Rationale-Serotonin transporter (SERT) knockout (−/−) mice have an altered phenotype in adulthood, including high baseline anxiety and depressive-like behaviors, associated with increased baseline extracellular serotonin levels throughout life.Objectives-To examine the effects of increases in serotonin following administration of the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP) in SERT wildtype (+/+), heterozygous (+/−) and −/− mice.Results-5-HTP increased serotonin in all five brain areas examined, with ~2-5-fold increases in SERT +/+ and +/− mice, and greater 4.5-11.7-fold increases in SERT −/− mice. Behaviorally, 5-HTP induced exaggerated serotonin syndrome behaviors in SERT −/− mice, with similar effects in male and female mice. Studies suggest promiscuous serotonin uptake by the dopamine transporter (DAT) in SERT −/− mice, and here, the DAT blocker GBR 12909 enhanced 5-HTP-induced behaviors in SERT −/− mice. Physiologically, 5-HTP induced exaggerated temperature effects in SERT-deficient mice. The 5-HT 1A antagonist WAY 100635 decreased 5-HTP-induced hypothermia in SERT +/+ and +/− mice, with no effect in SERT −/− mice, whereas the 5-HT 7 antagonist SB 269970 decreased this exaggerated response in SERT −/− mice only. WAY 100635 and SB 269970 together completely blocked 5-HTP-induced hypothermia in SERT +/− and −/− mice.Conclusions-These studies demonstrate that SERT −/− mice have exaggerated neurochemical, behavioral and physiological responses to further increases in serotonin, and provide the first evidence of intact 5-HT 7 receptor function in SERT −/− mice, with interesting interactions between 5-HT 1A and 5-HT 7 receptors. As roles for 5-HT 7 receptors in anxiety and depression were recently established, the current findings have implications for understanding the high anxiety and depressivelike phenotype of SERT-deficient mice.

Emerging evidence indicates that adolescence represents a developmental window of enhanced nicotine-induced neuroplasticity in rat forebrain. However, whether nicotine produces age-dependent structural alteration of neurons from medial prefrontal cortex remains to be determined. We characterized the dendritic morphology of layer V pyramidal neurons from prelimbic cortex following adolescent (P29-43) or adult (P80-94) nicotine pretreatment. Nicotine administration was via osmotic pump [initial dose 2.0 mg/(kg day), free base]. Five weeks after drug administration concluded, brains were processed for Golgi-Cox staining and pyramidal neurons digitally reconstructed for morphometric analysis. Overall, nicotine pretreatment produced increased basilar, but not apical, dendritic length of pyramidal cells, a finding consistent with previous work using adult animals. Given the compelling evidence for morphologically distinct functional subtypes of cortical pyramidal neurons, we endeavored to determine whether nicotine-induced dendritic alteration was specific to putative structural subtypes. Neurons were segregated into two groups based on the extent of dendritic arbor at the distal portion of the apical tree (i.e., the apical tuft). The size of the apical tuft was quantitatively determined using principal component analysis. Cells with small and elaborate apical tufts were classified as simple and complex, respectively. We found that adult nicotine pretreatment produced increased basilar dendritic length and branch number in simple but not complex pyramidal cells. In contrast, adolescent nicotine pretreatment produced a modest but significant increase in basilar dendritic length in complex but not simple cells. These data suggest that nicotine alters dendritic morphology of specific subpopulations of pyramidal neurons and that the subpopulation affected is dependent on the age of drug exposure.

The current studies are important, as they are the first to assess the effects of TCB-2 in mice, and are among the first to report the behavioral and neurophysiological effects of this conformationally restricted phenethylamine analog compound, which has 65-fold greater effects on signaling via the phosphoinositide versus arachidonic acid pathways.