Genetic Deletion of Trace Amine 1 Receptors Reveals Their Role in Auto-Inhibiting the Actions of Ecstasy (MDMA)

Cara, Benjamin Di; Maggio, Roberto; Aloisi, Gabriella; Rivet, Jean‐Michel; Lundius, Ebba Gregorsson; Yoshitake, Takashi; Svenningsson, Per; Brocco, Mauricette; Gobert, Alain P.; Groote, Lotte De; Cistarelli, Laetitia; Veiga, Sylvie; Montrion, Catherine de; Rodriguez, Marianne; Galizzi, Jean‐Pierre; Lockhart, Brian P.; Cogé, Francis; Boutin, Jean A.; Vayer, Philippe; Verdouw, P. Monika; Groenink, Lucianne; Millan, Mark J.

doi:10.1523/jneurosci.2502-11.2011

Cited by 85 publications

(97 citation statements)

References 75 publications

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“…Instead, heightened sensitivity to MA-induced hypothermia was associated with low MA intake and greater sensitivity to MA-induced aversion. MA is an agonist at TAAR1 (Bunzow et al, 2001;Reese et al, 2014;Wolinsky et al, 2007) and the outcome of hypothermia is in agreement with other reports of TAAR1 agonist-induced hypothermia in rodents (Di Cara et al, 2011;Fantegrossi et al, 2013;Panas et al, 2010;Sabol et al, 2013). Thus, it appears that TAAR1 mediates MA-induced hypothermia and that the immediate hypothermic effect of MA may have a role in curbing MA intake in MALDR, Taar1 +/+ and Taar1 +/ − mice.…”

Section: Taar1 and Methamphetamine Intakesupporting

confidence: 91%

“…Acute and chronic MA can induce hyperthermia (Bowyer et al, 1994;Sabol et al, 2013), but hypothermia may occur at lower doses and 18-20°C ambient temperatures (Sabol et al, 2013). MA-induced hypothermia may be partly regulated by TAAR1, since other TAAR1 agonists induce hypothermia (Di Cara et al, 2011;Fantegrossi et al, 2013;Panas et al, 2010), and Taar1 − / − mice do not exhibit hypothermia to doses of the MA-like drug, MDMA, that induce hypothermia in +/+ mice (Di Cara et al, 2011). Likewise, Taar1 − / − mice do not display hypothermia to MA, but the dose of MA used in this published study did not induce hypothermia in +/+ mice (Panas et al, 2010), so further study is needed.…”

Section: Introductionmentioning

confidence: 99%

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Trace Amine-Associated Receptor 1 Regulation of Methamphetamine Intake and Related Traits

Harkness

Shi

Janowsky

et al. 2015

Neuropsychopharmacol

149

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Continued methamphetamine (MA) use is dependent on a positive MA experience and is likely attenuated by sensitivity to the aversive effects of MA. Bidirectional selective breeding of mice for high (MAHDR) or low (MALDR) voluntary consumption of MA demonstrates a genetic influence on MA intake. Quantitative trait locus (QTL) mapping identified a QTL on mouse chromosome 10 that accounts for greater than 50% of the genetically-determined differences in MA intake in the MAHDR and MALDR lines. The trace amine-associated receptor 1 gene (Taar1) is within the confidence interval of the QTL and encodes a receptor (TAAR1) that modulates monoamine neurotransmission and at which MA serves as an agonist. We demonstrate the existence of a non-functional allele of Taar1 in the DBA/2J mouse strain, one of the founder strains of the selected lines, and show that this non-functional allele co-segregates with high MA drinking and with reduced sensitivity to MA-induced conditioned taste aversion (CTA) and hypothermia. The functional Taar1 allele, derived from the other founder strain, C57BL/6J, segregates with low MA drinking and heightened sensitivity to MA-induced CTA and hypothermia. A role for TAAR1 in these phenotypes is corroborated in Taar1 transgenic mice: Taar1 knockout mice consume more MA and exhibit insensitivity to MA-induced CTA and hypothermia, compared with Taar1 wild-type mice. These are the first data to show that voluntary MA consumption is, in part, regulated by TAAR1 function. Behavioral and physiological studies indicate that TAAR1 function increases sensitivity to aversive effects of MA, and may thereby protect against MA use.

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Section: Taar1 and Methamphetamine Intakesupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Trace Amine-Associated Receptor 1 Regulation of Methamphetamine Intake and Related Traits

Harkness

Shi

Janowsky

et al. 2015

Neuropsychopharmacol

149

View full text Add to dashboard Cite

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“…Higher serotonergic vs. dopaminergic activity has been associated with a lower abuse potential of a drug [4,[23][24][25]. Amphetamines such as MDMA and methamphetamine have been shown to inhibit their own neurochemical and locomotor stimulant effects via TAAR 1 activation [76]. The lack of serotonergic activity and lack of TAAR 1 -mediated "auto-inhibition" in particular with the pipradrol derivatives may contribute to the more stimulant-like and addictive properties of this class of designer compounds compared with classic amphetamines, including MDMA [4].…”

Section: Taar 1 Bindingmentioning

confidence: 99%

Pharmacological profiles of aminoindanes, piperazines, and pipradrol derivatives

Simmler

Rickli

Schramm

et al. 2014

Biochemical Pharmacology

108

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Aminoindanes, piperazines, and pipradrol derivatives are novel psychoactive substances found in "Ecstasy" tablets as replacements for 3,4-methylenedioxymethamphetamine (MDMA) or substances sold as "ivory wave." The pharmacology of these MDMA-and methylphenidate-like substances is poorly known. We characterized the pharmacology of the aminoindanes 5,6-methylenedioxy-2-aminoindane (MDAI), 5-iodoaminoindane (5-IAI), and 2-aminoindane (2-AI), the piperazines meta-chlorophenylpiperazine (m-CPP), trifluoromethylphenylpiperazine (TFMPP), and 1-benzylpiperazine (BZP), and the BZP, D2PM, and 2-DPMP lacked serotonergic activity and TAAR 1 binding, in contrast to the aminoindanes and phenylpiperazines. In summary, all of the substances were monoamine transporter inhibitors, but marked differences were found in their 3 DAT vs. SERT inhibition profiles, release properties, and receptor interactions. The pharmacological profiles of D2PM and 2-DPMP likely predict a high abuse liability.

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“…We also found that amphetamines not only bind to rodent receptors but also human TAAR 1 . In rodents, non--keto amphetamines inhibit their own stimulant effects via TAAR 1 activation (Di Cara et al, 2011). The lack of this TAAR 1 -mediated "auto-inhibition"…”

mentioning

confidence: 99%

Monoamine transporter and receptor interaction profiles of novel psychoactive substances: Para-halogenated amphetamines and pyrovalerone cathinones

Rickli

Hoener

Liechti

2015

European Neuropsychopharmacology

169

188

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The pharmacology of novel psychoactive substances is mostly unknown. We evaluated the transporter and receptor interaction profiles of a series of para-(4)-substituted amphetamines and pyrovalerone cathinones. We tested the potency of these compounds to inhibit the norepinephrine (NE), dopamine (DA), and serotonin (5-HT) transporters (NET, DAT, and SERT, respectively) using human embryonic kidney 293 cells that express the respective human transporters. We also tested the substance-induced efflux of NE, DA, and 5-HT from monoamine-loaded cells, binding affinities to monoamine receptors, and 5-HT 2B receptor activation.Para- (4)

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Genetic Deletion of Trace Amine 1 Receptors Reveals Their Role in Auto-Inhibiting the Actions of Ecstasy (MDMA)

Cited by 85 publications

References 75 publications

Trace Amine-Associated Receptor 1 Regulation of Methamphetamine Intake and Related Traits

Trace Amine-Associated Receptor 1 Regulation of Methamphetamine Intake and Related Traits

Pharmacological profiles of aminoindanes, piperazines, and pipradrol derivatives

Monoamine transporter and receptor interaction profiles of novel psychoactive substances: Para-halogenated amphetamines and pyrovalerone cathinones

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