Elsevier

Drug and Alcohol Dependence

Volume 147, 1 February 2015, Pages 1-19
Drug and Alcohol Dependence

Review
Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter

https://doi.org/10.1016/j.drugalcdep.2014.12.005Get rights and content

Highlights

  • Effects of atypical dopamine transporter (DAT) ligands are described.

  • Atypical DAT inhibitors include benztropine, GBR 12909, or modafinil.

  • Atypical DAT substrates include those derived from phenethylamine or cathinone.

  • Atypicality can point to targets for the development of stimulant misuse treatment.

Abstract

Background

Treatment of stimulant-use disorders remains a formidable challenge, and the dopamine transporter (DAT) remains a potential target for antagonist or agonist-like substitution therapies.

Methods

This review focuses on DAT ligands, such as benztropine, GBR 12909, modafinil, and DAT substrates derived from phenethylamine or cathinone that have atypical DAT-inhibitor effects, either in vitro or in vivo. The compounds are described from a molecular mechanistic, behavioral, and medicinal–chemical perspective.

Results

Possible mechanisms for atypicality at the molecular level can be deduced from the conformational cycle for substrate translocation. For each conformation, a crystal structure of a bacterial homolog is available, with a possible role of cholesterol, which is also present in the crystal of Drosophila DAT. Although there is a direct relationship between behavioral potencies of most DAT inhibitors and their DAT affinities, a number of compounds bind to the DAT and inhibit dopamine uptake but do not share cocaine-like effects. Such atypical behavior, depending on the compound, may be related to slow DAT association, combined sigma-receptor actions, or bias for cytosol-facing DAT. Some structures are sterically small enough to serve as DAT substrates but large enough to also inhibit transport. Such compounds may display partial DA releasing effects, and may be combined with release or uptake inhibition at other monoamine transporters.

Conclusions

Mechanisms of atypical DAT inhibitors may serve as targets for the development of treatments for stimulant abuse. These mechanisms are novel and their further exploration may produce compounds with unique therapeutic potential as treatments for stimulant abuse.

Introduction

Stimulant-use disorder is defined in the Diagnostic and Statistical Manual of Psychiatric Disorders, 5th edition (DSM-5) as a pattern of use of amphetamine-like compounds, cocaine, or other stimulants resulting in clinically significant impairment or distress as manifested by at least two out of eleven listed problems within a 12-month period (American Psychiatric Association, 2013). Prevalence at a national level is most frequently estimated from the National Survey on Drug Use and Health (NSDUH), an annual household-based survey among individuals at least 12 years of age in the US population (see Gerlach et al., 2014). Past-year non-medical use of prescription stimulants in 2012 was between 2 and 4% in different age categories between 16 and 34 years of age; comparable numbers were for illicit stimulants 1–4% and cocaine (including crack) 1–5% (NSDUH data available from Substance Abuse and Mental Health Services Administration (SAMSHA) website). In comparison, the “Monitoring the Future” survey (Johnston et al., 2014) in selected schools indicates for 12th grade students in 2012 a past-year non-medical use of 7.9% of amphetamines (including methamphetamine) and 2.9% of cocaine. The amount of non-medical use that leads to stimulant-use disorders is unknown. In this context, it can be noted that stimulants accounted for 3.3% of all drug-related emergency department visits for non-medical drug use in 2011 (Gerlach et al., 2014). Trends in Admissions by Primary Substance of Abuse (TEDS) to drug abuse treatment facilities show that 6% of all admissions in 2011 were for primary involvement of methamphetamine/amphetamines and 8% for cocaine (including crack). In this respect, stimulants and cocaine (14%) are similar to marijuana/hashish (18%), following on the heels of opiates (25%) and alcohol (39%; TEDS data available from SAMSHA website). Statistics for 2011 on Poison Centers showed the involvement of stimulants and street drugs (excluding analgesics) in 3% of all exposures (Gerlach et al., 2014).

Treatment of stimulant-use disorders remains a formidable challenge. In the absence of effective pharmacotherapy, behavioral therapies comprise the mainstay of treatment. Pharmacotherapeutic potential has been tested for numerous compounds. Among non-stimulant treatment agents tried, the following have moderate potential and warrant future studies: naltrexone, disulfiram for individuals with a certain genotype, doxazosin, and vaccines (for recent review see Phillips et al., 2014). Given that psychostimulants target the dopamine transporter (DAT), the DAT became an early preclinical focus for discovery of treatment compounds. A seminal study by Kitayama et al. (1992) identified DAT residues differentially important for cocaine binding and DA uptake, opening up the possibility to block the effect of cocaine with a compound that overlaps the binding domain of cocaine but not that of dopamine (Dopamine Sparing Cocaine Antagonist, see Carroll et al. (2002) and Rothman et al. (1993)). Until recently, such an antagonist has been elusive (see Section 4).

Separate from the idea of a potential cocaine antagonist is the interest in DAT as a target for agonist-like substitution therapy (Grabowski et al., 2001, Negus and Mello, 2003, Grabowski et al., 2004, Negus et al., 2007, Mello and Negus, 2007); see also recent review by Howell and Negus (2014). There is promising pre-clinical and clinical evidence for efficacy of the DAT substrates d-amphetamine, d-phenmetrazine and sustained-release d-methamphetamine (Negus et al., 2009, Banks et al., 2013a, Banks et al., 2013c, Phillips et al., 2014), making a strong case for further work on this group of medications. Prodrug formulations of d-amphetamine (lisdexamfetamine) and phenmetrazine (phendimetrazine), for which abuse has not been reported, are especially promising. Oral cocaine in coca tea does not lead to misuse and has been argued to show promise as agonist substitution therapy (Llosa and Llosa, 2005). Furthermore, modafinil has potential efficacy in treating patients with cocaine use disorders. Modafinil blunted cocaine-induced euphoria in controlled human laboratory studies (Dackis et al., 2003, Malcolm et al., 2006, Hart et al., 2008). An early clinical trial pointed to an appreciable positive effect of modafinil on drug use outcome (Dackis et al., 2005), but other trials gave mixed results (Anderson et al., 2009, Dackis et al., 2012). As pointed out in a Commentary by O’Brien (2012), patients addicted to cocaine with additional alcohol dependence do not reduce their cocaine use with modafinil (see also Anderson et al., 2009). Modafinil appears most useful for the treatment of moderate cocaine use disorder in combination with behavioral therapy. (The material on modafinil was covered by the presentation by Charles O’Brien in the Behavior, Biology, and Chemistry: Translational Research in Addiction 2014 symposium. Due to other commitments, Dr. O’Brien could not participate in this review.) Modafinil shares properties with other compounds now recognized as “atypical” DAT inhibitors, and along with recently developed atypical DA releasers it renews interest in the DAT as a pharmacotherapeutic target for treatment of stimulant-use disorders.

Atypical DAT ligands are those that have effects that deviate from those expected, either in vitro or in vivo (Tanda et al., 2009, Schmitt et al., 2013). Typical DAT blockers, at high enough concentrations or doses are expected to (i) to fully inhibit DA uptake, and (ii) to fully inhibit binding of another blocker, as well as release of substrate by reversed transport. Typical DAT releasers are expected to fully release another substrate accumulated in cell or synaptosomes. Behaviorally, typical DAT blockers or releasers are expected to (i) stimulate locomotor behavior, and (ii) reinforce behavior, and as a result be subject to abuse. Examples of typical DAT blockers or releasers are cocaine or amphetamine, respectively. Examples of atypical DAT inhibitors are benztropine (BZT) and GBR 12909 (for more details see reviews by Tanda et al. (2009) and Schmitt et al. (2013)). Examples of atypical DAT releasers are 3,4-methylenedioxyethylamphetamine (MDEA) and PAL-1045 (Rothman et al., 2005, Rothman et al., 2012).

Section snippets

Conformational cycle for dopamine uptake

In order to understand possible mechanisms for atypicality at the molecular level, it is important to examine the conformational cycle for substrate translocation. Fig. 1A shows different conformational stages of the DAT during a DA uptake cycle, depicted for a homology model of hDAT based on the bacterial leucine transporter (LeuT), a prokaryotic member of the neurotransmitter/sodium symporter (NSS) protein family (Yamashita et al., 2005, Zhou et al., 2007, Singh et al., 2007, Singh et al.,

Dopamine transporter hypothesis and atypicality

The dopamine transporter (DAT) hypothesis originated with a highly influential paper published in Science (Ritz et al., 1987). That paper hypothesized that DAT inhibitors will have cocaine-like effects differing primarily in potency. Radioligand binding techniques were used to establish the affinity of a number of drugs for the DAT and compared those relative affinities to potencies of the drugs in self-administration procedures. There was a direct relationship between these behavioral

Atypical releasers

The classical DA releasing agents amphetamine and methamphetamine are two of the few medications to show promise in controlled clinical trials as treatments for stimulant addiction (Grabowski et al., 2004, Mooney et al., 2009, Karila and Reynaud, 2009). They also decrease cocaine self-administration behavior in non-human primate models of addiction (Wojnicki et al., 1999, Negus and Mello, 2003, Negus et al., 2007, Negus et al., 2009). These studies provide support for using classical DA

Concluding remarks

Over the past three decades substantial advances have been made in the understanding of the neurobiological mechanisms of the behavioral and reinforcing effects of cocaine. Though more needs to be accomplished before an avenue to a medical treatment against cocaine abuse becomes clear, many new pharmacological agents targeting the DAT have been discovered, and some of these have effects very different from those producing the abuse liability of cocaine. These atypical compounds have shed some

Role of funding source

The research was supported by National Institutes of Health grants R01 DA019676 (MEAR), MH083840 (MEAR), DA12970 (BEB), as well as travel support from the Behavior, Biology, and Chemistry: Translational Research in Addiction 2014 symposium. Funding for the BBC conference was made possible, in part, by R13DA029347 from the National Institute on Drug Abuse. The research of JLK, WCH, MHB, JSP, and RBH is supported by the NIDA Intramural Research Programs. The content is solely the responsibility

Contributors

MEAR, BEB, and JLK wrote the first draft based on collective conceptual input of all authors at the symposium. All authors edited, substantially revised, are responsible for, and approved the content of the submitted review.

Conflict of interest

The NIH is the owner, and J.L.K. is one of several inventors, on patents covering some of the compounds described in this paper. Temple University and New York University are owners, and M.E.A.R. is one of the two inventors, on patents regarding C-1 cocaine analogs.

Acknowledgements

We thank Dr. Amy Newman for supplies of R- and S-modafinil used to produce results shown in Fig. 5.

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    This paper was presented by M.E.A.R., B.E.B., J.L.K. and C.O’B. in a symposium at the Behavior, Biology, and Chemistry: Translational Research in Addiction meeting on March 15, 2014 in San Antonio, TX entitled “Non-classical pharmacology of the dopamine transporter and addiction.”.

    1

    These authors contributed equally to this work.

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