Selective activation of the trace amine-associated receptor 1 decreases cocaine's reinforcing efficacy and prevents cocaine-induced changes in brain reward thresholds

https://doi.org/10.1016/j.pnpbp.2015.05.014Get rights and content

Highlights

  • The effects of Trace amine-associated receptor 1 (TAAR1) activation on cocaine's reward and reinforcement are studied in rats.

  • Trace amine-associated receptor 1 (TAAR1) activation produced a downward shift in the dose–response for cocaine self-administration.

  • Trace amine-associated receptor 1 (TAAR1) activation prevented cocaine-induced lowering of self-stimulation thresholds.

Abstract

The newly discovered trace amine-associated receptor 1 (TAAR1) has emerged as a promising target for medication development in stimulant addiction due to its ability to regulate dopamine (DA) function and modulate stimulants' effects. Recent findings indicate that TAAR1 activation blocks some of the abuse-related physiological and behavioral effects of cocaine. However, findings from existing self-administration studies are inconclusive due to the very limited range of cocaine unit doses tested. Here, in order to shed light on the influence of TAAR1 on cocaine's reward and reinforcement, we studied the effects of partial and full activation of TAAR1on (1) the dose–response curve for cocaine self-administration and (2) cocaine-induced changes in intracranial self-stimulation (ICSS). In the first experiment, we examined the effects of the selective full and partial TAAR1 agonists, RO5256390 and RO5203648, on self-administration of five unit-injection doses of cocaine (0.03, 0.1, 0.2, 0.45, and 1 mg/kg/infusion). Both agonists induced dose-dependent downward shifts in the cocaine dose–response curve, indicating that both partial and full TAAR1 activation decrease cocaine, reinforcing efficacy. In the second experiment, RO5256390 and the partial agonist, RO5263397, dose-dependently prevented cocaine-induced lowering of ICSS thresholds. Taken together, these data demonstrated that TAAR1 stimulation effectively suppresses the rewarding and reinforcing effects of cocaine in self-administration and ICSS models, supporting the candidacy of TAAR1 as a drug discovery target for cocaine addiction.

Introduction

Cocaine addiction is a chronic relapsing disease for which effective pharmacotherapies are lacking (Karila et al., 2011). Changes in dopamine (DA) transmission occurring during and after cocaine exposure are believed to contribute critically to drug reinforcement (Volkow et al., 1997), withdrawal (Rossetti et al., 1992, Weiss et al., 1992), and relapse (Volkow et al., 2006). Consequently, the search for effective pharmacotherapies has primarily focused on developing pharmacological agents able to alter the DA system, by either acting as a substitute for the stimulant drug or exerting antagonistic actions through preventing binding of the stimulant to the dopamine transporter (DAT) (Gorelick et al., 2004, Rothman et al., 2008). However, one of the shortcomings of DA-based therapies is the emergence of side effects, particularly after prolonged exposure. In this context, the recently discovered trace amine-associated receptor 1 (TAAR1), by virtue of its unique ability to modulate DA function, has arisen as a novel therapeutic target to treat cocaine addiction (Revel et al., 2012, Sotnikova et al., 2009).

TAAR1 belongs to a family of G protein-coupled receptors that was found to be activated by trace amines (TAs) (Borowsky et al., 2001, Bunzow et al., 2001), a group of endogenous amines that have long been implicated in the psychoactive actions of motor stimulants (Berry, 2004, Burchett and Hicks, 2006). TAAR1 is expressed in brain monoaminergic nuclei and colocalized with the DAT in a subset of DA neurons (Borowsky et al., 2001, Lindemann et al., 2008, Xie and Miller, 2007). Genetic deletion of Taar1 leads to elevated spontaneous discharge of DA neurons in the ventral tegmental area (VTA) (Lindemann et al., 2008), increased DA level in the nucleus accumbens (NAc) (Leo et al., 2014), enhanced sensitivity to psychostimulant-induced hyperactivity, and conditioned place preference (CPP) (Achat-Mendes et al., 2012) and elevated striatal DA release (Lindemann et al., 2008, Wolinsky et al., 2007). Taken together, these observations indicate that TAAR1 is a key neuromodulator of DA transmission.

Several highly selective TAAR1 ligands have become recently available, opening the door for direct investigation of the specific physiological and behavioral effects of pharmacological activation of this receptor. DA neuron firing frequency in the VTA was shown to be decreased by a full TAAR1 agonist (Revel et al., 2011, Revel et al., 2013) and increased by an antagonist and a partial agonist (Revel et al., 2012, Revel et al., 2013, Bradaia et al., 2009). In animal models, several TAAR1 agonists demonstrated an ability to suppress cocaine-induced locomotor hyperactivity (Revel et al., 2011, Revel et al., 2012), behavioral sensitization (Thorn et al., 2014b), CPP (Thorn et al., 2014a), and reinstatement of cocaine seeking (Pei et al., 2014, Thorn et al., 2014a), as well as cocaine-stimulated DA overflow in the NAc (Pei et al., 2014). However, there has been no systematic examination of the functional contribution of TAAR1 to the rewarding and reinforcing effects of cocaine. Although existing evidence indicates that TAAR1 activation suppresses cocaine self-administration, only a limited range of cocaine unit doses have been examined (Pei et al., 2014, Revel et al., 2012, Thorn et al., 2014a), making it difficult to determine whether reduced cocaine taking is due to agonistic or antagonistic actions of TAAR1 on cocaine reinforcement.

To address this important question, one objective of the present study was to examine the shifts produced by selective partial and full TAAR1 agonism on the dose–response curve for cocaine self-administration. A second objective was to study the impact of TAAR1 activation on cocaine's ability to alter brain reward. The facilitating effects of cocaine on brain reward function can be modeled in the intracranial self-stimulation (ICSS) paradigm and are manifested as a decrease in ICSS thresholds (Wise, 1996). Consequently, we used this well-validated model to assess the effects of partial and full TAAR1 agonists on cocaine-induced reductions in ICSS thresholds.

Section snippets

Subjects

Male Long–Evans rats (n = 36) were sourced from the University of Canterbury and male Wistar rats (n = 24) from F. Hoffmann-La Roche Ltd (Basel, Switzerland). All animals were housed in temperature- and humidity-controlled colony rooms with a 12-hr light/dark cycle (lights off at 8 AM). Rats for the ICSS experiments were given food ad libitum. Rats in the cocaine dose–response experiments were given a maintenance diet and kept at 100% of the weight; they were at 7 days post-surgery (Ferragud et al.,

RO5203648 and RO5256390 dose-dependently shifted the cocaine self-administration dose–response curve downward

First, we tested the ability of RO5203648 and RO5256390 to shift the cocaine self-administration dose–response curve. Five experimental groups (n = 7–8 per group) were matched for responses and number of infusions obtained in the last three cocaine self-administration training sessions. ANOVA for lever presses during the last three pre-training sessions revealed a significant effect of lever (active vs. inactive, F1, 33 = 393.04, p < .0001). Similarly, one-way ANOVA showed no significant differences

Discussion

From a behavioral viewpoint, the involvement of TAAR1 in cocaine reward and reinforcement is not clearly understood. The present data provide a straightforward demonstration that partial and full pharmacological activation of TAAR1 reduces the reinforcing and rewarding properties of cocaine, thereby explaining the previously reported reduction in cocaine intake induced by partial TAAR1 stimulation. We determined that the selective TAAR1 partial and full agonists, RO5203648 and RO5256390,

Author contributions

Yue Pei, Patrick Mortas, Marius Hoener, and Juan J. Canales designed the experiments. Yue Pei conducted the self-administration experiments and Patrick Mortas performed the ICSS study. Yue Pei, Patrick Mortas, Marius Hoener, and Juan J. Canales analyzed the data. Yue Pei and Juan J. Canales wrote the paper.

Acknowledgements

This work was supported by grants to J.J.C. from the Spanish Ministry of Health (ISCIII, grant PI10/00297) and from F. Hoffman-La Roche Ltd. We thank Dr. Jean-Luc Moreau for expert advice in the ICSS experiments and Silvana de Freitas for technical assistance.

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