Regional changes in density of serotonin transporter in the brain of 5‐HT1A and 5‐HT1B knockout mice, and of serotonin innervation in the 5‐HT1B knockout

5‐HT1A knockout (KO) mice display an anxious‐like phenotype, whereas 5‐HT1B KOs are over‐aggressive. To identify serotoninergic correlates of these altered behaviors, autoradiographic measurements of 5‐HT1A and 5‐HT1B serotonin (5‐HT) receptors and transporter (5‐HTT) were obtained using the radioligands [3H]8‐OH‐DPAT, [125I]cyanopindolol and [3H]citalopram, respectively. By comparison to wild‐type, density of 5‐HT1B receptors was unchanged throughout brain in 5‐HT1A KOs, and that of 5‐HT1A receptors in 5‐HT1B 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‐HT1B 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‐HT1B 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‐HT1B receptors do not adapt in 5‐HT1A KOs, nor do 5‐HT1A receptors in 5‐HT1B KOs. (ii) 5‐HTT is down‐regulated in several brain regions of 5‐HT1A and 5‐HT1B KO mice. (iii) This down‐regulation could contribute to the anxious‐like phenotype of the 5‐HT1A 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‐HT1B 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‐HT1B receptors.