Since 1991, there has been a disturbing increase in the abuse of the potent stimulant, methamphetamine (METH) in both adolescents and young adults. We and others have investigated the short- and long-term effects of METH on dopamine (DA) and serotonergic (5HT) systems of young adult rats (typically 60-90 postnatal day; PND). Because of reports that younger animals (20-40 PND), corresponding to the human adolescent developmental stage, are less likely to experience METH-induced long-term changes in DA systems, little METH-related research has been conducted on this population. In preliminary studies, we confirmed that multiple high doses of METH cause deficits of 50-70 percent in striatal DA parameters after 7 d in 90 PND, but not 40 PND, male rats. In contrast, METH-induced short-term (1 h after treatment) responses by DA systems were very similar in both the 40 and 90 PND groups. Surprisingly, we did not observe an age-dependent difference in either the short- or long-term responses by the 5HT systems to METH treatment. Because of these age-dependent differential responses, it is important to study and compare the effects of METH on both young (corresponding to human adolescence) and more mature (corresponding to human adults) animals. In order to elucidate the age-dependent effects of METH abuse, this proposal will test the hypothesis that there are age-related differential long- but not short-term responses by DA systems to METH; however, the developmental pattern of response to METH is different for the 5HT system. This hypothesis will be tested by achieving the following Specific Aims: A. Determine the pattern of the age-dependent differential response by DA systems to METH, and compare these age-related effects to those observed in 5HT systems. B. Determine the mechanism responsible for the age-dependent DA differential responses to METH. C. Determine the consequences of the age-dependent differential response to METH. The studies associated with this specific aim are based on the interesting observation that exposure of adolescent rats (i.e., 40 PND), which as noted above, are refractory to the long-term DA deficits caused by METH, makes these animals also refractory when later challenged as adults (90 PND) with high doses of METH. The mechanism and selectivity of this phenomenon will be studied.
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