alexa Preclinical Efficacy of Novel Vesicular Monoamine Transporter 2 Inhibitors as Antagonists of d-Methamphetamine Self-Administration in Rats | Open Access Journals
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Journal of Alcoholism & Drug Dependence
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Preclinical Efficacy of Novel Vesicular Monoamine Transporter 2 Inhibitors as Antagonists of d-Methamphetamine Self-Administration in Rats

Takato Hiranita*

Division of Neurotoxicology, National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), 3900 NCTR Road, Jefferson, AR 72079-9501, USA

Corresponding Author:
Takato Hiranita
Division of Neurotoxicology,
National Center for Toxicological Research (NCTR),
U.S. Food and Drug Administration (FDA),
3900 NCTR Road, Jefferson, AR 72079-9501, USA
Tel: +61-3-9214-5596, +61-3-5327-6335
E-mail: [email protected]

Received date: October 08, 2015 Accepted date: October 19, 2015 Published date: October 27, 2015

Citation: Hiranita T (2015) Preclinical Efficacy of Novel Vesicular Monoamine Transporter 2 Inhibitors as Antagonists of d-Methamphetamine Self-Administration in Rats. J Alcohol Drug Depend 3:e127. doi:10.4172/2329-6488.1000e127

Copyright: © 2015 Hiranita T. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

A series of studies by Drs. Linda Dwoskin and Michael Bardo demonstrated the preclinical efficacy of novel vesicular monoamine transporter 2 (VMAT2) inhibitors as antagonists of d-methamphetamine self-administration in rats.

Editorial

A series of studies by Drs. Linda Dwoskin and Michael Bardo demonstrated the preclinical efficacy of novel vesicular monoaminetransporter 2 (VMAT2) inhibitors as antagonists of d-methamphetamineself-administration in rats [1-6]. This is an important finding since there is a lack of FDA-approved medications to treat amphetamine-type stimulant abuse. There are also few if any candidate compounds that show preclinical efficacy as amphetamine antagonists (e.g. [7]).

Reinforcing effects of stimulants result from their common capacity to increase extracellular dopamine(DA) levels in terminal regions of mesolimbic dopaminergic neurons [8]. Amphetamines are substrates for the dopamine transporter (DAT), while cocaine inhibits DA uptake and functions as a DAT inhibitor [8]. Thus stimulants function as indirect DA agonists. In addition to the DAT, uptake of amphetamines into cytoplasm via DAT results in DA release into synaptic clefts through actions at the cytoplasmic vesicular monoamine transporter 2 (VMAT2) in the brain [8]. Thus VMAT2 is a potential target of action for amphetamines. Consistent with this hypothesis, Drs. Dwoskin and Bardo demonstrated that novel VMAT2 inhibitors can decrease d-methamphetamine self-administration in rats [1-6]. Importantly, the d-methamphetamine-antagonist effects of VMAT2 inhibitors were specific for the reinforcing effects of d-methamphetamine. For example, a VMAT2 inhibitor N-(1,2R-dihydroxylpropyl)-2,6- cis-di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A) was more potent in decreasing self-administration responding for d-methamphetamine than in decreasing that of cocaine [5] or foodreinforced responding [5,6]. The pharmacological specificity relative to food-reinforced responding was demonstrated with other novel VMAT2 inhibitors lobelane [4], meso-transdiene [3], and cis-2,5- di-(2-phenethyl)-pyrrolidine hydrochloride (UKCP-110) [1]. In addition, another group previously demonstrated a lack of effect for the prototype VMAT2 inhibitor reserpine on cocaine self-administration using rhesus monkeys [9]. In contrast, the prototype VMAT2 inhibitor (±)-tetrabenazine failed to exhibit pharmacological specificity. (±)-Tetrabenazine was equipotent in decreasing self-administration responding for d-methamphetamine and food reinforced responding [2].

The novel VMAT2 inhibitors possess a clinically preferential profile since the duration of action as d-methamphetamine antagonists in vivo lasted at least 60 minutes [1-6], which is approximately 12-fold longer than the elimination half-life of the prototype VMAT2 inhibitor(±)-tetrabenazine [10]. However, the novel VMAT2 inhibitors need improvement to be useful clinically since they possess relatively low affinity for VMAT2 (Ki values >2,000 nM, see Table 1). VMAT2 is a cytoplasmic protein and VMAT2 inhibitors need to penetrate plasma membranes in vivo.

Compound VMAT2 ([3H]dihydrotetrazenazine binding)
(±)-Tetrabenazine 13 (± 1) [11]
GZ-793A 8,290 (± 2,790) [12]
Lobelane 2,040 (± 640) [13]
970 (± 190) [1]
Meso-Transdiene 9,880 (± 2,220) [14]
UKCP-110 2,660 (± 366) [1]
d-Methamphetamine 80,100 (± 19,500) [13]
No inhibition at 100 µM [15]
d-Amphetamine No inhibition at 100 µM [15]
Cocaine No inhibition at 100 µM [16]

Table 1: Inhibition by various compounds of specific binding to the VMAT2 (Ki Value, nM).

Despite the fact that the novel VMAT2 inhibitors exhibited low affinities for VMAT2, the series of studies by Drs. Dwoskin and Bardo demonstrated the preclinical efficacy of a novel class of antagonists for d-methamphetamine self-administration. Although it is still relatively unknown how amphetamines increase DA levels in synaptic clefts, these findings suggest that development of VMAT2 inhibitors as a specific amphetamine antagonists in vivo is possible.

Acknowledgements

The present work was supported by the Division of Neurotoxicology/NCTR/ U.S. FDA. The information in the present article is not a formal dissemination of information by the FDA and does not represent agency position or policy.

References

  1. Beckmann JS (2010) The novelpyrrolidine nor-lobelane analog UKCP-110 [cis-,5-di-(2-phenethyl)-pyrrolidinehydrochloride] inhibits VMAT2 function, methamphetamine-evoked dopaminerelease, and methamphetamine self-administration in rats. J Pharmacol ExpTher 335: 841-851.
  2. Meyer AC(2011) Tetrabenazineinhibition of monoamine uptake and methamphetamine behavioral effects: Locomotoractivity, drug discrimination and self-administration. Neuropharmacology61: 849-856.
  3. Horton DB, Siripurapu KB, Norrholm SD, Culver JP, Hojahmat M, et al.(2011) Meso-Transdiene analogs inhibit vesicular monoamine transporter-2function and methamphetamine-evoked dopamine release. J Pharmacol Exp Ther336: 940-951.
  4. Neugebauer NM, Harrod SB, Stairs DJ, Crooks PA, Dwoskin LP, et al.(2007) Lobelane decreases methamphetamine self-administration in rats. EurJ Pharmacol 571: 33-38.
  5. Beckmann JS, Denehy ED, Zheng G, Crooks PA, Dwoskin LP, et al.(2012) The effect of a novel VMAT2 inhibitor, GZ-793A, on methamphetaminereward in rats. Psychopharmacology (Berl) 220: 395-403.
  6. Wilmouth CE, Zheng G, Crooks PA, Dwoskin LP, Bardo MT (2013) Oraladministration of GZ-793A, a VMAT2 inhibitor, decreases methamphetamineself-administration in rats. Pharmacol Biochem Behav 112: 29-33.
  7. Hiranita T, Kohut SJ, Soto PL, Tanda G, Kopajtic TA, et al. (2014)Preclinical efficacy of N-substituted benztropine analogs as antagonistsof methamphetamine self-administration in rats. J Pharmacol Exp Ther 348:174-191.
  8. Fasano A, Bentivoglio AR (2009) Tetrabenazine. Expert OpinPharmacother 10: 2883-2896.
  9. WilsonMC, Schuster CR (1974) Aminergic influences on intravenous cocaineself-administration by Rhesus monkeys. Pharmacol Biochem Behav 2: 563-571.
  10. DaSilvaJN, Kilbourn MR (1992) In vivo binding of [11C]tetrabenazine to vesicularmonoamine transporters in mouse brain. Life Sci 51: 593-600.
  11. Nickell JR, Siripurapu KB, Vartak A, Crooks PA, Dwoskin LP (2014)The vesicular monoamine transporter-2: An important pharmacological targetfor the discovery of novel therapeutics to treat methamphetamine abuse.Adv Pharmacol 69: 71-106.
  12. Horton DB, Siripurapu KB, Zheng G, Crooks PA, Dwoskin LP (2011)Novel N-, 2-dihydroxypropyl analogs of lobelane inhibit vesicularmonoamine transporter-2 function and methamphetamine-evoked dopaminerelease. J Pharmacol Exp Ther 339: 286-297.
  13. Nickell JR, Krishnamurthy S, Norrholm S, Deaciuc G, Siripurapu KB,et al. (2010) Lobelane inhibits methamphetamine-evoked dopamine releasevia inhibition of the vesicular monoamine transporter-2. J Pharmacol ExpTher 332: 612-621.
  14. Zheng G, Dwoskin LP, Deaciuc AG, Norrholm SD, Crooks PA (2005)Defunctionalized lobeline analogues: structure-activity of novel ligandsfor the vesicular monoamine transporter. J Med Chem 48: 5551-5560.
  15. Schwartz K, Weizman A, Rehavi M (2006) The effect ofpsychostimulants on [3H] dopamine uptake and release in rat brain synapticvesicles. J Neural Transm (Vienna) 113: 1347-1352.
  16. Partilla JS, Dempsey AG, Nagpal AS, Blough BE, Baumann MH, et al.(2006) Interaction of amphetamines and related compounds at the vesicularmonoamine transporter. J Pharmacol Exp Ther 319: 237-246.
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