Monoamine transporters psychostimulants

Neurotransmitter transport can be electrogenic if it results in the net translocation of electrical charge (e.g. if more cations than anions are transferred into the cell interior). Moreover, some transporters may direction-ally conduct ions in a manner akin to ligand-gated ion channels this ion flux is not coupled to substrate transport and requires a separate permeation pathway associated with the transporter molecule. In the case of the monoamine transporters (DAT, NET, SERT) the sodium current triggered by amphetamine, a monoamine and psychostimulant (see Fig. 4) is considered responsible for a high internal sodium concentration... 

Fleckenstein, A.E., Hanson, G.R. Impact of psychostimulants on vesicular monoamine transporter function. Eur. J. Pharmacol. 479 283, 2003. 

Psychostimulants generally act by increasing the level of extracellular monoamine. The mechanisms responsible include inhibition of plasma membrane monoamine transport and, in particular, stimulation of flux reversal, which may occur by... 

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. 

Riddle EL, Fleckenstein AE, Hanson GR (2005) Role of monoamine transporters in mediating psychostimulant effects. AAPS J 7 E847-E851. 

Methamphetamine (MAP) is a psychostimulant that induces enhanced arousal and euphoria acutely, and psychosis and addiction chronically. MAP enters the terminals/neuron via the monoamine transporters (dopamine transporter DAT, serotonin transporter SERT, or norepinephrine transporter NET), displaces... 

Psychostimulants have been demonstrated to affect dopaminergic signaling by altering DAT and VMAT function (Fleckenstein et al., 2009). Such alterations can be neurotoxic and may provide a role for the monoamine transporters in Parkinson s disease (Fleckenstein et al., 2009). 

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). 

Fleckenstein AE, Volz TJ, Hanson GR (2009) Psychostimulant-induced alterations in vesicular monoamine transporter-2 function Neurotoxic and therapeutic implications. Neuropharmacology 56 133-138... 

Howell LL, Kimmel HL (2008) Monoamine transporters and psychostimulant addiction. Biochem Pharmacol 75 196-217... 

Jayanthi LD, Ramamoorthy S (2005) Regulation of monoamine transporters influence of psychostimulants and therapeutic antidepressants. AAPS J 7 E728-E738 Jayanthi LD, Samuvel DJ, Ramamoorthy S (2004) Regulated intemahzation and phosphorylation of the native norepinephrine transporter in response to phorbol esters. Evidence for localization in Upid rafts and Upid raft-mediated internalization. J Biol Chem 279 19315-19326 Jess U, Betz H, Schloss P (1996) The membrane-bound rat serotonin transporter, SERTl, is an oligomeric protein. FEBS Letters 394 44 6... 

Rothman RB, Baumann MH (2003) Monoamine transporters and psychostimulant drugs. Eur J Pharmacol 479 23-40... 

These transporters represent established targets of many psychostimulants and antidepressants, which exert their potent psychotropic action via interference with transporter function, resulting in a rise in extracellular levels of monoamines (4,8). Some neuron-specific toxins can enter the cells through plasma membrane monoamine transporters, thereby revealing the additional functional role of transporters as a molecular gateway for neurotoxins (6,9). 

An interesting aspect of CNS function revealed by the studies of monoamine transporter mutant mice is the subtle interplay between neurotransmitter systems. Genetic manipulation of one system can create a situation that results in the unmasking of subtle, but nonetheless important, contributions of another neurotransmitter system. For example, the contribution of 5-HT and/or NE systems to the rewarding properties of psychostimulants had been suspected but never demonstrated in such a direct way (28,57,69,88). 

Han D, Gu H (2006) Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs. BMC Pharmacol 6 6... 

Psychostimulant pharmacology involves an augmented release of noradrenaline and dopamine into the synaptic cleft. The presence of monoamine neurotransmitters in the synaptic cleft is regulated in a variety of ways in response to an action potential. Around 70-80% of all transmitter molecules return into the presynaptic neuron by uptake using an energy-dependent reuptake transport protein that is embedded in the neuronal membrane. A smaller fraction... 

---