Modafinil Occupies Dopamine and Norepinephrine Transporters in Vivo and Modulates the Transporters and Trace Amine Activity in Vitro

Madras, Bertha K.; Xie, Zhihua; Lin, Zhicheng; Jassen, Amy J.; Panas, Helen N.; Lynch, Laurie J.; Johnson, Ryan; Livni, Eli; Spencer, Thomas; Bonab, Ali; Miller, Gregory M.; Fischman, Alan J.

doi:10.1124/jpet.106.106583

Cited by 303 publications

(274 citation statements)

References 54 publications

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“…Although the receptor pharmacology of modafinil is not fully understood, it appears to occupy both dopamine and norepinephrine transporters at therapeutic doses (Madras et al, 2006). In this study, modafinil pretreatment significantly reduced the subjective response to cocaine in the absence of producing unpleasant side effects and significantly reduced cocaine self-administration in a dose-dependent fashion (Hart et al, 2008).…”

Section: Medications Development For Cocaine Dependencementioning

confidence: 56%

The role of human drug self-administration procedures in the development of medications

Comer

Ashworth²,

Foltin

et al. 2008

Drug and Alcohol Dependence

136

148

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The purpose of this review is to illustrate the utility and value of employing human self-administration procedures in medication development, including abuse liability assessments of novel medications and evaluation of potential pharmacotherapies for substance use disorders. Traditionally, human abuse liability testing has relied primarily on subjective reports describing drug action by use of questionnaires; similarly, drug interactions between putative treatment agents and the drugs of abuse have relied on these measures. Subjective reports are highly valued because they provide qualitative and quantitative information about the characteristics of central and peripheral pharmacodynamic effects as well as safety and tolerability. However, self-administration procedures directly examine the behavior of interest -that is, drug taking. The present paper 1) reviews the most commonly used human self-administration procedures, 2) discusses the concordance of subjective reports and selfadministration within the context of medications development for substance use disorders, focusing primarily on illustrative examples from development efforts with opioid and cocaine dependence, and 3) explores the utility of applying self-administration procedures to assess the abuse liability of novel compounds, including "abuse deterrent" formulations (ADFs). The review will focus on opioid and cocaine dependence because a rich database from both clinical laboratory and clinical trial research exists for these two drug classes. The data reviewed suggest that drug-induced changes in self-administration and subjective effects are not always concordant. Therefore, assessment of selfadministration in combination with subjective effects provides a more comprehensive picture that may have improved predictive validity for translating to the clinical setting.

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Section: Medications Development For Cocaine Dependencementioning

confidence: 56%

The role of human drug self-administration procedures in the development of medications

Comer

Ashworth²,

Foltin

et al. 2008

Drug and Alcohol Dependence

136

148

View full text Add to dashboard Cite

show abstract

“…One recent set of studies reported that the wake-promoting drug, modafinil, which is approved as a treatment for narcolepsy, was able to reduce cocaine intake in a dependent cohort . Intriguingly, modafinil inhibits both DAT and NET, and both its locomotor and wake-promoting effects are attenuated by a1AR blockade in rodents and nonhuman primates (Duteil et al, 1990;Hermant et al, 1991;Stone et al, 2002;Madras et al, 2006). Perhaps its efficacy in treating cocaine dependence is also tied to a1AR signaling, although influences on glutamatergic transmission are another possibility (Ferraro et al, 1999;Dackis and O'Brien, 2003).…”

Section: Other Noradrenergic Compounds Affecting Drug Abusementioning

confidence: 99%

There and Back Again: A Tale of Norepinephrine and Drug Addiction

Weinshenker

Schroeder

2006

Neuropsychopharmacol

319

277

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Fueled by anatomical, electrophysiological, and pharmacological analyses of endogenous brain reward systems, norepinephrine (NE) was identified as a key mediator of both natural and drug-induced reward in the late 1960s and early 1970s. However, reward experiments from the mid-1970s that could distinguish between the noradrenergic and dopaminergic systems resulted in the prevailing view that dopamine (DA) was the primary 'reward transmitter' (a belief holding some sway still today), thereby pushing NE into the background. Most damaging to the NE hypothesis of reward were studies demonstrating that NE receptor antagonists and NE reuptake inhibitors failed to impact drug self-administration. In recent years new tools, such as genetically engineered mice, and new experimental paradigms, such as reinstatement of drug seeking following withdrawal, have propelled NE back into the awareness of addiction researchers. Of particular interest is disulfiram, an inhibitor of the NE biosynthetic enzyme dopamine b-hydroxylase, which has demonstrated promising efficacy in the treatment of cocaine dependence in preliminary clinical trials. The purpose of this review is to synthesize the new data linking NE to critical aspects of DA signaling and drug addiction, with a focus on psychostimulants (eg, cocaine), opiates (eg, morphine), and alcohol.

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“…Miller, Madras and their colleagues Madras et al, 2006). Based on the ventral midbrain localization of rodent TAAR1 transcripts reported by Borowsky et al, (2001) and Bunzow et al (2001) plus the ability of DA, AMPH, and METH to functionally stimulate the receptor it was of obvious interest to explore possible interactions between TAAR1 and the DAT.…”

Section: Physiology Of the Vertebrate Trace Amine-associated Receptorsmentioning

confidence: 99%

Trace amine-associated receptor 1—Family archetype or iconoclast?

Grandy

2007

Pharmacology & Therapeutics

176

211

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Interest has recently been rekindled in receptors that are activated by low molecular weight, noncatecholic, biogenic amines that are typically found as trace constituents of various vertebrate and invertebrate tissues and fluids. The timing of this resurgent focus on receptors activated by the 'trace amines' (TAs) β-phenylethylamine (PEA), tyramine (TYR), octopamine (OCT), synephrine (SYN), and tryptamine (TRYP) is the direct result of two publications that appeared in 2001 describing the cloning of a novel G protein-coupled receptor (GPCR) referred to by their discoverers as TA1 (Borowsky et al., 2001) and TAR1 (Bunzow et al., 2001). When heterologously expressed in Xenopus laevis oocytes and various eukaryotic cell lines recombinant rodent and human TA receptors dosedependently couple to the stimulation of cAMP production. Structure-activity profiling based on this functional response has revealed that in addition to the TAs, other biologically active compounds containing a 2 carbon aliphatic side chain linking an amino group to at least one benzene ring are potent and efficacious TA receptor agonists with amphetamine, methamphetamine, 3-iodothyronamine, thyronamine, and dopamine among the most notable. Almost 100 years after the search for TA receptors began numerous TA1/TAR1-related sequences, now called Trace AmineAssociated Receptors (TAARs), have been identified in the genome of every species of vertebrate examined to date. Consequently, even though heterologously expressed TAAR1 fits the pharmacological criteria established for a bona fide TA receptor a major challenge for those working in the field is to discern the in vivo pharmacology and physiology of each purported member of this extended family of GPCRs. Only then will it be possible to establish whether TAAR1 is the family archetype or an iconoclast.

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Modafinil Occupies Dopamine and Norepinephrine Transporters in Vivo and Modulates the Transporters and Trace Amine Activity in Vitro

Cited by 303 publications

References 54 publications

The role of human drug self-administration procedures in the development of medications

The role of human drug self-administration procedures in the development of medications

There and Back Again: A Tale of Norepinephrine and Drug Addiction

Trace amine-associated receptor 1—Family archetype or iconoclast?

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