Monoamine transporters cocaine

VMATs are not inhibited by drugs such as cocaine, tricyclic antidqnessants and selective serotonin reuptake inhibitors that affect plasma membrane monoamine transport. Amphetamines have relatively selective effects on monoaminergic cells due to selective uptake by plasma membrane monoamine transporters, but their effect appears to be mediated by their ability as weak bases to reduce ApH, the driving force for vesicular monoamine transport that leads to efflux of the vesicular contents into the cytoplasm. 

Pill, C., Drobny, H., Reither, H., Homykiewicz, O., and Singer, E.A., Mechanism of the dopaminereleasing actions of amphetamine and cocaine plasmalemmal dopamine transporter versus vesicular monoamine transporter, Mol. Pharmacol., 47, 368, 1995. 

Wilson J., Levey A., Bergeron C. et al. Striatal dopamine, dopamine transporter, and vesicular monoamine transporter in chronic cocaine users. Ann. Neurol. 40 428, 1996. 

Transporters for dopamine (DAT), serotonin (SERT) and norepinephrine (NET) are the initial targets for psychomotor stimulants. By interacting with these transporters (Chs 12 and 13), psychomotor stimulants increase extracellular levels of monoamine neurotransmitters. Cocaine is a monoamine uptake inhibitor. The reinforcing effects of cocaine correlate best with its binding potency at the DAT. However, experiments with monoamine transporter-deficient mice suggest that cocaine actions at... 

Rocha, B. A. Stimulant and reinforcing effects of cocaine in monoamine transporter knockout mice. Eur. J. Pharmacol. 479 107-115,2003. 

Interestingly, we have recently identified a mutation of a tyrosine in the third intracellular loop of the hDAT that causes a major alteration in the conformational equilibrium of the transport cycle, and thus as such is comparable to mutants on G protein-coupled receptors causing constitutive isomerization of the receptor to the active state (66). Most importantly, this conclusion is based on the observation that mutation of the tyrosine completely reverts the effect of Zn2+ at the endogenous Zn2+ binding site in the hDAT (50,51) from potent inhibition of transport to potent stimulation of transport (Fig. 6). In the absence of Zn2+, transport capacity is reduced to less than 1% of that observed for the wild-type, however, the presence of Zn2+ in only micromolar concentrations causes a close to 30-fold increase in uptake (66). Moreover, it is found that the apparent affinities for cocaine and several other inhibitors are substantially decreased, whereas the apparent affinities for substrates are markedly increased (66). Notably, the decrease in apparent cocaine affinity was around 150-fold and thus to date the most dramatic alteration in cocaine affinity reported upon mutation of a single residue in the monoamine transporters (66). 

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. 

Mechanism of action of cocaine and amphetamine on synaptic terminal of dopamine (DA) neurons. Left Cocaine inhibits the dopamine transporter (DAT), decreasing DA clearance from the synaptic cleft and causing an increase in extracellular DA concentration. Right Since amphetamine (Amph) is a substrate of the DAT, it competitively inhibits DA transport. In addition, once in the cell, amphetamine interferes with the vesicular monoamine transporter (VMAT) and impedes the filling of synaptic vesicles. As a consequence, vesicles are depleted and cytoplasmic DA increases. This leads to a reversal of DAT direction, strongly increasing nonvesicular release of DA, and further increasing extracellular DA concentrations. 

Cocaine (Fig. 13—3) has two major properties it is both a local anesthetic and an inhibitor of monoamine transporters, especially dopamine (Fig. 13—4). Cocaine s local anesthetic properties are still used in medicine, especially by ear, nose, and throat specialists (otolaryngologists). Freud himself exploited this property of cocaine to help dull the pain of his tongue cancer. He may have also exploited the second property of the drug, which is to produce euphoria, reduce fatigue, and create a sense of mental acuity due to inhibition of dopamine reuptake at the dopamine transporter. Cocaine also has similar but less important actions at the norepinephrine and the serotonin transporters (Fig. 13—3). Cocaine may do more than merely block the transporter—it may actually release dopamine (or norepinephrine or serotonin) by reversing neurotransmitter out of the presynaptic neuron via the monoamine transporters (Fig. 13—4). 

Brown JM, Hanson GR, Fleckenstein AE (2001) Regulation of the vesicular monoamine transporter-2 a novel mechanism for cocaine and other psychostimulants. J Pharmacol Exp Ther 296 762-767. 

Wang YM, Gainetdinov RR, FumagaUi F, Xu F, Jones SR, Bock CB, Miller GW, Wightman RM, Caron MG (1997) Knockout of the vesicular monoamine transporter 2 gene results in neonatal death and supersensitivity to cocaine and amphetamine. Neuron 19 1285-1296. 

The effect of released norepinephrine wanes quickly, because -90% is transported back into the axoplasm by a specific transport mechanism (norepinephrine transporter, NAT) and then into storage vesicles by the vesicular transporter (neuronal reuptake). The NAT can be inhibited by tricyclic antidepressants and cocaine. Moreover, norepinephrine is taken up by transporters into the effector cells (extraneuronal monoamine transporter, EMT). Part of the norepinephrine undergoing reuptake is enzymatically inactivated to normetanephrine via catecholamine O-methyltransferase (COMT, present in the cytoplasm of postjunctional cells) and to dihydroxymandelic acid via monoamine oxidase (MAO, present in mitochondria of nerve cells and postjunctional cells). 

Indirect sympathomimetics (B) in the narrow sense comprise amphetamine-like substances and cocaine. Cocaine blocks the norepinephrine transporter (NAT), besides acting as a local anesthetic. Amphetamine is taken up into varicosities via NAT, and from there into storage vesicles (via the vesicular monoamine transporter), where it displaces NE into the cytosol. In addition, amphetamine blocks MAO, allowing cytosolic NE concentration to rise unimpeded. This induces the plasmalemmal NAT to transport Luellmann, Color Atlas of Pharmacology All rights reserved. Usage subject to terms... 

Psychostimulants exert their effects by increasing levels of extracellular neurotransmitter. Psychostimulants are classified as uptake inhibitors or releasers. Cocaine is an example of an uptake inhibitor (Table 2). Cocaine exerts its effects by binding to DAT, NET, or SERT. This binding prevents the transport of neurotransmitter, resulting in increased synaptic neurotransmitter levels. Amphetamines such as MDMA are classified as releasers. They are substrates of the monoamine transporters. Releasers reverse the direction of transport from inward to outward, leading to an increase in the levels of neurotransmitter in the synaptic cleft (Fleckenstein et al., 2007 Rothman and Baumann, 2003). 

NE secretion can be effectively decreased by administration of reserpine, an alkaloid isolated from a small woody perennial found in India (Rauwolfia), which has a high affinity for the vesicular monoamine transporter-2 (VMAT-2) and as such prevents NE storage. Alternatively, NE secretion can be increased by administration of tyramine (decarboxylated tyrosine), which is a constituent of a variety of foods including red wine, pickled herring and cheese. Amphetamine has a similar effect, which is most prominently manifested in the CNS. The termination of NE effects can be circumvented by the administration of cocaine, which blocks NE transport into presynaptic nerve endings (NET) an effect, which is also shared by some of the first generation antidepressants, such as imipramine. 

Uhl GR, Hall FS, Sora I. 2002. Cocaine, reward, movement and monoamine transporters. Mol. Psychiatry 7 21 -26... 

An attempt will be made here to distill down the essence of the SAR of cocaine as it relates to its stimulant properties. In many cases, compounds have been reported that have not been tested in vivo, but have only been compared for affinity at the monoamine transporters or in an in vivo assay. Some of these data will be summarized if they are reported in the context of the stimulant effects of cocaine. Similarly, there have been numerous attempts to develop cocaine analogs that may bind to the dopamine transporter and actually block the stimulant or reinforcing effects of cocaine itself, in efforts to develop treatments for cocaine addiction. This chapter largely ignores many of those studies unless they contain in vivo data suggestingthey are relevant to a discussion of stimulant effects. Nevertheless, because stimulant properties have been associated with bindingto the DAT, a good deal of the SAR discussion here must be discussed in the context of in vitro DAT affinity. 

Additional radioligands have recently been developed for probing the DA transporter proteins that are highly characteristic gene products of DA neurons and nerve terminals in the basal ganglia. Cocaine(53 Fig. 12.1 l)bindsto the DA transporter (DAT) and other monoamine transporters, but radiolabeled cocaine... 

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