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Dopamine can be autoxidized to superoxides and quinones. Superoxides can form hydroxyl radicals that are highly reactive with lipids, proteins and DNA leading to neuronal damage and cell death. We used a clonal catecholaminergic cell line (CATH.a) derived from the central nervous system to evaluate the effects of dopamine on cell death, lipid peroxidation and DNA base damage. Dopamine produces cell death in CATH.a cells and this is associated with an increase in annexin binding, which is an early indicator of apoptosis. Incubation of CATH.a cells with deferoximine, an iron chealator, partially antagonizes dopamineinduced cell death. In CATH.a cells, dopamine produces an increase in both lipid peroxidation, as measured by cis-parinaric acid fluorescence, and DNA oxidative base damage, as measured by 8-hydroxy-2'-deoxyguanosine formation. Cell death was inhibited 84-92% by the hydrophilic antioxidants, dithiothreitol, L-cysteine, and N-acetylcysteine. The lipophilic vitamins, retinol and vitamin E and the vitamin E analog, Trolox, inhibited dopamine-induced cell death by 18-33%. The lipophilic antioxidants probucol, propyl glycol and butylated hydroxyanisone had no inhibitory effect on dopamine-induced cell death. These data suggest that damage to DNA and lipids may be partially responsible for dopamine-induced cell death in CATH.a cells.

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Changes in the tissue levels of 3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and dopamine in the frontal cortex, hypothalamus, nucleus accumbens, and striatum were evaluated after 0.5-4 h of footshock (2 mA, for 3 s every 30 ±5 s) in Fischer rats. 3-MT, DOPAC, and HVA levels in the four brain areas peaked at 0.5 h and in most cases returned to baseline values within 4 h. No changes were found in dopamine levels. Repeated footshock stress was evaluated by administering 10 footshock sessions (0.5 h, two per day for 5 days). At the end of the 10th footshock session, 3-MT levels were higher than at the end of the first footshock session in three of the four brain regions, indicating sensitization of dopamine release. No differences were found between the first and 10th footshock sessions in DOPAC and HVA levels. Fourteen days after the 10th footshock session, the levels of 3-MT, DOPAC, and HVA were the same as in control rats in all four brain regions. A 0.5-h footshock challenge presented 14 days after the 10th footshock session attenuated DOPAC levels in the hypothalamus and nucleus accumbens. In contrast, DOPAC and HVA levels in the frontal cortex showed sensitization after footshock challenge, and a similar trend was apparent for 3-MT levels. These results indicate that repeated footshock stress induces generalized sensitization of dopamine release and turnover in some areas of the brain of Fischer rats. This sensitization may persist in the cortical but not subcortical dopamine neurons after discontinuation of the treatment. Key Words: Frontal cortex-Nucleus accumbens-3-Methoxytyramine-3,4-Dihydroxyphenylacetic acidHomovanillic acid-Stress. J. Neurochem. 68, 2024-2031 (1997).Catecholamine neurons in the PNS and CNS are involved in mediating homeostatic responses to many stresses. These responses are usually represented by enhanced activities of the sympathetic nervous system and of noradrenergic and dopaminergic neurons in the brain (McCarty et a!., 1988;Deutch and Roth, 1990;Deutch, 1993; see Chrousos et al., 1995). In addition, both acute and repeated stress can also affect an organism's ability to respond to a subsequent stress. This change can be either an enhanced response (sensitization) or an attenuated response (habituation). The stimulant drugs cocaine and amphetamine also produce similar sensitization or tolerance after repeated administration, and in some cases, these effects show crosstolerance/sensitization with stress (Antelman et al., 1980;Robinson et al., 1987;Kalivas and Duffy, 1989; Kalivas, 1991, 1993). Dopaminergic areas of the brain are especially sensitive to inescapable stress and exhibit increases in dopamine release measured by dialysis or 3-methoxytyramine (3-MT) formation and increases in dopamine turnover measured by the levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), or homovanillic acid (HVA) (Roth et al., 1988;Abercrombie et al., 1989;Deutch and Roth, 1990;Imperato et al., 1990Imperato et al., , 1991Puglisi-Allegr...