Psychostimulants such as methylphenidate and amphetamine are the preferred treatment for Attention Deficit Hyperactivity Disorder (ADHD), yet surprisingly little research has been done on the long- term effects of psychostimulant use. Recently, pilot work in my laboratory has revealed that rats treated chronically with amphetamine during development will show long-term reductions in striatal protein kinase A (PKA) activity that are still observable in adulthood. This long-term decline in PKA activity is of great potential importance, since the phosphorylation of proteins is one of the primary ways in which neuronal activity is regulated. Therefore, the goal of this project is to determine whether the reduction in PKA activity, induced by early chronic treatment with amphetamine, is due to a drug-induced alteration in dopamine system functioning. Specifically, this project will assess whether chronic treatment with amphetamine during the preweanling period will: (a) affect the number or affinity of dopamine D1 and/or D2 receptors in adult rats; (b) produce permanent alterations in the expression of proteins associated with dopamine receptor activation (i.e., DARPP-32 and CREB); and (C) affect drug- and novelty-induced place preference conditioning of adult rats. In the first experiment, homogenate binding techniques will be used to determine the effects of chronic early amphetamine treatment on the number and affinity of dopamine D1 and D2 receptors in rat striatum. The second experiment will use immunoblotting to assess changes in the phosphorylation and expression of DARPP-32 and CREB. Since PKA phosphorylates both of these proteins, it is expected that phosphorylation of DARPP-32 and CREB will be depressed in rats previously given amphetamine treatment. In the third experiment, the behavioral consequences of early chronic amphetamine treatment will be assessed using novelty- and morphine-induced placed preference conditioning. These behavioral paradigms will be used to determine whether chronic amphetamine treatment has a long-term impact on brain reward systems. In summary, these experiments represent a systematic attempt to understand the long-term effects of chronic psychostimulant treatment during development. We believe that the results of this project will have important implications for the pharmacotherapeutic treatment of ADHD.
| McDougall, S A; Zavala, A R; Karper, P E et al. (2001) Chronic amphetamine exposure during the preweanling period does not affect avoidance learning or novelty-seeking of adult rats. Neurobiol Learn Mem 75:338-45 |
| Crawford, C A; Zavala, A R; Karper, P E et al. (2000) Long-term effects of postnatal amphetamine treatment on striatal protein kinase A activity, dopamine D(1)-like and D(2)-like binding sites, and dopamine content. Neurotoxicol Teratol 22:799-804 |
| Crawford, C A; Zavala, A R; Karper, P E et al. (2000) Amphetamine treatment during the preweanling period produces enduring changes in striatal protein kinase A activity. Pharmacol Biochem Behav 66:835-40 |
| Karper, P E; Nazarian, A; Crawford, C A et al. (2000) Role of dopamine D(1) receptors for kappa-opioid-mediated locomotor activity and antinociception during the preweanling period: a study using D(1) receptor knockout mice. Physiol Behav 68:585-90 |
