Effects of single and multiple doses of desipramine (DMI) on endogenous levels of 3-methoxy-4-hydroxyphenylglycol-sulfate (MOPEG-SO4) in rat brain

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-SO₄) 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-SO₄ brain levels. On the other hand, DMI did not antagonize the increase in MOPEG-SO₄ induced in the cortex-hippocampus by stimulation of the locus coeruleus. These observations indicate that the effect of DMI on MOPEG-SO₄ 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-SO₄. 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.