Towards an understanding of the psychostimulant action of amphetamine and cocaine
Cocaine and amphetamine are psychostimulant drugs that are illicitly used; they affect sensory perception by targeting the neurotransmitter: sodium symporters (NSS) at the synapses between neurons. They both increase the concentration of the neurotransmitter in the synaptic cleft but by different means.
The physiological role of NSS is the reuptake of their endogenous substrate. For this task, they exploit the pre-existing sodium-gradient across the cellular membrane that is maintained by the activity of the sodium:potassium pump. This reuptake process terminates synaptic transmission because the neurotransmitter is removed from the synaptic cleft — and its action on pre- and postsynaptic receptor molecules is stopped.
Amphetamines induce the reverse operation of distinct NSS family members, whereas cocaine merely inhibits the same transporters and thereby blocks the reuptake of neurotransmitter. These effects, although completely different in molecular mechanism, lead to an increase in the synaptic concentration of non-exocytotically released neurotransmitters. While these actions have long been appreciated, the underlying mechanistic details have been surprisingly difficult to understand. The advent of a crystal structure of a prokaryotic NSS protein and the concomitant development of homology models for eukaryotic NSS family members generated novel insights into the structure-function relationships of this clinically relevant class of transporters. Ultimately, we hope to understand the effects of amphetamines and cocaine on a molecular level to elucidate their profound effects on sensory perception.
KeywordsDopamine Transporter Sympathomimetic Amine Neurotransmitter Transporter Reverse Transport Psychostimulant Effect
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