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Lower anxiogenic effects of serotonin agonists are associated with lower activation of amygdala and lateral orbital cortex in adolescent male rats.

ABSTRACT: There has been controversy over use of selective serotonin reuptake inhibitors (SSRIs) to treat affective disorders in children and adolescents due to clinical reports of increased risk for suicidal ideation and behavior during treatment, and animal studies showing changes in adult anxiety- and depressive-like behaviors after repeated treatment during adolescence. However, the acute effect of serotonergic drugs on affective behavior during adolescence is poorly understood. We investigated serotonergic modulation of anxiety-like behavior in adolescent (PN28-32) and adult (PN67-73) male rats using the SSRI fluoxetine, the 5-HT(1A) agonist 8-OH DPAT, and the 5-HT? agonist mCPP. Acute treatment with fluoxetine (10 mg/kg, i.p.) produced greater anxiogenic effects in adults than adolescents in the light/dark (LD) test for anxiety-like behavior, but fluoxetine (2.5, 5, and 10 mg/kg, i.p.) increased extracellular serotonin in the medial prefrontal cortex similarly in both ages. Adults were also more sensitive to the anxiogenic effects of 8-OH DPAT (0.25 and 0.5 mg/kg, i.p.), but not mCPP (0.5 and 1 mg/kg, i.p.), in the LD test. Fluoxetine (10 mg/kg) stimulated greater increases in c-Fos expression across the extended amygdala in adults than in adolescents, and 8-OH DPAT (0.5 mg/kg) produced greater increases in c-Fos in the lateral orbital cortex and central nucleus of the amygdala in adults. These data show that lower anxiogenic effects of acute SSRIs in adolescents are associated with lesser activation of cortical and amygdala brain regions. This immaturity could contribute to the different profile of behavioral effects observed in adolescents and adults treated with SSRIs.

SUBMITTER: Arrant AE

PROVIDER: S-EPMC3812685 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Lower anxiogenic effects of serotonin agonists are associated with lower activation of amygdala and lateral orbital cortex in adolescent male rats.

Arrant Andrew E AE Coburn Elizabeth E Jacobsen Jacob J Kuhn Cynthia M CM

Neuropharmacology 20130615

There has been controversy over use of selective serotonin reuptake inhibitors (SSRIs) to treat affective disorders in children and adolescents due to clinical reports of increased risk for suicidal ideation and behavior during treatment, and animal studies showing changes in adult anxiety- and depressive-like behaviors after repeated treatment during adolescence. However, the acute effect of serotonergic drugs on affective behavior during adolescence is poorly understood. We investigated seroto ...[more]

PMID: 23774134

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Project description:The serotonin transporter (SERT) gene, especially the short allele of the human serotonin transporter linked polymorphic region (5-HTTLPR), has been associated with the development of stress-related neuropsychiatric disorders. In line, exposure to early life stress in SERT knockout animals contributes to anxiety- and depression-like behavior. However, there is a lack of investigation of how early-life exposure to beneficial stimuli, such as tactile stimulation (TS), affects later life behavior in these animals. In this study, we investigated the effect of TS on social, anxiety, and anhedonic behavior in heterozygous SERT knockouts rats and wild-type controls and its impact on gene expression in the basolateral amygdala. Heterozygous SERT+/- rats were submitted to TS during postnatal days 8-14, for 10 min per day. In adulthood, rats were assessed for social and affective behavior. Besides, brain-derived neurotrophic factor (Bdnf) gene expression and its isoforms, components of glutamatergic and GABAergic systems as well as glucocorticoid-responsive genes were measured in the basolateral amygdala. We found that exposure to neonatal TS improved social and affective behavior in SERT+/- animals compared to naïve SERT+/- animals and was normalized to the level of naïve SERT+/+ animals. At the molecular level, we observed that TS per se affected Bdnf, the glucocorticoid-responsive genes Nr4a1, Gadd45β, the co-chaperone Fkbp5 as well as glutamatergic and GABAergic gene expression markers including the enzyme Gad67, the vesicular GABA transporter, and the vesicular glutamate transporter genes. Our results suggest that exposure of SERT+/- rats to neonatal TS can normalize their phenotype in adulthood and that TS per se alters the expression of plasticity and stress-related genes in the basolateral amygdala. These findings demonstrate the potential effect of a supportive stimulus in SERT rodents, which are more susceptible to develop psychiatric disorders.

Project description:Orbitofrontal cortex (OFC), medial frontal cortex (MFC), and amygdala mediate stimulus-reward learning, but the mechanisms through which they interact are unclear. Here, we investigated how neurons in macaque OFC and MFC signaled rewards and the stimuli that predicted them during learning with and without amygdala input. Macaques performed a task that required them to evaluate two stimuli and then choose one to receive the reward associated with that option. Four main findings emerged. First, amygdala lesions slowed the acquisition and use of stimulus-reward associations. Further analyses indicated that this impairment was due, at least in part, to ineffective use of negative feedback to guide subsequent decisions. Second, the activity of neurons in OFC and MFC rapidly evolved to encode the amount of reward associated with each stimulus. Third, amygdalectomy reduced encoding of stimulus-reward associations during the evaluation of different stimuli. Reward encoding of anticipated and received reward after choices were made was not altered. Fourth, amygdala lesions led to an increase in the proportion of neurons in MFC, but not OFC, that encoded the instrumental response that monkeys made on each trial. These correlated changes in behavior and neural activity after amygdala lesions strongly suggest that the amygdala contributes to the ability to learn stimulus-reward associations rapidly by shaping encoding within OFC and MFC.SIGNIFICANCE STATEMENT Altered functional interactions among orbital frontal cortex (OFC), medial frontal cortex (MFC), and amygdala are thought to underlie several psychiatric conditions, many related to reward learning. Here, we investigated the causal contribution of the amygdala to the development of neuronal activity in macaque OFC and MFC related to rewards and the stimuli that predict them during learning. Without amygdala inputs, neurons in both OFC and MFC showed decreased encoding of stimulus-reward associations. MFC also showed increased encoding of the instrumental responses that monkeys made on each trial. Behaviorally, changes in neural activity were accompanied by slower stimulus-reward learning. The findings suggest that interactions among amygdala, OFC, and MFC contribute to learning about stimuli that predict rewards.

Dataset Information

Lower anxiogenic effects of serotonin agonists are associated with lower activation of amygdala and lateral orbital cortex in adolescent male rats.

Publications

Lower anxiogenic effects of serotonin agonists are associated with lower activation of amygdala and lateral orbital cortex in adolescent male rats.

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