Abstract
Cocaine methiodide (CM), a charged cocaine analog, cannot pass the blood brain barrier. It has been assumed the effects of systemic CM represent cocaine actions in peripheral tissues. However, the IC50 values of CM have not been clearly determined for the major cocaine targets: dopamine, norepinephrine, and serotonin transporters, and sodium channels. Using cells transfected with individual transporters from mice and synaptosomes from mouse striatum tissues, we observed that the inhibition IC50 values for monoamine uptake by CM were 31-fold to 184-fold higher compared to cocaine at each of the transporters. In dorsal root ganglion neurons, cocaine inhibited sodium channels with an apparent IC50 of 75 µM, while CM showed no observable effect at concentrations up to 3 mM. These results indicate that an equal dose of CM will not produce an equivalent peripheral effect of cocaine.
Highlights
Cocaine produces complex behavioral and physiological effects including: addiction and locomotor stimulation, cardiac arrhythmias, and hormonal changes [1,2]
Since Cocaine methiodide (CM) cannot pass across the blood brain barrier, it had been used in studies attempting to separate the central nervous system (CNS) effects from the peripheral effects of cocaine
The data presented in this paper shows very substantial differences between potencies of cocaine and CM in inhibition of major cocaine target proteins
Summary
Cocaine produces complex behavioral and physiological effects including: addiction and locomotor stimulation, cardiac arrhythmias, and hormonal changes [1,2]. Cocaine produces effects in the central nervous system (CNS) primarily by inhibiting three monoamine transporters, DAT, NET and SERT [3] These transporters clear neurotransmitters from neural synapses and surrounding areas through monoamine reuptake [1]. Cocaine inhibition of these reuptake processes results in prolonged monoamine elevation in brain regions that promote reward and addiction [1]. Cocaine blocks sodium channels but with lower potencies (50 mM or higher) [5] These cocaine targets are expressed in both the CNS and the peripheral systems [6,7]
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