This research application is a request for funding to continue to characterize the neurotoxicity (NT) of drugs that are pharmacologically and structurally related to methamphetamine (METH). We are interested in determining long term NT in relationship-to neurochemical, morphological and behavioral alterations. We propose to examine these characteristics in specific abused drugs including METH, d-amphetamine (AMPH), methylenedioxymethamphetamine (MDMA) cathinone (CATH), methcathinone (METHCATH), as well as the combination of fenfluramine (FEN) and phentermine (PHEN); the latter two clinically prescribed drugs have low abuse potential but bear structural and pharmacological similarities to the above four drugs of abuse. The extent, duration and short and long term consequences of the NT engendered by these drugs are important to our understanding and treating the consequences of drug abuse. We will investigate several aspects of drug engendered NT including: The functional relationships between ambient temperature (AMB TEMP) and core body temperature (CORE TEMP) as they affect lethality and NT; the importance of these relationships stem from observations that increased AMB and CORE TEMP have been associated with lethality in humans taking MDMA, and increased AMB TEMP and CORE TEMP have been associated with increased mortality and NT in rats. CATH and METHCATH as well as the combination of FEN/PHEN; the former two are widely abused and there are preliminary data to suggest that these drugs are NT, and the FEN/PHEN combination is being used medicinally. It is important to continue basic NT studies to determine if these drugs meet all the criteria for NT. We will also compare the apparent recovery of neurons in the dopamine (DA) and serotonin (5HT) systems after administration of METH, AMPH, and FEN. We will examine the long-term effects of MDMA, METH, AMPH and FEN using quantitative autoradiography as well as the range and length of behavioral impairments caused by drugs that engender NT. We have data suggesting that transmitter depletions seen after drug administration lead to changes in reaction time or increased impulsive behavior in rats. The latter has further important implications because neurochemical alterations in humans may be associated with impulsive behavior including aggression, further drug abuse, criminality and unsafe sex that may lead to HIV and AIDS.
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