Dopaminergic Remodeling During a Critical Developmental Window: Linking Drug Use to Adult Aggression

Excerpt

Behaviors can be shaped and modulated by the dopamine system, which can be remodeled in adolescents due to environmental factors, including pharmacologic exposure, stress, and rewarding experiences, leading to various adolescent-onset neuropsychiatric disorders [1‐3]. A deficiency of dopamine transporter (DAT), responsible for reuptaking extracellular DA, hinders DA clearance, causing elevated extracellular DA levels that impair dopaminergic function and its connections [4]. In clinical settings, patients with a hypofunction of the dopaminergic system often use drugs that can block DAT and increase DA levels. However, the rapid increase in extracellular DA levels during adolescence, which contains a sensitive developmental period, can trigger a chain reaction and alter the function of the DA system, potentially leading to adolescent-onset neuropsychiatric diseases. For instance, the use of methylphenidate (MPH) in adolescents with attention deficit hyperactivity disorder (ADHD) leads to prolonged elevated extracellular signal-regulated protein kinase-1/2 in the ventral tegmental area (VTA), heightening stress sensitivity and contributing to adult depression. In addition, MPH use in adolescents can cause emotional dysfunction due to a heightened salivary cortisol response to social stress. Animal studies have demonstrated that amphetamine can affect neuronal endings during development and interfere with the maturation of brain structures [5‐7]. The sensitive developmental period, characterized by heightened brain plasticity, is critical for remodeling neuronal circuits [8, 9]. Therefore, it is important to elucidate the mechanisms and boundaries of the sensitive period in order to better understand the long-term effects of using drugs that affect the DA system during adolescence and to provide guidance for the appropriate use of psychostimulants (Fig. 1).

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