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

Abstract

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.

In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1

“…Consequently, the psychoactive TAAR1 ligands likely exert autoregulatory effects on their TAAR1-independent effects, such as reducing drug-induced DA release in the striatum (Di Cara et al, 2011). Given that studies in rodents have reported autoregulatory effects of the psychostimulant TAAR1 ligands amphetamine, methamphetamine, and MDMA (Lindemann et al, 2008;Di Cara et al, 2011;Achat-Mendes et al, 2012;Harkness et al, 2015), these species differences at TAAR1 could be relevant to the translational validity of preclinical studies. Particularly for novel psychoactive substances with large TAAR1 species differences, the abuse liability that is evaluated in rodent models may actually underestimate the risk for addiction that is posed by the drugs in humans.…”

“…Methamphetamine and amphetamine increase locomotor activity to a greater extent in TAAR1 KO mice compared with WT mice (Achat-Mendes et al, 2012). TAAR1 also plays a role in contingent oral methamphetamine intake (Harkness et al, 2015). Similar to amphetamine and methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA) significantly increased extracellular striatal DA and 5-HT levels to a greater extent in TAAR1 KO mice compared with WT mice (Di Cara et al, 2011).…”

Trace Amines and Their Receptors

“…In animals with decreased TAAR1 levels either due to KO (Di Cara et al, 2011;Achat-Mendes et al, 2012;Sukhanov et al, 2016) or an endogenous defunctionalizing mutation (Harkness et al, 2015;Reed et al, 2018), increases in acquisition and retention of conditioned place preference (CPP) (Achat-Mendes et al, 2012), hyperlocomotion (Achat-Mendes et al, 2012;Sukhanov et al, 2016), reinstatement (Sukhanov et al, 2016), self-administration (Harkness et al, 596 Reed et al, 2018), and toxicity (Miner et al, 2017), along with decreased autoinhibitory effects (Di Cara et al, 2011), were seen in response to either amphetamine, methamphetamine, or 3,4-methylenedioxymethamphetamine (MDMA). Such effects suggested that TAAR1 agonists may be beneficial in reducing the abuse potential of amphetamines and TAAR1 agonists have now been confirmed to decrease the behavioral sensitization, self-administration, reinstatement, drug-seeking behavior, and withdrawalinduced impulsivity observed in response to methamphetamine administration (Jing et al, 2014;Cotter et al, 2015;Pei et al, 2017;Xue et al, 2018).…”

Reproducibility and replicability of rodent phenotyping in preclinical studies

“…Even highly curated lines such as the DBA/2J inbred mouse strain maintained at the Jackson Laboratory might develop spontaneous mutations that are carried forward in standard commercially-available stocks. Such a previously unknown polymorphism was recently shown to affect both methamphetamine consumption and Trace Amine-Associated Receptor 1 function (Harkness et al, 2015; Shi et al, 2016). Non-replicable results sometimes reflect the naivete of our expectations, despite our best efforts to imagine what the “environment” is for a mouse, given their many sensory, social and biological differences from humans.…”

“…Performance differences in cognitive tests between mouse strains and/or mutants might emerge due to the differential impact of specific and unspecific stressors, emotional (anxiety) differences and other involved motivational aspects (Youn et al, 2012), particularly in complex tasks involving higher cortical functions, thereby following the arousal-performance relation of the Yerkes-Dodson law (reviewed by Diamond et al, 2007) that has been known for more than 100 years. In contrast, other behavioral measures such as locomotor activity are highly correlated over successive days in the DualCage, indicating high stability and therefore probably better replicability as well (Hager et al, 2014). Individual differences may be conceived as a disturbance increasing variability of the test cohort thereby reducing statistical power.…”