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 al tered behaviors, autoradiographic measurements of 5-HT1A and 5-HT1B seroton in (5-HT) receptors and transporter (5-HTT) were obtained using the radioli gands [H-3]8-OH-DPAT, [I-125]cyanopindolol and [H-3]citalopram, respectivel y. By comparison to wild-type, density of 5-HT1B receptors was unchanged th roughout brain in 5-HT1A KOs, and that of 5-HT1A receptors in 5-HT1B KOs. I n contrast, decreases in density of 5-HTT binding were measured in several brain regions of both genotypes. Moreover, 5-HTT binding density was signif icantly increased in the amygdalo-hippocampal nucleus and ventral hippocamp us of the 5-HT1B KOs. Measurements of 5-HT axon length and number of axon v aricosities 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 result s: (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 se veral territories of 5-HT innervation. (iv) The 5-HT hyperinnervation in th e amygdalohippocampal nucleus and ventral hippocampus of 5-HT1B KOs could p lay 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.