Monoamine transporters drug targeting

Zheng Q Dwoskin LP, Crooks PA. (2006) Vesicular monoamine transporter 2 Role as a novel target for drug development. AAPS J 8 E682-E692. 

Pharmacologic targeting of monoamine transporters. Commonly used drugs such as antidepressants, amphetamines, and cocaine target monoamine (norepinephrine, dopamine and serotonin) transporters with different potencies. A shows the mechanism of reuptake of norepinephrine (NE) back into the noradrenergic neuron via the norepinephrine transporter (NET), where a proportion is sequestered in presynaptic vesicles through the vesicular monoamine transporter (VMAT). and C show the effects of amphetamine and cocaine on these pathways. See text for details. 

Relatively little attention has been given to another important aspect of transporter function. Several lines of evidence have suggested that drugs affecting monoamine transporters can significantly modulate presynaptic neuronal homeostasis (17-22). However, until genetic animal models with targeted disruption of these transporters became available (23-25), this homeostatic role of plasma membrane transporters was not fully appreciated. 

It is possible that antidepressant drugs have other targets in addition to their actions at cell surface monoamine transporters. AI-Damluji and Kopin (107) have described a novel amine uptake process in peptide-containing hypothalamic neurons, which they, named "transport-P." Like the vesicular transporters this process is driven by a proton gradient, but it is distinct from the vesicular transporters in being insensitive to reserpine, but sensitive to a variety of tricyclic antidepressants at micromolar concentrations (108). It is not clear, however, what role if any transport-P plays in the inactivation of the monoamine neurotransmitters. 

This drug class includes cocaine and amphetamine derivatives 916 Transporters for dopamine (DAT), serotonin (SERT) and norepinephrine (NET) are the initial targets for psychomotor stimulants 916 Cocaine and amphetamines produce neuronal adaptations by repeatedly elevating monoamine levels 917... 

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