Interaction of central nervous system drugs with synaptosomal transport processes

Interaction of a wide range of central nervous system (CNS) drugs with the transport of 5-hydroxytryptamine (5-HT) and norepinephrine (NE) into synaptosomes from cerebral cortex was investigated. By determining the effect on Na,K-ATPase, the interaction of these drugs with the synaptic transport of Na + and K+ was also assessed. Although of different numerical value, the order of potency of the drugs in inhibiting the uptakes of both biogenic amines was comparable. Furthermore, similar inhibition constants were obtained for the low affinity uptake of 5-HT and the uptake of NE. Desipramine and amphetamine strongly inhibited both uptake processes. The narcotic drugs displayed a wide range of inhibitory potency. An exceptionally strong, but not stereospecific, effect was obtained with levorphanol, which inhibited 5-HT uptake with a Ki of 0.7 [mu]M. While methadone and pentazocine had inhibition constants between 20 and 50 [mu]M, morphine, codeine and naloxone were markedly weak inhibitors with Ki, values extending into the mM range. The uptake of both 5-HT and NE was strongly inhibited by quinacrine. Among the drugs investigated, only methadone showed substantial inhibition of synaptosomal Na,K-ATPase. The reversible inhibition of the enzyme by the drug was diminished at concentrations of Na + and K + reflecting synaptic discharge. The drug partially bound to the ouabain site of Na,K-ATPase and also inhibited the Mg-activated component. The feasibility and experimental conditions were established for using a modified crude mitochondrial fraction as synaptosomal preparation to study transport processes in general and the uptake of biogenic amines in particular.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/21656/1/0000040.pd