Effect of Cocaine and Desmethylimipramine on the Uptake, Retention and Metabolism of 3H-5-Hydroxytryptamine in Rat Brain Slices1

Abstract

Uptake and metabolism of ³H-5-hydroxytryptamine (³H-5-HT) in slices of hypothalamus, brain stem, caudate nucleus and parietal cortex were examined in vitro. The results indicate that ³H-5-HT taken up by neurons is firmly retained and that there are regional differences in the uptake and retention of ³H-5-HT. For example, the caudate had a significantly greater maximum rate of uptake and binding (V_max) than the other brain areas tested, particularly the cortex. In contrast, the caudate appeared to have the lowest apparent affinity for ³H-5-HT uptake (K_m). Uptake and retention of ³H-5-HT by four brain areas were markedly inhibited by cocaine and desmethylimipramine (DMI) in vitro. The inhibitory effect of both drugs was noncompetitive in nature, with exception of the hypothalamus where DMI competitively blocked the uptake of ³H-5-HT. The fact that cocaine and DMI failed to reduce the formation of ³H-5-hydroxyindoleacetic acid despite their potent blocking action of ³H-5-HT uptake suggests that a significant amount of ³H-5-HT is oxidatively deaminated at extraneuronal sites. This extraneuronal metabolism of 5-hydroxytryptamine may play an important role in regulating the action of this neurotransmitter.