 8‐OH‐DPAT‐induced hypothermia. Finally, in gonadectomized knockout 5‐HTT mice, treatment with testosterone or estradiol restored the DRN neuronal firing sensitivity to 8‐OH‐DPAT back to sham control level in males or females, respectively. These data indicate that sexual hormones participate in the mechanisms responsible for the desensitization of 5‐HT 1A autoreceptors in knockout 5‐HTT mice. The differential effects of testosterone and estradiol on 5‐HT 1A ‐mediated control of 5‐HT neurotransmission might be related to the well‐established gender differences in the vulnerability to depression.