Psychotic states are induced following prolonged exposure to amphetamine-like drugs; thus, their effects in the central nervous system (CNS) are of interest because they may reveal the neurochemical etiology of mental disorders such as schizophrenia. For instance, systemic high doses of methamphetamine (METH) decrease the activity of the biosynthetic enzymes of dopamine (DA), a transmitter system suspected to be an etiological factor in psychotic states, and of serotonin (5-HT) as well as the concentration of these transmitters. Recently 3,4-methylenedioxymethamphetamine (MDMA), which also is thought to have psychosis-inducing properties, has attracted a great deal of attention due to its selective action on the serotonergic system. Interestingly, local injections of METH or MDMA into the brain fail to produce the neurochemical changes observed when these drugs are administered systemically. This observation suggests that a peripheral action of these drugs contributes to the CNS neurochemical changes. The well-known observation that amphetamine analogs increase the secretion of glucocorticoids, and that these hormones can exacerbate endogenous psychotic disorders in humans suggests that adrenal hormones may play a role in mediating the neurochemical changes induced by these drugs and contribute to their psychogenic action. Preliminary results support this hypothesis as adrenalectomy resulted in a blockade of the MDMA-induced changes in the activity of hippocampal tryptophan hydroxylase (TPH), the biosynthetic enzyme of 5-HT, while corticosterone (CORT) treatment reinstated the drug effects in adrenalectomized animals. The objectives of the present study are to evaluate the role of corticosterone in the neurochemical changes of the central dopaminergic and serotonergic systems induced by METH and MDMA, and to identify the possible mechanism whereby such interaction occurs. Neurochemical changes will be assessed in the frontal cortex, nucleus accumbens, neostriatum and hippocampus of the rat, as these brain structures are thought to participate in psychotic disorders. The impact of the adrenal hormones will be identified by comparing the effects of the drugs on normal and adrenalectomized animals. The role of CORT in mediating the drug-induced changes will be confirmed by implanting CORT pellets in adrenalectomized animals and determining if the drug effects are restored. Determination of TPH activity, the concentration of 5-HT and its metabolite as well as determination of 5-HT uptake by synaptosomes will be used to assess the impact of the amphetamine analogs on the serotonergic systems. Determination of tyrosine hydroxylase (TH) activity, the biosynthetic enzyme of DA, concentrations of DA and its metabolites as well as determination of DA uptake in synaptosomes from the nucleus accumbens and neostriatum will be used to assess the impact of the adrenal hormones on the drug-induced changes in the dopaminergic system. It is expected that the results from this research will help to elucidate the nature of interactions between corticosteroids and the central monoaminergic systems.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Small Research Grants (R03)
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Neurosciences Research Review Committee (BPN)
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University of Utah
Schools of Pharmacy
Salt Lake City
United States
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