The neuropeptide, neurotensin (NT), appears to play an important role in regulating dopamine (DA) pathways; thus, NT antagonizes DA effects when administered into the nucleus accumbens and striatum and consequently attenuates the motor responses (i.e., locomotion and rearing) to low doses of stimulants of abuse, like methamphetamine (METH). In a reciprocal manner, increases in DA release (such as that induced by METH) profoundly alter NT activity associated with accumbens and striatal DA terminals, causing opposite changes in NT concentration when DA D-l or D-2 receptors are stimulated. These findings suggest a complex interaction between NT and DA systems; because of that interaction NT may have an important influence on responses to CNS stimulants, such as METH. Thus, the principal objective of this proposal is to identify the effects of endogenous NT systems on the changes in DA activity and motor behavior caused by various METH treatments and to elucidate the mechanisms of these effects. The objectives of this proposal will be achieved by determining the consequences of antagonizing endogenous NT activity, with either a selective antiserum raised against NT or a nonpeptide NT antagonist (SR 48692), on the effects of METH. Surprising initial data suggest that NT systems are activated and antagonize DA and motor responses to low (0.5 mg/kg), but, are shut down and have no effect in the presence of high (5 mg/kg) doses of METH. These findings will be extended and the involved DA systems identified. Other findings suggest that NT involvement in the response to low METH doses relates to increased activity caused by DA D-2 receptors. In contrast, NT systems in the response to high doses of METH are shut down by DA D-l and N-methyl-D- aspartate (NMDA; a glutamate subtype) receptors. These hypotheses will be tested. The effects of METH or selective Dl and D2 agonists and antagonists, will be determined by measuring DA and/or NT release with microdialysis probes or push-pull cannulae implanted into the nucleus accumbens, neostriatum or ventricles. The motor response to METH will be evaluated by a Digiscan """"""""Micro"""""""" Analyzer combined with a trained observer blind to the treatment. A better understanding of how METH affects limbic and extrapyramidal NT systems and how they in turn contribute to the response caused by this stimulant may lead to the development of novel therapies for the acute and chronic problems of METH abuse. In addition, these studies will help elucidate the mechanisms whereby important midbrain dopaminergic pathways are regulated and possibly suggest new approaches for treating related psychiatric and motor disorders.
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