Aging and haloperidol-induced dopamine turnover in the nigro-striatal pathway of C57BL/6J mice

The responsiveness of male C57BL/6J mice to acute haloperidol (2.5 mg/kg, IP) was studied throughout the average adult lifespan (4, 8, 12, 21, 28 months) by effects on dopamine (DA) turnover, as estimated by DA loss after alpha-methyl-p-tyrosine (AMPT). Previously, striatal receptors for spiroperidol (a related butyrophenone) decreased progressively after 3 months to a loss of 40% by 28 months [29]. Haloperidol treatment (2 hours) accelerated striatal DA turnover similarly in all age groups, by about 100%. The haloperidol-induced accumulation of 3,4-dihydroxyphenylacetic acid (DOPAC) was not significantly impaired in AMPT treated mice with age. These results suggest that the age-related loss of butyrophenone binding sites may not limit acute compensatory responses to blockade of the remaining sites by a large dose of haloperidol. Regional differences in DA metabolism were detected between the substantia nigra (cell bodies and dendrites) and striatum (axonal terminals). Dopamine turnover and DOPAC levels were less in striatum than in substantia nigra; each region had a characteristic DOPAC/DA ratio (nigra, 38%; striatum, 7%); and, DOPAC levels did not precisely covary with DA turnover between regions. The constancy of DOPAC/DA ratios in controls and after AMPT treatment, in all ages suggests that a constant fraction of DA continued to be released and catabolized to DOPAC despite major decrease of DA after blockade of synthesis of DA.