Chronic cocaine and rat brain catecholamines: long-term reduction in hypothalamic and frontal cortex dopamine metabolism.

The short- (1 h after last treatment) and long- (1, 6, and 12 weeks after treatment) term effects of repeated cocaine administration on catecholamine metabolism were evaluated in the rat brain. The concentrations of norepinephrine (NE), dopamine (DA) and their metabolites were measured in the hypothalamus, frontal cortex, septum, striatum and nucleus accumbens. Except for a short-term increase in hypothalamic NE content, NE and its major metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), did not change after chronic cocaine treatment in any of the brain regions analysed. The immediate (short-term) effects of chronic cocaine administration on DA metabolism included significant reductions in DOPAC in the frontal cortex, septum, nucleus accumbens, striatum and hypothalamus. In addition, DA was reduced in the frontal cortex and nucleus accumbens. In none of these brain regions was the concentration of HVA significantly changed. The short-term reductions in DA metabolism observed in the striatum and nucleus accumbens disappeared within one week of termination of cocaine treatment. Following cocaine treatment there were, however, reductions in frontal cortex DOPAC, 1 and 6 weeks following withdrawal, and in HVA 12 weeks after withdrawal. The combined molar concentrations of DOPAC and HVA at the three withdrawal periods (1, 6 and 12 weeks) were reduced, suggesting attenuated frontal cortex DA turnover. In the hypothalamus, DA metabolites were reduced after 6 weeks withdrawal. Twelve weeks after cocaine withdrawal hypothalamic HVA, as well as DOPAC plus HVA, were significantly increased suggesting compensation had taken place. The clinical effects following cocaine withdrawal in humans may be related to long-term changes in DA metabolism similar to those found in rat brain.