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BMC Pharmacology Biomed Central CORE Metadata, citation and similar papers at core.ac.uk Provided by Springer - Publisher Connector BMC Pharmacology BioMed Central Research article Open Access Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Dawn D Han1 and Howard H Gu*1,2 Address: 1Department of Pharmacology, The Ohio State University College of Medicine, USA and 2Department of Psychiatry, The Ohio State University College of Medicine, 333 West 10th Avenue, Columbus, Ohio 43210, USA Email: Dawn D Han - [email protected]; Howard H Gu* - [email protected] * Corresponding author Published: 03 March 2006 Received: 03 November 2005 Accepted: 03 March 2006 BMC Pharmacology2006, 6:6 doi:10.1186/1471-2210-6-6 This article is available from: http://www.biomedcentral.com/1471-2210/6/6 © 2006Han and Gu; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: The plasma membrane neurotransmitter transporters terminate neurotransmissions by the reuptake of the released neurotransmitters. The transporters for the monoamines dopamine, norepinephrine, and serotonin (DAT, NET, and SERT) are targets for several popular psychostimulant drugs of abuse. The potencies of the psychostimulant on the monoamine transporters have been studied by several laboratories. However, there are significant discrepancies in the reported data with differences up to 60-fold. In addition, the drug potencies of the 3 monoamine transporters from mouse have not been compared in the same experiments or along side the human transporters. Further studies and systematic comparisons are needed. Results: In this study, we compared the potencies of five psychostimulant drugs to inhibit human and mouse DAT, SERT and NET in the same cellular background. The KI values of cocaine to inhibit the 3 transporters are within a narrow range of 0.2 to 0.7 µM. In comparison, methylphenidate inhibited DAT and NET at around 0.1 µM, while it inhibited SERT at around 100 µM. The order of amphetamine potencies was NET (KI = 0.07–0.1 µM), DAT (KI ≈ 0.6 µM), and SERT (KI between 20 to 40 µM). The results for methamphetamine were similar to those for amphetamine. In contrast, another amphetamine derivative, MDMA (3–4 methylenedioxymethamphetamine), exhibited higher potency at SERT than at DAT. The human and mouse transporters were similar in their sensitivities to each of the tested drugs (KI values are within 4-fold). Conclusion: The current and previous studies support the following conclusions: 1) cocaine blocks all 3 monoamine transporters at similar concentrations; 2) methylphenidate inhibits DAT and NET well but a 1000-fold higher concentration of the drug is required to inhibit SERT; 3) Amphetamine and methamphetamine are most potent at NET, while being 5- to 9-fold less potent at DAT, and 200- to 500-fold less potent at SERT; 4) MDMA has moderately higher apparent affinity for SERT and NET than for DAT. The relative potencies of a drug to inhibit DAT, NET and SERT suggest which neurotransmitter systems are disrupted the most by each of these stimulants and thus the likely primary mechanism of drug action. Page 1 of 7 (page number not for citation purposes) BMC Pharmacology 2006, 6:6 http://www.biomedcentral.com/1471-2210/6/6 Background The potencies of different psychostimulant drugs at the Drug abuse is a serious problem in the United States and monoamine transporters have been studied and reported around the world that places tremendous social and eco- by different laboratories [9,10,13-15]. However, there are nomical burdens on individuals and on the whole society significant discrepancies among the reported data and the [1]. Psychostimulants are a group of drugs that stimulate differences are up to 60-fold. For instance, the inhibition the activity of the central nervous system and produce a constant (KI) for amphetamine to inhibit DA uptake in rat series of effects in humans, such as increasing heart rate synaptosomes was reported to be 0.034 µM in one study and respiration, improving alertness, elevating mood and [16], while it was reported to be 2.3 µM in cultured cells self-confidence, and producing euphoria [2]. Common expressing rat DAT [9]. The MDMA KI value to inhibit rat psychostimulant drugs include: cocaine, methylphenidate SERT was determined to be 0.24 µM [15] and 2.6 µM [13]. (Ritalin), amphetamine, methamphetamine, and MDMA The KI values for cocaine to inhibit rat DAT in vitro ranged [2]. Some of these psychostimulants are useful medica- from 0.33 µM to 2.0 µM [9,17]. These differences are tions that have long been used for treating various disor- likely due to different experimental procedures employed ders such as attention deficit hyperactivity disorder by each laboratory, the different expression systems or tis- (ADHD), narcolepsy, and obesity, while they are also sue preparation methods used, and different qualities of addictive substances that could cause serious adverse drugs used. effects when abused [2]. Psychostimulant abuse is a major public health problem in the United States. According to Therefore, it is important to compare DAT, NET and SERT the 2003 National Survey on Drug Use and Health [3], in their responses to psychostimulants in the same cellu- cocaine and amphetamine are two of the most abused lar background, using a uniform protocol and drugs. One drugs while methamphetamine abuse has become a grow- of our earlier studies compared the cloned DAT, NET and ing concern and 12.3 million Americans age twelve and SERT transporters stably expressed in LLC-PK1 cells, but older had tried methamphetamine at least once in their the available transporter cDNAs were from different spe- lifetimes. Methylphenidate is commonly prescribed as cies [10]. In another study, human clones of the DAT, NET Ritalin to treat ADHD. As the number of Ritalin prescrip- and SERT transporters were stably expressed in HEK293 tion increases, drug and law enforcement agencies are see- cells and the uptake inhibition by selected drugs including ing an increase in Ritalin drug dealing and the illicit use of some psychostimulants were compared [14]. Several Ritalin as a recreational drug [3]. The abuse of MDMA, other studies examined rat transporters using synapto- also known as Ecstasy, has also spread to a wide range of somes prepared from rat brains [13,15,18,19]. So far, settings and demographic subgroups and more than 10 there is no study focusing on the comparison of psychos- million people have tried MDMA at least once [3]. timulant potencies among the mouse monoamine trans- porters and how they compare to the human transporters. Plasma membrane neurotransmitter transporters termi- With the ever wider use of genetically modified mouse nate neurotransmissions by the reuptake and recycling of models in recent years, experimental data that compare the released neurotransmitters [4,5]. The transporters for drug effects between human and mouse monoamine the monoamines dopamine, norepinephrine, and serot- transporters are becoming increasingly important. onin (DAT, NET, and SERT) belong to a family of Na+/Cl- -dependent neurotransmitter transporters, which are In the present study, we compared the potencies of five intrinsic membrane proteins containing 12 putative trans- psychostimulant drugs in inhibiting human and mouse membrane domains [6,7]. Psychostimulants, such as monoamine transporters in the same background and cocaine, methylphenidate, and amphetamine related using the same procedure. The drugs examined were compounds interrupt the reuptake process by DAT, NET cocaine, methylphenidate, amphetamine, methampheta- and SERT [8-11]. Consequently, neurotransmissions are mine, and MDMA. Our results provide new information prolonged and the extracellular concentrations of these and confirm most of the published data while differ from amine transmitters are elevated, resulting in complex neu- some of the previous results. This study, combined with rochemical changes and profound psychiatric effects [12]. results from other studies, provides very useful informa- In order to understand the effects of these psychostimu- tion about which neurotransmission pathways are likely lant drugs, it is critical to determine which transporter or to be affected the most by each of the drugs, which gives neurotransmitter systems are most affected at low, insight into primary mechanisms of drug actions. medium, or high drug doses. A thorough understanding of the pharmacological profile for each psychostimulant Results and discussion drug would be helpful for the development of treatment Transiently transfected cells are used to determine the KI protocols for stimulant overdose and dependence. values for drugs inhibiting wild type and mutant monoamine transporters in our laboratory and other lab- oratories [20-26]. Fluctuations in transporter expression Page 2 of 7 (page number not for citation purposes) BMC Pharmacology 2006, 6:6 http://www.biomedcentral.com/1471-2210/6/6 1.2 1B 1A Cocaine 1.2 Methylphenidate (Ritalin) 1.0 1.0 0.8 0.8 0.6 0.6 mDAT mDAT hDAT 0.4 hDAT 0.4 mNET mNET hNET hNET Transport Activity 0.2 0.2 mSERT mSERT hSERT hSERT 0.0 0.0 -9 -8 -7 -6 -5 -4 -3 -9 -8 -7 -6 -5 -4 -3 Log[drug], M Log[drug], M 1.2 1C Amphetamine 1.2 1D Methamphetamine 1.0 1.0 0.8 0.8 0.6 0.6 mDAT mDAT hDAT 0.4 hDAT 0.4 mNET mNET hNET hNET Transport Activity 0.2 0.2 mSERT mSERT hSERT hSERT 0.0 0.0 -9 -8 -7 -6 -5 -4 -3 -9 -8 -7 -6 -5 -4 -3 Log[drug], M Log[drug], M 1.2 1E MDMA 1.0 0.8 0.6 mDAT phDAT 0.4 mNET 0.2 phNET mSERT % Transport Activity 0.0 phSERT -9 -8 -7 -6 -5 -4 -3 Log[drug], M DrugFigure inhibition 1 profiles of mouse and human monoamine transporters by psychostimulants Drug inhibition profiles of mouse and human monoamine transporters by psychostimulants.
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