Trace amine-associated receptor 1 regulation of methamphetamine-induced neurotoxicity

Abstract

Trace amine-associated receptor 1 (TAAR1) is activated by methamphetamine (MA) and modulates dopaminergic (DA) function. Although DA dysregulation is the hallmark of MA-induced neurotoxicity leading to behavioral and cognitive deficits, the intermediary role of TAAR1 has yet to be characterized. To investigate TAAR1 regulation of MA-induced neurotoxicity, Taar1 transgenic knock-out (KO) and wildtype (WT) mice were administered saline or a neurotoxic regimen of 4 i.p. injections, 2 hr apart, of MA (2.5, 5, or 10 mg/kg). Temperature data were recorded during the treatment day. Additionally, striatal tissue was collected 2 or 7 days following MA administration for analysis of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and tyrosine hydroxylase (TH) levels, as well as glial fibrillary acidic protein (GFAP) expression. MA elicited an acute hypothermic drop in body temperature in Taar1-WT mice, but not in Taar1-KO mice. Two days following treatment, DA and TH levels were lower in Taar1-KO mice compared to Taar1-WT mice, regardless of treatment, and were dose-dependently decreased by MA. GFAP expression was significantly increased by all doses of MA at both time points and greater in Taar1-KO compared to Taar1-WT mice receiving MA 2.5 or 5 mg/kg. Seven days later, DA levels were decreased in a similar pattern: DA was significantly lower in Taar1-KO compared to Taar1-WT mice receiving MA 2.5 or 5 mg/kg. TH levels were uniformly decreased by MA, regardless of genotype. These results indicate that activation of TAAR1 potentiates MA-induced hypothermia and TAAR1 confers sustained neuroprotection dependent on its thermoregulatory effects.

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).…”

Depression‐like symptoms of withdrawal in a genetic mouse model of binge methamphetamine intake

“…46 Some studies have suggested that the maintenance of drug intake and relapse to drug intake after forced abstinence, are associated with functional switches of monoaminergic and glutamatergic systems. However, because mice with functional TAAR1 will not voluntarily consume MA, 41 a forced exposure model would be required to study this, as has been used to examine the role of TAAR1 in sensitivity to MA-induced neurotoxicity.…”

“…However, because mice with functional TAAR1 will not voluntarily consume MA, 41 a forced exposure model would be required to study this, as has been used to examine the role of TAAR1 in sensitivity to MA-induced neurotoxicity. 46 Some studies have suggested that the maintenance of drug intake and relapse to drug intake after forced abstinence, are associated with functional switches of monoaminergic and glutamatergic systems. 29,[47][48][49] Microdialysis studies reported higher basal levels of serotonin in the nucleus accumbens (NAc) of MAHDR mice, compared to MALDR mice, as well as resistance in MAHDR mice to MA-induced elevations of serotonin in the medial prefrontal cortex that occurred in MALDR mice.…”

Teratogen update: Amphetamines

“…The trace amine-associated receptor 1 (TAAR1) is a Gcoupled receptor expressed in the monoaminergic regions of the brain (Lam et al, 2018). When activated by appropriate ligands including methamphetamine, dopaminergic function is modulated (Miner, Elmore, Baumann, Phillips, & Janowsky, 2017). Amphetamine also has actions at the acetylcholine, serotonin, opioid, and glutamine receptors, and increases blood flow in the brain (Faraone, 2018).…”