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.
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D002746:Chlorpromazine / Q000494:pharmacology; D003891:Desipramine / Q000008:administration & dosage / Q000494:pharmacology*; D004347:Drug Interactions; D004558:Electric Stimulation; D006018:Glycols / Q000378:metabolism*; D008125:Locus Coeruleus / Q000502:physiology; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D010643:Phenoxybenzamine / Q000494:pharmacology; D051381:Rats; D013997:Time Factors
D006018:Glycols; D010643:Phenoxybenzamine; D008734:Methoxyhydroxyphenylglycol; D003891:Desipramine; D002746:Chlorpromazine; D009638:Norepinephrine