A partial trace amine-associated receptor 1 agonist exhibits properties consistent with a methamphetamine substitution treatment

Abstract

Recent evidence suggests that the trace amine-associated receptor 1 (TAAR1) plays a pivotal role in the regulation of dopamine (DA) transmission and psychostimulant action. Several selective TAAR1 agonists have previously shown efficacy in models of cocaine addiction. However, the effects of TAAR1 activation on methamphetamine (METH)-induced behaviours are less well understood, as indeed are the underlying neurochemical mechanisms mediating potential interactions between TAAR1 and METH. Here, in a progressive ratio schedule of reinforcement the partial TAAR1 agonist, RO5263397, reduced the break-point for METH self-administration, while significantly increasing responding maintained by food reward. Following self-administration and extinction training, RO5263397 completely blocked METH-primed reinstatement of METH seeking. Moreover, when used as a substitute, unlike a low dose of METH, which sustained vigorous responding when substituting for the training dose of METH, RO5263397 was not self-administered at any dose, thus exhibiting no apparent abuse liability. Fast-scan cyclic voltammetry experiments showed that RO5263397 prevented METH-induced DA overflow in slices of the nucleus accumbens, while having no effect on DA transmission in its own right. Collectively, the present observations demonstrate that partial TAAR1 activation decreases the motivation to self-administer METH, blocks METH-primed reinstatement of METH seeking and prevents METH-induced DA elevations in the nucleus accumbens, and strongly support the candidacy of TAAR1-based medications as potential substitute treatment in METH addiction.

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). Consistent with the TAAR1-mediated effects being due to an interaction with D2R, the above-described effects are associated with a decrease in nucleus accumbens dopamine overflow (Cotter et al, 2015;Pei et al, 2017).…”

“…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). Consistent with the TAAR1-mediated effects being due to an interaction with D2R, the above-described effects are associated with a decrease in nucleus accumbens dopamine overflow (Cotter et al, 2015;Pei et al, 2017).…”

“…In contrast, addictive agents that do not strongly invoke the dopamine reward pathways are not affected by manipulation of TAAR1 activity. TAAR1 agonists do not affect the propensity of rodents to self-administer sucrose (Revel et al, 2012b;Jing et al, 2014;Pei et al, 2014Pei et al, , 2017Cotter et al, 2015). Likewise, TAAR1-KO also does not affect sucrose self-administration (Lynch et al, 2013).…”

Amphetamines signal through intracellular TAAR1 receptors coupled to Gα13 and GαS in discrete subcellular domains

“…TAAR1 knockout (KO) mice are hypersensitive to AMPH [6], and antagonists of TAAR1 modulate the locomotor activation produced by methamphetamine [7], cocaine [8], and other psychostimulants. The addictive properties of methamphetamine [9,10] and cocaine [11][12][13] also appear to be regulated by the receptor.…”

Pharmacological characterization of a high-affinity p-tyramine transporter in rat brain synaptosomes

“…In 2001, a family of vertebrate G protein-coupled receptors, subsequently termed trace amine-associated receptors (TAAR), was identified, a sub-set of which were selectively activated by the trace amines34. Subsequently much effort has been devoted to the study of these receptors, in particular TAAR1, which has been shown to modulate dopaminergic56789 serotonergic6 and glutamatergic61011 transmission; interact with dopamine (DAT)121314, noradrenaline (NET)14, 5-HT (SERT)14 and glutamate (EAAT2)15 transporters; decrease craving for various psychostimulants161718; and regulate appetite1019, sleep710 and cognitive function710. Based on this, TAAR1 agonists and/or partial agonists have been proposed as novel therapeutics for schizophrenia10 and drug abuse20.…”