ONTOGENY OF NEUROADAPTIVE RESPONSES TO PSYCHOSTIMULANTS

Nathan S. Kline Institute For Psych Res, Orangeburg NY

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Abstract

Exposure of children to psychostimulants has increased markedly, both in the form of therapeutic treatment of Attention Deficit Hyperactivity Disorder, and in the form of illicit drug use. Commonly used drugs are amphetamine and cocaine, respectively. Little information is available on the developmental pharmacology of these widely used agents. Behavioral responses elicited by psychostimulants in immature animals differ from those in the adult. The neuronal "molecular adaptive responses" that mediate these behaviors have not been studied in the immature animal. Some of the key molecules that are involved in psychostimulant action are related to dopaminergic neurotransmission and include tyrosine hydroxylase, the dopamine transporter, D1 receptors, adenylyl cyclase, DARPP- 32 (dopamine and cyclic AMP-regulated phosphoprotein of Mr 32,000), ERK (extracellular signal regulated kinase), and BDNF (brain derived neurotrophic factor). It is possible that age- related differences in the behavioral responses to psychostimulants are due to age-related differences in the "molecular adaptations" to the drugs. The differential molecular responses to psychostimulants in young animals may well be attributable to naturally occurring differences in the absolute and relative levels of key molecules during development. Further, since BDNF plays a crucial role in the expression of some of these molecules during development, this peptide may modulate age-dependent responses to psychostimulants. Preliminary data, demonstrating differential regulation, in fetuses versus adult animals, of adenylyl cyclase activity, DARPP-32, and FRAs (fos-related antigens) following chronic cocaine administration, support these hypotheses. Identification of the molecular adaptations occurring in response to psychostimulants in different age groups could have profound implications for the use and the sequelae of their therapeutic or illicit use in children. In order to elucidate age-specific molecular adaptive responses to psychostimulants in immature animals, it is proposed: 1) To determine the ontogeny of key molecules involved in the neuroadaptive responses to psychostimulants and their regulation by BDNF; 2) To demonstrate developmentally regulated differences in the molecular responses to chronic psychostimulant administration, especially during the post-weanling and peri-adolescent ages; and 3) To elucidate mechanisms involved in age-specific responses to psychostimulants, using wildtype and BDNF knock-out mice.