Regional changes in density of serotonin transporter in the brain of 5‐HT 1A and 5‐HT 1B knockout mice, and of serotonin innervation in the 5‐HT 1B knockout

5‐HT 1A knockout (KO) mice display an anxious‐like phenotype, whereas 5‐HT 1B KOs are over‐aggressive. To identify serotoninergic correlates of these altered behaviors, autoradiographic measurements of 5‐HT 1A and 5‐HT 1B serotonin (5‐HT) receptors and transporter (5‐HTT) were obtained using the radioligands [ 3 H]8‐OH‐DPAT, [ 125 I]cyanopindolol and [ 3 H]citalopram, respectively. By comparison to wild‐type, density of 5‐HT 1B receptors was unchanged throughout brain in 5‐HT 1A KOs, and that of 5‐HT 1A receptors in 5‐HT 1B KOs. In contrast, decreases in density of 5‐HTT binding were measured in several brain regions of both genotypes. Moreover, 5‐HTT binding density was significantly increased in the amygdalo‐hippocampal nucleus and ventral hippocampus of the 5‐HT 1B KOs. Measurements of 5‐HT axon length and number of axon varicosities by quantitative 5‐HT immunocytochemistry revealed proportional increases in the density of 5‐HT innervation in these two regions of 5‐HT 1B KOs, whereas none of the decreases in 5‐HTT binding sites were associated with any such changes. Several conclusions could be drawn from these results: (i) 5‐HT 1B receptors do not adapt in 5‐HT 1A KOs, nor do 5‐HT 1A receptors in 5‐HT 1B KOs. (ii) 5‐HTT is down‐regulated in several brain regions of 5‐HT 1A and 5‐HT 1B KO mice. (iii) This down‐regulation could contribute to the anxious‐like phenotype of the 5‐HT 1A KOs, by reducing 5‐HT clearance in several territories of 5‐HT innervation. (iv) The 5‐HT hyperinnervation in the amygdalo‐hippocampal nucleus and ventral hippocampus of 5‐HT 1B KOs could play a role in their increased aggressiveness, and might also explain their better performance in some cognitive tests. (v) These increases in density of 5‐HT innervation provide the first evidence for a negative control of 5‐HT neuron growth mediated by 5‐HT 1B receptors.