Abstract
A single administration of desipramine (DMI) (10 mg/kg, i.p.) decreased brain levels and probenecid-induced accumulation rate of 3-methoxy-4-hydroxyphenylglycol-sulfate (MOPEG-SO 4) in rats. To investigate the mechanism of this action, the interaction of DMI with NA receptor blockers and its effects on electrical stimulation were evaluated. It was found that phenoxybenzamine (20 mg/kg) or chlorpromazine (10 mg/kg) completely prevented the DMI-induced decrease in MOPEG-SO 4 brain levels. On the other hand, DMI did not antagonize the increase in MOPEG-SO 4 induced in the cortex-hippocampus by stimulation of the locus coeruleus. These observations indicate that the effect of DMI on MOPEG-SO 4 is more likely to be due to a reduction of neuronal impulse flow mediated by a negative feed-back mechanism resulting from impairment of reuptake than to a direct effect on NA catabolism. In contrast to the effect of a single dose, the repeated administration of DMI (10 mg/kg, twice a day for 3 days) did not significantly reduce the rate of probenecid-induced accumulation of MOPEG-SO 4. This development of tolerance to the metabolite-decreasing effects of DMI indicates that complex adaptive changes occur in the NA system upon repeated DMI administration.
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