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Published on: August 25, 2014
Neonatal treatment with para-chlorophenylalanine (pCPA) induces adolescent hyperactivity associated with changes in
Verónica Trujillo1, Tays Araújo Camilo2, Evandro Valentim-Lima2
1Laboratory of Molecular Neuroendocrinology, Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil; Department of Physiology, Facultad de Ciencias Exactas, Físicas y Naturales, Universidad Nacional de Córdoba, Córdoba, Argentina.
Insights
Neonatal disruption of the serotonin system via tryptophan hydroxylase (TPH) inhibition in rats leads to lasting neurochemical changes and increased adolescent hyperactivity. This suggests a link between early TPH impairment and neurobehavioral disorders like ADHD.
Area of Science:
- Neuroscience
- Developmental Biology
- Behavioral Science
Background:
- Disruption of the brain serotoninergic (5-HT) system during development causes persistent alterations in neuronal function and behavior.
- Early life neurochemical imbalances can impact lifelong behavioral regulation.
Purpose of the Study:
- To investigate the long-term effects of neonatal tryptophan hydroxylase (TPH) inhibition on the 5-HT system and related neuropeptides in rats.
- To examine the impact of developmental TPH inhibition on adolescent social play and locomotor behaviors.
Main Methods:
- Rats were treated neonatally with para-chlorophenylalanine (pCPA) to inhibit TPH.
- Levels of 5-HT, Crh, Trh, Htr2c, and VGF were measured in specific brain regions (DRN, PVN, prefrontal cortex).
- Adolescent behaviors including social play, locomotion, and activity were assessed.
Main Results:
- pCPA treatment induced sex-dependent decreases in 5-HT levels in the dorsal raphe nucleus (DRN).
- Neonatal pCPA increased social play and locomotor behaviors in adolescent rats.
- Changes in hypothalamic-pituitary-adrenal (HPA) axis related gene expression (Crh, Trh) and sex dimorphisms in prefrontal cortex gene expression (Htr2c, VGF) were observed.
Conclusions:
- Neonatal TPH inhibition causes lasting, sex-dependent alterations in the 5-HT system and neuroendocrine function.
- These neurochemical changes are associated with a hyperactivity-like phenotype during adolescence.
- Impaired TPH function during development may contribute to neurobehavioral disorders characterized by hyperactivity and impulsivity, such as ADHD.
Abstract:
Disruption of the brain serotoninergic (5-HT) system during development induces long-lasting changes in molecular profile, cytoarchitecture, and function of neurons, impacting behavioral regulation throughout life. In male and female rats, we investigate the effect of neonatal tryptophan hydroxylase (TPH) inhibition by using para-chlorophenylalanine (pCPA) on the expression of 5-HTergic system components and neuropeptides related to adolescent social play behavior regulation. We observed sex-dependent 5-HT levels decrease after pCPA-treatment in the dorsal raphe nucleus (DRN) at 17 and 35 days. Neonatal pCPA-treatment increased playing, social and locomotory behaviors assessed in adolescent rats of both sexes. The pCPA-treated rats demonstrated decreased Crh (17 days) and increased Trh (35 days) expression in the hypothalamic paraventricular nucleus (PVN). There was sex dimorphism in Htr2c (17 days) and VGF (35 days) in the prefrontal cortex, with the females expressing higher levels of it than males. Our results indicate that neonatal pCPA-treatment results in a long-lasting and sex-dependent DRN 5-HT synthesis changes, decreased Crh, and increased Trh expression in the PVN, resulting in a hyperactivity-like phenotype during adolescence. The present work demonstrates that the impairment of TPH function leads to neurobehavioral disorders related to hyperactivity and impulsivity, such as attention deficit hyperactivity disorder (ADHD).
