Characterization of 5-ht6 receptor and expression of 5-ht6 mRNA in the rat brain during ontogenetic development

Abstract

We have determined the pharmacological characteristics of the rat 5-ht₆ receptor stably expressed in CHO cells. Moreover, using RT-PCR experiments the in vivo expression of the gene encoding this receptor was studied in rat at various embryonic days (ED) starting from ED₁₀ to birth (PN₀) and at post-natal days (PN) up to PN₃₆. The pharmacological analysis of the [³H]5-HT binding in stably transfected CHO cells expressing rat 5-ht₆ receptors revealed the presence of a single class of high affinity saturable binding sites for 5-HT corresponding to an affinity constant: Kd = 27.2±3.4 nM. This receptor also exhibited a high affinity for a number of typical and atypical antipsychotics, tricyclic antidepressant drugs and ergot alkaloïds. In stably transfected CHO cells, serotonin elicited a potent stimulation of adenylyl cyclase activity which was blocked by antipsychotic and antidepressant drugs. These results confirm the hypothesis that 5-ht₆ receptors may correspond to an important target for atypical antipsychotics and reveal an original pharmacological profile for this receptor. The study of the ontogeny of the 5-ht₆ mRNA in rat developing brain showed that 5-ht₆ mRNA were first detectable with a high level on ED₁₂, slighly decreased up to ED₁₇ and then remained stable at high level until the adult age. The ontogenetic pattern of 5-ht₆ mRNA expression appeared to correlate with the occurence of the first cell bodies of serotonergic neurons; the early expression of 5-ht₆ mRNA and the fact that this receptor is positively coupled to the production of cAMP may suggest a role for 5-ht₆ receptor in the early growth process involving the serotonergic system.