Dopamine transporter amphetamine

The amphetamine-like properties of trace amines are best described for PEA which shares close structural similarity to amphetamine and can displace monoamine neurotransmitters from synaptic vesicles and trigger their release into the synaptic cleft by acting on the dopamine transporter. However, this effect is only observed at high, supra-physiological PEA concentrations and thus might not occur under physiological conditions. 

Carboni, E., Spielewoy, C., Vacca, C., Norten-Bertrand, M., Giros, B., and DiChiara, G., Cocaine and amphetamine increase extracellular dopamine in the nucleus accumbens of mice lacking the dopamine transporter gene, J. Neurosci., 21, 1, 2001. 

Jacocks, H.M. and Cox, B.K., Serotonin-stimulated [3H]dopamine via reversal of the dopamine transporter in rat striatum and nucleus accumbens a comparison with release elicited by potassium, N-methyl-D-aspartic acid, glutamic acid and D-amphetamine, J. Pharmacol. Exp. Ther., 262, 356, 1992. 

Kahlig, K.M., Binda, F., Khoshbouei, H., Blakely, R.D., McMahon, D.G., Javitch, J.A., and Galli, A., Amphetamine induces dopamine efflux through a dopamine transporter channel, PNAS, 102, 3495, 2005. 

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. 

Lott, D.C., Kim, S., Cook, E.H., and de Wit, H., Dopamine transporter gene associated with diminished subjective response to amphetamine, Neuropharmacology, 1, 2004. 

Giros, B., Jabar, M., Jones, S.R., Wightman, R.M., Caron, M.G. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature. 379 606, 1996. 

Other knockout models that could be used to validate candidate genes include mice that lack monoamine oxidase A (MAO-A), which have demonstrated altered behavior and alcohol tolerance [54]. Transgenic mice in which the dopamine transporter gene has been deleted show striking hyperactivity via enhanced persistence of dopamine which is not altered by cocaine or amphetamine administration [55]. Knockouts of the serotonin IB receptor are also available and are best used as models of vulnerability to drug abuse [56]. 

It is now possible to image not only postsynaptic, but pre-synaptic and intrasynaptic neurotransmission (Fig. 58-5). Presynaptic sites, such as the dopamine transporter and the serotonin transporter the presynaptic dopamine vesicular transporter (VMAT-2) and the acetylcholine transporter extrasynaptic sites such as the enzymes which break down neurotransmitters, e.g. MAO A and MAO B with radioligands that bind to post or pre-synaptic sites, i.e. dopamine competing with radioligands such as UC raclopride (see Fig. 58-9) (PET (Fig. 58-10) can be measured under basal conditions or following drugs which either decrease (e.g. AMPT) or increase (e.g. intravenous amphetamine) intrasynaptic dopamine. 

Spielewoy, C., Biala, G., Roubert, C., Hamon, M., Betancur, C., and Giros, B. (2001) Hypolocomotor effects of acute and daily d-amphetamine in mice lacking the dopamine transporter. Psychopharmacology 159, 2-9. 

Sitte, H. H., Huck, S Reither, H., Boehm, S., Singer, E. A., and PiU, C. (1998) Carrier-mediated release, transport rates, and charge transfer induced by amphetamine, tyramine, and dopamine in mammalian cells transfected with the human dopamine transporter../. Neu-rochem. 71,1289-1297. 

The dopamine transporter has been a target for developing pharmacotherapies for a number of CNS disorders including ADHD, stimulant abuse, depression and Parkinson s disease. Several excellent reviews in this area have been recently published [28-30]. The dopamine reuptake inhibitor methylphenidate has been successfully used for decades in the management of ADHD in children and adolescents. It remains a first-line treatment along with amphetamine for this disorder [31,32]. 

FIGURE 2.9 Dopaminergic synapse. The release of dopamine (1) can be enhanced by compounds such as amphetamine and methylphen-idate (1). Once released, dopamine binds to two types of dopamine receptors. The family of D1 receptors includes the D1 and D5 receptor (2) and the family of D2 receptors includes the D2, D3, and D4 receptors (3). Dopamine is removed from the synapse via cleavage by catechol-O-methyl-transferase (COMT) or via reuptake by the dopamine transporter (4). 

Dopamine is removed from the synapse via two mechanisms. First, COMT degrades intrasynaptic DA. Second, the dopamine transporter (DAT) [see (4) in Fig. 2.9], a Na /CD-dependent neurotransmitter transporter, transports DA in either direction, depending on the concentration gradient. The DAT is blocked selectively by drugs such as cocaine, amphetamine, bupropion, and nomifensine. 

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. 

Giros, Bruno, Mohamed Jaber, Sara R. Jones, R. Mark Wightman, and Marc G. Caron. 1996. "Hyperlocomotion and Indifference to Cocaine and Amphetamine in Mice Lacking the Dopamine Transporter." Nature 379 606-12. 

Synaptic dopamine transporters are inhibited by various psychotropic alkaloids including the tropane alkaloid cocaine [189, 190], the indole alkaloid ibogaine [191] and by amphetamine (methylphenethylamine) and related compounds [192, 193]. 

The most commonly used agents to enhance attention in attention deficit disorder are the stimulants methylphenidate and ( -amphetamine. Other effective stimulants are not as widely used, pemoline because of liver toxicity and methamphetamine because of its greater abuse potential. Methylphenidate and ( -amphetamine act predominantly by releasing dopamine from presynaptic dopamine terminals (Figs. 12— 2 and 12—3). These agents not only block the dopamine transporter but may actually... 

FIGURE 12-3. When (/-amphetamine binds to the presynaptic dopamine transporter on the dopamine neuron, it not only blocks dopamine reuptake but actually causes dopamine release. There may be a preference or selectivity for cortical over striatal dopamine presynaptic terminals by (/-amphetamine, so lower doses may have preferential effects on attention rather than on motor activity. Methylphenidate has a similar action, which is not quite as rapid but longer-lasting in many patients. 

FIGURE 12-4. The enantiomer of -amphetamine is /-amphetamine, which has no preference between the norepinephrine and the dopamine transporters. Thus, it will target both the norepinephrine reuptake site (shown here), as well as the dopamine reuptake site (shown in Fig. 12-2). -Amphetamine is selective for the dopamine transporter. 

Fog JU, Khoshbouei H, Holy M, Owens WA, Vaegter CB, Sen N, Nikandrova Y, Bowton E, McMahon DG, Colbran RJ, Daws LC, Sitte HH, Javitch JA, Galli A, Gether U (2006) Calmodulin kinase II interacts with the dopamine transporter C terminus to regulate amphetamine-induced reverse transport. Neuron 51 417—429. 

Khoshbouei H, Sen N, Guptaroy B, Johnson L, Lund D, Gnegy ME, Galli A, Javitch JA (2004) N-terminal phosphorylation of the dopamine transporter is required for amphetamine-induced efflux. PLoS Biol 2 E78. 

Budygin EA, Brodie MS, Sotnikova TD, Mateo Y, John CE, Cyr M, Gainetdinov RR, Jones SR (2004) Dissociation of rewarding and dopamine transporter-mediated properties of amphetamine. Proc Natl Acad Sci 707(20) 7781-7786. 

---