EFFECTS OF DESMETHYLIMIPRAMINE AND COCAINE ON THE UPTAKE, RETENTION AND METABOLISM OF H³-TYRAMINE IN RAT BRAiN SLICES

¹ Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan

Slices of hypothalamus, brainstem, parietal cortex and caudate from rat brain were incubated in Krebs-Ringer solution at 37°C for 20 minutes with H³- tyramine (1.4 x 10^-7 M). Slices from all areas synthesized H³-p-hydroxyphenylacetic acid (H³-p-HPAA) and H³-octopamine. In addition, some of the H³-tyramine which was taken up was retained unmetabolized. Although caudate slices made less H³-octopamine, these slices made more H³-p-HPAA and retained much more H³-tyramine than slices from the other areas. Neither H³-octopamine nor H³-p-hydroxymande1ic acid was found in bathing solutions or washes of slices from any area. Cocaine (10^-6-3 x 10^-4 M), when added to the incubation flask 15 minutes before the addition of H³-tyramine, caused a decrease in both H³-octopamine and H³-p-HPAA synthesis as well as a decrease in the amount of H³- tyramine retained. In contrast, desmethylimipramine (DMI, 10^-7 and 10^-6 M), when added to the incubation flask 15 minutes before the H³-tyramine, caused a marked decrease in the synthesis of H³-octopamine but did not decrease the synthesis of H³-p-HPAA or diminish the retention of H³-tyramine. Similar results were obtained with slices from rats pretreated with DMI (2-60 mg/kg, i.p.) one hour before sacrifice. The inhibition of H³-octopamine synthesis caused by DMI, both in vivo and in vitro, was noncompetitive, whereas that produced by cocaine was competitive. Cocaine (10^-4 M) and DMI (60 mg/ kg and 10^-6 M), when added to homogenates of hypothalamus, had no effect on the synthesis of either H³-p-hydroxymandelic acid or ³-p-HPAA. These results indicate that cocaine blocks the uptake of H³-tyramine at the neuronal membrane. In contrast, low doses of DMI do not prevent the uptake of H³-tyramine at the neuronal membrane and subsequent synthesis of H³-p-HPAA, but do prevent the uptake of H³-tyramine into the intraneuronal sites where it is converted into H³-octopamine.

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