Effects of the Trace Amine-Associated Receptor 1 Agonist RO5263397 on Abuse-Related Effects of Cocaine in Rats

Abstract

Animal knockout studies suggest that trace amine-associated receptor (TAAR) 1 is involved in behavioral effects of psychostimulants such as cocaine. Recently, several highly selective TAAR 1 agonists have been discovered. However, little is known of the impact of TAAR 1 agonists on abuse-related effects of cocaine. Here, we report the effects of a TAAR 1 agonist RO5263397 on several abuse-related behavioral effects of cocaine in rats. RO5263397 was evaluated for its effects on cocaine-induced behavioral sensitization, conditioned place preference (CPP), cue- and cocaine prime-induced reinstatement of cocaine-seeking behavior, and cocaine self-administration using behavioral economic analysis. RO5263397 reduced the expression of cocaine behavioral sensitization, cue- and cocaine prime-induced reinstatement of cocaine seeking, and expression but not development of cocaine CPP. Behavioral economic analysis showed that RO5263397 increased the elasticity of the cocaine demand curve, but did not change cocaine consumption at minimal prices. Taken together, this is the first systematic assessment of a TAAR 1 agonist on a range of behavioral effects of cocaine, showing that RO5263397 was efficacious in reducing cocaine-mediated behaviors. Collectively, these data uncover essential neuromodulatory roles of TAAR 1 on cocaine abuse, and suggest that TAAR 1 may represent a novel drug target for the treatment of cocaine addiction.

TAAR1 modulates cortical glutamate NMDA receptor function

“…Both full and partial TAAR1 agonists are known to be effective in reversing hyperactivity in pharmacologic or genetic models of hyperdopaminergia and NMDA deficiency in mice (Revel et al, 2012;Revel et al, 2013). Interestingly, TAAR1-KO mice are more prone to the addictive properties of methamphetamine, ethanol, and MDMA (Di Cara et al, 2011;Achat-Mendes et al, 2012;Lynch et al, 2013), while recent reports from different groups have demonstrated that TAAR1 full and partial agonists reduce cocaine-conditioned place preference, self-administration, and relapse (Revel et al, 2012;Pei et al, 2014;Thorn et al, 2014a;Thorn et al, 2014b). As impulsivity is considered to be a specific trait in the pathophysiology of drug addiction, it is possible that TAAR1 can reduce addictive behaviors in part through PFC-related mechanisms.…”

Trace Amines and Their Receptors

“…Intriguingly, TAAR1 agonists appear to have a similar beneficial anticraving effect in all such instances (Tables 6 and 8). Responses to cocaine (which itself is not a ligand for TAAR1), as well as drugtaking behaviors induced by its administration, are modified by TAAR1 agonists such that agonist-induced decreases in cocaine CPP (Thorn et al, 2014a), both cueand drug-primed reinstatement (Pei et al, 2014;Thorn et al, 2014a), hyperactivity (Revel et al, 2011(Revel et al, , 2013, reward memory , self-administration , sensitization (Thorn et al, 2014a,b), and withdrawal-induced drug seeking (Pei et al, 2014) have all been reported. Furthermore, TAAR1 activation causes a downward shift in dose-response curves for cocaine reward efficacy, confirming lesser rewarding properties.…”

Neuronal Functions and Emerging Pharmacology of TAAR1

“…Thus, while when administered prior to cocaine conditioning, TAAR1 agonist did not modify the development of the CPP, it could reduce the expression of the already established CPP when administered prior to the test session. Also in a model of cocaine relapse, the cocaine-primed reinstatement of cocaine seeking, TAAR1 activation reduced the relapse of the cocaine-seeking behavior [12]. Altogether, these data indicate that TAAR1 activation reduces the sensitizing, rewarding, and reinforcing effects of cocaine and TAAR1 should be explored further as a potential target for the treatment of cocaine addiction.…”

“…Regarding the mechanism of action, it is shown that TAAR1 activation reduces the dopamine release induced by cocaine, as measured by FCSV in the nucleus accumbens, without altering the DAT functions, suggesting an involvement of other mechanisms than direct interference with dopamine uptake such as the alteration of D2 receptors activity [7]. In another study, TAAR1 partial agonist has been used to reduce several cocaine-mediated behaviors [12,84]. First, TAAR1 agonist administration reduced the expression of cocaine behavioral sensitization.…”

“…Among them, TAAR1 has been mostly characterized with its particular role in the regulation of brain functions, although new intriguing functions of this receptor in the periphery are emerging. The initial observation from TAAR1 knockout (TAAR1-KO) mice was further strengthened by several recent studies using selective TAAR1 full and partial agonists, suggesting an important role for TAAR1 in the regulation of dopaminergic system and indicating TAAR1 as new potential target for the treatment of neuropsychiatric disorders such as schizophrenia, bipolar disorder, ADHD, and addiction [7][8][9][10][11][12]. Since the amount of literature on TAARs is increasing monthly, this review will focus on TAAR1 and particularly on recent reports that highlight TAAR1 influence on monoamine systems and its possible role in psychiatric diseases.…”