Serotonin‐1A receptor function in the dorsal raphe nucleus following chronic administration of the selective serotonin reuptake inhibitor sertraline

Serotonin‐1A (5‐HT 1A ) receptors in the dorsal raphe nucleus (DRN) function as somatodendritic autoreceptors, and therefore play a critical role in controlling serotonergic cell firing and serotonergic neurotransmission. We hypothesized that a decrease in the capacity of 5‐HT 1A receptors to activate G proteins was a general mechanism by which 5‐HT 1A receptors in the DRN are desensitized following chronic administration of selective serotonin reuptake inhibitors (SSRIs). Using in vivo microdialysis, we found that the ability of the 5‐HT 1A receptor agonist 8‐hydroxydipropylaminotetralin hydrobromide (8‐OH‐DPAT) (0.025 mg/kg, s.c.) to decrease extracellular 5‐HT levels in striatum was attenuated following chronic treatment of rats with the SSRIs sertraline or fluoxetine. This apparent desensitization of somatodendritic 5‐HT 1A autoreceptor function was not accompanied by a decrease in 5‐HT 1A receptor sites in the coupled, high‐affinity agonist state as measured by the binding of [3H]8‐OH‐DPAT. In marked contrast to what was observed following chronic administration of fluoxetine, 5‐HT 1A receptor‐stimulated [ 35 S]GTPγS binding in the DRN was not altered following chronic sertraline treatment. Thus, desensitization of 5‐HT 1A somatodendritic autoreceptor function following chronic sertraline administration appears not to be due to a decrease in the capacity 5‐HT 1A receptors to activate G proteins in the DRN. Our findings suggest that the SSRIs may not be a homogeneous class of antidepressant drug with regard to the mechanism by which the function of somatodendritic 5‐HT 1A autoreceptors is regulated.