Adolescent male rats are less sensitive than adults to the anxiogenic and serotonin-releasing effects of fenfluramine

Abstract

Risk taking behavior increases during adolescence, which is also a critical period for the onset of drug abuse. The central serotonergic system matures during the adolescent period, and its immaturity during early adolescence may contribute to adolescent risk taking, as deficits in central serotonergic function have been associated with impulsivity, aggression, and risk taking. We investigated serotonergic modulation of behavior and presynaptic serotonergic function in adult (67–74 days old) and adolescent (28–34 days old) male rats. Fenfluramine (2 mg/kg, i.p.) produced greater anxiogenic effects in adult rats in both the light/dark and elevated plus maze tests for anxiety-like behavior, and stimulated greater increases in extracellular serotonin in the adult medial prefrontal cortex (mPFC) (1, 2.5, and 10 mg/kg, i.p.). Local infusion of 100 mM potassium chloride into the mPFC also stimulated greater serotonin efflux in adult rats. Adult rats had higher tissue serotonin content than adolescents in the prefrontal cortex, amygdala, and hippocampus, but the rate of serotonin synthesis was similar between age groups. Serotonin transporter (SERT) immunoreactivity and SERT radioligand binding were comparable between age groups in all three brain regions. These data suggest that lower tissue serotonin stores in adolescents limit fenfluramine-stimulated serotonin release and so contribute to the lesser anxiogenic effects of fenfluramine.

Axonal Control of the Adult Neural Stem Cell Niche

“…To address this question, we infused the 5HT-releasing agent fenfluramine (Arrant et al, 2013) into the lateral ventricle of adult mice (Figure 5N). Numbers of 5-bromo-2'-deoxyuridine (BrdU)-labeled cells and DCX+ neuroblasts significantly increased following 2-day infusion of fenfluramine, as compared to saline-infused controls (Figure 5O, P, S4E–P), suggesting 5HT induced an increase in proliferation and neurogenesis.…”

Sleep deprivation during late pregnancy produces hyperactivity and increased risk-taking behavior in offspring

“…Immature serotonergic system makes it vulnerable to stress even during early development (Spear, 2000;Arrant et al, 2013). As increased serotonin is associated with increased anxiety-related behaviour (Treit et al, 1993), decreased anxietyrelated behaviour, observed in the pups of sleep-deprived mothers, may be due to an immature serotonergic system.…”

Use of the light/dark test for anxiety in adult and adolescent male rats

“…Species, strain, and methodological differences may account for discrepancies between studies. Adolescent male rats (around PN28) have been reported as having either more or less anxiety-like behavior than adults in the LD test, and a study of adolescent male mice found greater anxiety-like behavior than adults [18–21]. Early adolescent male rats (PN28) do not exhibit anxiety-like behavior in the SI test, a behavior that does not mature until after the onset of puberty [22].…”

“…The LD test has been used to assess age differences in the response to stress and anxiogenic drugs in adolescent versus adult male rats [19–21]. Adolescents have been reported as exhibiting greater anxiogenic responses to stress, but are less sensitive to the anxiogenic effects of drugs targeting the endocannabinoid and serotonergic systems [19–21]. …”