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British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 2020 May 5;177(15):3403–3414. doi: 10.1111/bph.15061

TAAR1 agonists attenuate extended‐access cocaine self‐administration and yohimbine‐induced reinstatement of cocaine‐seeking

Jianfeng Liu 1, Bernard Johnson 1, Ruyan Wu 1,2, Robert Seaman Jr 1, Jimmy Vu 1, Qing Zhu 3, Yanan Zhang 4, Jun‐Xu Li 1,✉
PMCID: PMC7348092  PMID: 32246467

Abstract

Background and Purpose

The trace amine‐associated receptor 1 (TAAR1) negatively modulates dopamine transmission. Our previous studies demonstrated that TAAR1 agonists attenuated cue‐ and drug‐induced cocaine‐seeking and increased the elasticity of the cocaine demand curve, in the short‐access cocaine self‐administration model. Compulsive use of cocaine, which is an essential criterion of cocaine use disorder, can be induced by extended access to cocaine self‐administration.

Experimental Approach

To characterize the role of TAAR1 in compulsive cocaine use, we evaluated the effects of activation of TAAR1 on cocaine intake, cocaine binge and cue‐induced cocaine‐seeking using the extended‐access cocaine self‐administration model in adult male Sprague–Dawley rats. We also investigated the role of TAAR1 in stress‐triggered cocaine relapse by using the α2‐adrenoceptor antagonist yohimbine‐induced reinstatement of cocaine‐seeking.

Key Results

The selective TAAR1 partial agonist RO5263397 attenuated cocaine intake and did not develop tolerance during the 10‐day extended‐access cocaine self‐administration. RO5263397 reduced a 12‐h binge intake of cocaine after forced abstinence. RO5263397 also decreased cue‐induced cocaine‐seeking after prolonged abstinence from extended‐access cocaine self‐administration. Furthermore, RO5263397 and the selective TAAR1 full agonist RO5166017 reduced yohimbine‐induced reinstatement of cocaine‐seeking behaviour.

Conclusion and Implications

Activation of TAAR1 attenuated extended‐access cocaine self‐administration and stress‐induced cocaine reinstatement. These results suggest that TAAR1 agonists are promising pharmacological interventions to treat cocaine use disorder and relapse.

Abbreviations

FR

fixed ratio

NAc

nucleus accumbens

PFC

prefrontal cortex

RO5166017

(4S)‐4‐[(N‐ethylanilino)methyl]‐4,5‐dihydro‐1,3‐oxazol‐2‐amine

RO5263397

(4S)‐4‐(3‐Fluoro‐2‐methylphenyl)‐4,5‐dihydro‐1,3‐oxazol‐2‐amine

T(1)AM

3‐iodothyronamine

VTA

ventral tegmental area (VTA)

What is already known

  • In short‐access models, TAAR1 agonists reduce cue‐ and drug‐induced reinstatement and reinforce strength of cocaine.

  • Extended‐access models induce compulsive drug use behaviours, better mimicking those of human drug addiction.

What this study adds

  • TAAR1 agonists reduced cocaine intake and binge intake after abstinence in the extended‐access model.

  • TAAR1 agonists reduced yohimbine‐induced reinstatement of cocaine‐seeking.

What is the clinical significance

  • These results further support the potential utility of TAAR1 agonists to treat cocaine use disorder.

1. INTRODUCTION

Trace amine‐associated receptors (TAARs) are a family of receptors of trace amines, which are a group of endogenous amines present at nanomolar levels in the brain of vertebrates (Grandy, 2007). The TAAR1 (TA1 receptor) is the best‐characterized member of the TAARs (Gainetdinov, Hoener, & Berry, 2018; Liu & Li, 2018) and this receptor plays crucial roles in regulating some fundamental functions of the brain and is involved in several brain disorders such as schizophrenia and drug addiction (Grandy, 2007; Liu & Li, 2018; Revel et al., 2013).

A growing number of studies have suggested an inhibitory role of the TAAR1 system in regulating dopamine neurotransmission (Revel et al., 2011) and the potential of TAAR1 agonists for treating cocaine use disorder (Liu, Siemian, Seaman, Zhang, & Li, 2017; Thorn et al., 2014). Using a short‐access cocaine self‐administration model, in which animals maintain a stable cocaine intake pattern, earlier work showed that TAAR1 agonists reduced cocaine intake and cocaine relapse (Pei et al., 2014; Revel, Moreau, et al., 2012; Thorn et al., 2014). However, cocaine use disorder is characterized by loss of control of cocaine use and augmentation of cocaine consumption along with the passage of time (Koob & Volkow, 2010). Compared with the short‐access cocaine self‐administration, the extended‐access cocaine self‐administration (usually longer than 6 h daily) induces the phenotype of compulsive cocaine intake (Ahmed & Koob, 1998; Edwards & Koob, 2013). To further characterize the role of TAAR1 in cocaine use disorder, it is worthwhile to examine whether activation of TAAR1 would attenuate addiction‐related behaviours of cocaine in the extended‐access model of cocaine self‐administration, for example, escalation of cocaine intake, cocaine binge and cue‐induced cocaine‐seeking after prolonged abstinence (Conrad et al., 2008; Edwards & Koob, 2013; Gancarz‐Kausch, Adank, & Dietz, 2014).

Cocaine relapse can be modelled in animals by drug‐seeking and drug‐taking behaviour after forced abstinence as well as reinstatements after extinction (Dong, Taylor, Wolf, & Shaham, 2017). Besides drug‐associated cues and the drug itself, stress is a common factor in regular life that is able to trigger drug relapse in humans (Erb, Shaham, & Stewart, 1996; Mantsch, Baker, Funk, Le, & Shaham, 2016). The adrenergic system is known to be crucial for the effects of stress on relapse (Mantsch et al., 2016). For example, the α2‐adrenoceptor antagonist yohimbine is a widely used pharmacological stressor to trigger relapse‐like behaviour in preclinical studies (Lee, Tiefenbacher, Platt, & Spealman, 2004; Shepard, Bossert, Liu, & Shaham, 2004). Previous studies showed that the TAAR1 full agonist RO5166017 and partial agonist RO5203648 attenuated stress‐induced hyperthermia (Revel et al., 2011; Revel, Moreau, et al., 2012), suggesting that TAAR1 agonists have anti‐stress properties. The TAAR1 full agonists and partial agonists similarly attenuated abuse‐related behaviours of cocaine and nicotine (Liu et al., 2018; Pei et al., 2014; Sukhanov, Dorofeikova, Dolgorukova, Dorotenko, & Gainetdinov, 2018; Thorn et al., 2014). However, there is no study examining the effects of activation of TAAR1 by its full and partial agonists, on stress‐induced reinstatement of cocaine‐seeking behaviour.

This study has investigated the role of TAAR1 in cocaine reinforcement and relapse using models of extended‐access cocaine self‐administration and stress‐induced reinstatement of cocaine‐seeking. We examined the effects of the selective TAAR1 partial agonist RO5263397 on escalation of cocaine intake, cocaine binge and cue‐induced cocaine‐seeking in the extended‐access cocaine self‐administration model. We also assessed the effects of RO5263397 and the selective full agonist RO5166017 on yohimbine‐induced reinstatement of cocaine‐seeking.

2. METHODS

2.1. Animals

All animal care and experimental procedures were approved by the Institutional Animal Care and Use Committee, University at Buffalo, the State University of New York, and complied with the 2011 Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources on Life Sciences, National Research Council, National Academy of Sciences, Washington DC). Animal studies are reported in compliance with the ARRIVE guidelines (Kilkenny, Browne, Cuthill, Emerson, & Altman, 2010; McGrath & Lilley, 2015) and with the recommendations made by the British Journal of Pharmacology.

Adult male Sprague–Dawley rats (initial weight 260–280 g; Harlan, Indianapolis, IN) were housed individually on a 12/12‐h light/dark cycle with free access to water and food. A total of 97 rats were used in the present study. All studies were designed to generate groups of equal size and blinded analysis. To assure that there will be no difference among different groups of rats before treatment of TAAR1 agonists, we assigned rats into different groups based on the training of self‐administration in all experiments. The groups of rats were then assigned into treatments of vehicle and RO5263397 randomly. Experimenters were blinded to the group assignment. All behavioural studies were performed during the light cycle (8:00–20:00).

2.2. Characteristics of TAAR1 agonists used

Previous studies showed that the maximal cAMP levels induced by RO5263397 and RO5166017 in HEK293 cells expressing rat TAAR1 were 59%–85% and 81%–95% (stimulation of endogenous TAAR1 agonist PEA was set as 100%), respectively, suggesting that RO5263397 is a partial agonist and RO5166017 is a full agonist (Revel et al., 2011; Revel et al., 2013). The Ki and EC50 values of RO5263397 obtained from the cAMP assay in HEK293 cells expressing rat TAAR1 were higher than that of RO5166017 (Ki: RO526 = 9.1 nM; RO516 = 2.7 nM; EC50: RO526 = 47 nM, RO516 = 14 nM; MW: RO526 = 194.21, RO516 = 219.28), indicating that both RO5263397 and RO5166017 are potent TAAR1 agonists and the potency of RO5166017 is higher than RO5263397 in vitro (Revel et al., 2011; Revel et al., 2013). However, it should be noted that the potency and efficacy differences between the RO5263397 and RO5166017 are relatively small and this small difference may not predict the in vivo potencies given the much more complex in vivo factors such as pharmacokinetics. In brain slices, RO5263397 increases while RO5166017 inhibits the firing rate of DA neurons (Revel et al., 2011; Revel et al., 2013), which is the only evidence in the literature suggesting ex vitro/in vivo functional difference between the two compounds. Our previous studies showed that the minimal effective dose of RO5166017 to affect cocaine‐related behaviours was 10 mg·kg−1 (i.p., 10 min pretreatment) while RO5263397 was 3.2–5.6 mg·kg−1 (i.p., 10 min pretreatment) in rats (Liu, Thorn, Zhang, & Li, 2016; Thorn et al., 2014). Therefore, we used 10 mg·kg−1 RO5166017 and 5.6 mg·kg−1 RO5263397 in the present study. The dose of yohimbine was based on previous studies (Le, Harding, Juzytsch, Funk, & Shaham, 2005; Shepard et al., 2004).

2.3. Operant chambers

Eighteen standard operant chambers (Med Associates, St Albans, Vermont) were used for all cocaine self‐administration studies (Liu et al., 2017). Chambers contained two response levers; responses on the active (right) level were associated with the reinforcer cocaine, and responses on the inactive (left) lever were recorded and had no programmed consequence. Data were collected using Graphic State 3.03 software and an interface (Coulbourn Instruments Inc.). Stimulus presentations, cocaine infusions and data recording were controlled by Med‐PC IV software (Med Associates).

2.4. Acquisition and maintenance of cocaine self‐administration

The rats (weighing 280–300 g at the beginning of the experiments) were anaesthetized with ketamine and xylazine (75 and 5 mg·kg−1, respectively, i.p.). Rats were implanted with chronic indwelling jugular catheters as described in our previous studies (Liu et al., 2017; Liu et al., 2018). The rats were allowed to recover for at least 1 week after surgery. Catheters were flushed daily with 0.2‐ml solution of enrofloxacin (4 mg·ml−1) mixed in a heparinized saline solution (50 IU·ml−1 in 0.9% sterile saline) for 1 week after surgery to preserve catheter patency and prevent infection. In the acquisition phase, rats were trained to lever press for short‐access cocaine self‐administration (0.5 mg·kg−1·infusion−1; 2 h·session−1·day−1), during which responses to the active lever resulted in intravenous injections of cocaine under a fixed ratio (FR) schedule of reinforcement followed by a 30‐s time‐out period. Cocaine infusions were accompanied by a 5‐s illumination of the stimulus light above the active lever (right cue), and the house light was extinguished for the duration of the time‐out period. Sessions were terminated after either a 2‐h duration or 40 infusions had been earned, whichever occurred first. During this training phase, the response requirement was gradually increased from FR1 to FR5 over a period of 5‐day short‐access cocaine self‐administration. Rats that self‐administered more than 10 infusions of cocaine (2 h) on any day during the training were transited into next FR (FRs: 1, 2, 3 and 5). All rats were under FR5 on Day 5 in the study. Rats were then assigned to different groups with no difference in the acquisition of cocaine self‐administration. In the extended‐access experiments, rats were then moved to 10‐day maintenance of extended‐access cocaine self‐administration (0.5 mg·kg−1·infusion−1; 6 h·session−1·day−1). In the yohimbine experiments, rats were moved to 10‐day maintenance of short‐access cocaine self‐administration (0.5 mg·kg−1·infusion−1; 2 h·session−1·day−1).

2.5. Cocaine intake

For the cocaine intake test, daily RO5263397 (5.6 mg·kg−1, i.p.) or vehicle (1 ml·kg−1, i.p.) was given 10 min before the sessions of extended access to cocaine self‐administration. One day after the last cocaine intake test, an infusion of a small dose of ketamine (0.1 ml; 10 mg·ml−1) was administered through catheters to confirm patency of catheters.

2.6. Cocaine binge

After 10 days of extended‐access cocaine self‐administration, rats were then placed in home cages for a 10‐day forced abstinence period followed by the cocaine binge test. In the binge test, a single dose of RO5263397 (5.6 mg·kg−1, i.p.) or vehicle (1 ml·kg−1, i.p.) was given 10 min before an unlimited‐access cocaine self‐administration session (0.3 mg·kg−1·infusion−1; 12 h) (Gancarz‐Kausch et al., 2014). Catheters were flushed daily with 0.4‐ml heparinized saline solution (50 IU·ml−1 in 0.9% sterile saline) during abstinence. Patency of catheters was confirmed after cocaine binge test.

2.7. Cue‐induced cocaine‐seeking

Rats were tested for cue‐induced cocaine‐seeking 1 day or 45 days after the 10 days of extended‐access cocaine self‐administration sessions. Rats were placed in their home cage during abstinence, and no extinction was performed before tests. During the cue‐induced cocaine‐seeking test (1 h), active lever presses (FR5) resulted in the presentation of light cues in the same manner as during self‐administration sessions with no drug delivery. RO5263397 (5.6 mg·kg−1, i.p.) or vehicle (1 ml·kg−1, i.p.) was given 10 min before the test.

2.8. Yohimbine‐induced reinstatement of cocaine‐seeking

Rats were extinguished following the 10‐day maintenance period of short‐access cocaine self‐administration. In the RO5623397 experiment, 3 days of extinction (4 h·day−1) were used, during which lever presses had no consequence (no drug or cues). On the reinstatement test day, a 2‐h extinction session was conducted (2 h) before the reinstatement test to ensure sufficient extinction behaviour. RO5266397 (5.6 mg·kg−1, i.p.) or vehicle (1 mg·kg−1, i.p.) was administered 10 min after the extinction session. Yohimbine (2.5 mg·kg−1, i.p.) was given 10 min after RO5263397 administration. Reinstatement test during which lever presses had no programmed consequence (no drug or cues; 2 h) was conducted 30 min after yohimbine administration. In the RO5166017 experiment, 6 days of extinction (2 h·day−1) were used. Yohimbine was given 30 min before the reinstatement test (2 h). RO5166017 (10 mg·kg−1, i.p.) or vehicle (1 ml·kg−1, i.p.) was given 10 min before the injection of yohimbine (2.5 mg·kg−1, i.p.) (Le et al., 2005; Shepard et al., 2004).

2.9. Data and statistical analysis

All results are presented as mean ± SEM. Group size in the study was based on our previous studies and that of others. Statistical analysis was undertaken only for studies where each group size was at least n = 5. The declared group size was the number of independent values, and the statistical analysis was carried out using these independent values. Lever responses and infusions of cocaine were recorded and used as statistical data. We included all data generated in the behavioural tests in the statistical analysis. The cue‐induced cocaine‐seeking data were analysed by one‐way ANOVA followed by post hoc Bonferroni's test. All other data were analysed by two‐way or three‐way ANOVA, which were specified in Section 3, followed by post hoc Bonferroni's test. Post hoc tests were conducted only if F in ANOVA achieved statistical significance (P < 0.05) and there was no significant variance inhomogeneity. P < 0.05 was considered statistically significant. Five rats were excluded due to blockage of catheters. Two rats were excluded because of failure to acquire the short‐access cocaine self‐administration. No outlier was excluded in the present study. The data and statistical analysis comply with the recommendations of the British Journal of Pharmacology on experimental design and analysis in pharmacology (Curtis et al., 2018).

2.10. Materials

Cocaine hydrochloride was provided by the National Institute of Drug Abuse (Research Technology Branch, NIH, Rockville, MD). RO5263397 and RO5166017 were synthesized at Research Triangle Institute (purity >98%). Yohimbine hydrochloride was purchased from Sigma‐Aldrich (Cat # Y3125). Cocaine hydrochloride was dissolved in 0.9% physiological saline. RO5263397 and RO5166017 were dissolved in the vehicle, which contains 1 part absolute ethanol, 1 part Emulphor‐620 (Rhodia) and 18 parts physiological saline (Liu et al., 2018; Thorn et al., 2014).

2.11. Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Harding et al., 2018), and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20 (Alexander et al., 2019).

3. RESULTS

3.1. Activation of TAAR1 attenuates cocaine intake in the extended‐access cocaine self‐administration model

A previous study demonstrated that activation of TAAR1 reduced cocaine self‐administration in a short‐access cocaine self‐administration model in rats (Revel, Moreau, et al., 2012). To evaluate the role of TAAR1 in the compulsive use of cocaine, we examined the effect of the TAAR1 partial agonist RO5263397 on cocaine intake in the extended‐access model. Rats underwent short‐access cocaine self‐administration (2 h·day−1) training with gradually increased FRs (from FR1 to FR5). No difference between vehicle and RO5263397 groups was found during the training session (Figure 1a). Rats were then maintained extended‐access self‐administration (6 h·day−1) under FR5 for 10 days. RO5263397 (5.6 mg·kg−1, i.p.) or vehicle was administered 10 min before extended‐access training sessions daily. Two‐way repeated‐measures ANOVA was conducted to analyse the cocaine self‐administration behaviour, which revealed significant effects of Treatment and Time (Figure 1b). Post hoc analysis showed that RO5263397 reduced cocaine intake across the 10 days of extended access to cocaine self‐administration. We further analysed the hourly patterns of cocaine intake on Day 1 and Day 10. RO5263397 significantly attenuated cocaine intake within all 6 h on Day 1 (Figure 1c) and Day 10 (Figure 1d). It is worth noting that, although both groups of rats showed escalation in cocaine intake during the maintenance of cocaine self‐administration (infusions of cocaine: Day 10 vs. Day 1), the rats that received RO5263397 on the last day only self‐administered the amount of cocaine similar to that of vehicle on the first day (64 vs. 60 infusions of cocaine; Figure 1b). These results indicate that activation of TAAR1 attenuates cocaine intake in the extended‐access cocaine self‐administration.

FIGURE 1.

FIGURE 1

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Activation of TAAR1 attenuates extended‐access cocaine self‐administration behaviour. (a) No difference was found between vehicle and RO5263397 groups during the training of cocaine self‐administration. (b) Daily administration of the TAAR1 agonist RO5263397 (5.6 mg·kg−1, i.p.) decreased infusions of cocaine in the 10 days of extended‐access cocaine self‐administration. (c) RO5263397 reduced cocaine intake across the 6‐h self‐administration on the first day. (d) Chronic treatment of RO5263397 did not develop tolerance on the last day of cocaine self‐administration. Data are expressed as mean ± SEM; *P < 0.05, significantly different from vehicle; n = 7 per group

3.2. Activation of TAAR1 decreases cocaine binge after abstinence

After abstinence from cocaine use, cocaine abusers often experience relapse episodes of binge cocaine‐taking. To determine the role of TAAR1 in binge use of cocaine, we evaluated the effects of RO5263397 on a 12‐h unlimited‐access cocaine self‐administration session following a period of abstinence. Two‐way repeated‐measures ANOVA was conducted to analyse the maintenance of extended‐access cocaine self‐administration, which found no significant effect of Group in cocaine infusions (Figure 2a). A binge cocaine test was conducted after 10 days of abstinence. Two‐way repeated‐measures ANOVA was conducted to analyse the hourly cocaine infusions, revealing a significant effect of Treatment (Figure 1b). Post hoc analysis showed that the vehicle group of rats self‐administered the highest cocaine injections in the first hour (26.5 infusions) and then maintained stable but fewer infusions of cocaine during the remaining hours (about 21 infusions·h−1). RO5263397 attenuated cocaine intake across all the cocaine binge sessions. Further analysis revealed that RO5263397 significantly attenuated the accumulative infusions of cocaine, as an interaction of Treatment × Time, and total active level presses (Figure 1c). A locomotion test was conducted 2 days after the binge test. RO5263397 had no effect on locomotor activity. These results suggest that activation of TAAR1 decreases cocaine binge.

FIGURE 2.

FIGURE 2

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Activation of TAAR1 reduces cocaine binge after abstinence from extended‐access cocaine self‐administration. (a) No difference was found between vehicle and RO5263397 groups in the maintenance of extended‐access cocaine self‐administration. (b) A single dose of RO5263397 (5.6 mg·kg−1, i.p.) significantly reduced cocaine binge (12 h) after 10 days of abstinence from cocaine use. (c) RO5263397 decreased cumulative infusions of cocaine and total active lever presses in the cocaine binge test. (d) RO5263397 did not affect locomotor activity. Data are expressed as mean ± SEM; *P < 0.05, significantly different from vehicle; n = 6–7 per group

3.3. Activation of TAAR1 reduces cue‐induced cocaine‐seeking after prolonged abstinence

Drug‐paired cues can induce drug‐seeking after abstinence. Importantly, the gradual increase in cue‐induced drug‐seeking behaviour over time, a phenomenon termed incubation, may be a critical factor contributing to drug relapse. Therefore, we assessed the effect of RO5263397 on cue‐induced cocaine‐seeking after short‐ and long‐term abstinence (Day 1 and Day 45) following extended‐access cocaine self‐administration. Rats were trained to self‐administer cocaine or saline for 6 h·day−1 (Figure 3a). The cocaine rats were assigned to vehicle and RO5263397 treatment groups according to their extended‐access cocaine self‐administration performance (n = 6–7 per group). To avoid potential interaction effects of two behavioural tests, different groups of rats were tested on Abstinence Day 1 and Day 45. Cue‐induced cocaine‐seeking test (no cocaine was administered before or during test) was conducted on Day 1 and Day 45. For the Abstinence Day 1, one‐way ANOVA showed a significant effect of active lever presses. Post hoc analysis showed that cocaine‐paired cue triggered high levels of active lever presses in the cocaine‐vehicle group, but not in the saline‐vehicle group. Pretreatment with RO5263397 attenuated cue‐induced cocaine‐seeking. RO5263397 had no effect on inactive lever presses (Figure 3b). Prolonged abstinence (Day 45) induced a significant 1.7‐fold increase in presses on the inactive lever, compared with Day 1 abstinence. One‐way ANOVA analysed cue‐induced cocaine‐seeking on Day 45, revealing a significant effect. Post hoc analysis showed that RO5263397 attenuated cocaine‐paired cue‐induced responses on active lever without affecting the responses on inactive lever (Figure 3c). To test whether RO5263397 could reinstate cocaine‐seeking, a group of rats (n = 6) was trained to self‐administer cocaine for 6 h·day−1 and underwent extinction (10 days) during which no cue or drug was administered. One day after extinction, rats received an injection of RO5263397 (5.6 mg·kg−1) and underwent RO5263397‐induced reinstatement of cocaine‐seeking 10 min after RO5263397 administration. A cue‐induced reinstatement of cocaine‐seeking test was conducted 1 day later. One‐way repeated‐measures ANOVA showed that cocaine‐associated cue but not RO5263397 reinstated cocaine‐seeking (Figure 3d). These results indicate that activation of TAAR1 attenuates cue‐induced cocaine‐seeking after prolonged abstinence.

FIGURE 3.

FIGURE 3

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Activation of TAAR1 depresses cue‐induced cocaine‐seeking after abstinence from extended‐access cocaine self‐administration. (a) Rats self‐administered high infusions of cocaine but not saline, with gradual increases in the extended‐access self‐administration. (b) The cocaine‐associated cue‐induced cocaine‐seeking on the first day of abstinence, which was attenuated by RO5263397 (5.6 mg·kg−1, i.p.). (c) Cue‐induced cocaine‐seeking incubated after 45 days of abstinence. Pretreatment of RO5263397 also reduced cue‐induced cocaine‐seeking on this day. (d) Cue but not RO5263397 triggered cocaine‐seeking. Data are expressed as mean ± SEM; *P < 0.05, significantly different as indicated; # P < 0.05, significantly different from cocaine‐vehicle on the Abstinence Day 1. n = 6–7 per group

3.4. Activation of TAAR1 disrupts yohimbine‐induced reinstatement of cocaine‐seeking

Our previous study demonstrated that activation of TAAR1 attenuated cue‐ and drug‐induced reinstatement of cocaine‐seeking (Thorn et al., 2014). However, drug relapse could be induced by other factors such as stress (Shaham, Shalev, Lu, de Wit, & Stewart, 2003). To characterize the role of TAAR1 in the stress‐induced relapse of cocaine‐seeking, we first examined the effect of RO5263397 on the reinstatement of cocaine‐seeking behaviour induced by the α2‐adrenoceptor antagonist yohimbine. Rats were extinguished for 3 days following cocaine self‐administration. The two groups (n = 9 per group) showed no difference in self‐administration (Figure 4a) or extinction (Figure 4b). Then rats were treated with yohimbine to reinstate cocaine‐seeking behaviour following two additional sessions of extinction. Two‐way repeated‐measures ANOVA analysed the active level presses, revealing an interaction of Treatment × Extinction. Post hoc analysis showed that yohimbine induced high presses on the active lever compared with the last session of extinction. RO5263397 reduced yohimbine‐induced reinstatement of cocaine‐seeking. Yohimbine and RO5263397 did not affect inactive lever responses (Figure 4c).

FIGURE 4.

FIGURE 4

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Activation of TAAR1 decreases yohimbine‐induced reinstatement of cocaine‐seeking. (a) Training of cocaine self‐administration in the experiment of RO5263397. (b) Four days of four‐session daily extinction of cocaine self‐administration. (c) Yohimbine was administered after an additional session of extinction. Yohimbine significantly induced reinstatement of cocaine‐seeking, which was reduced by RO5263397 (5.6 mg·kg−1, i.p.). (d) Training of cocaine self‐administration in the experiment of RO5166017. (e) Six days of 2‐h extinction of cocaine self‐administration. (f) Yohimbine induced higher responding in the active lever but not inactive lever in the vehicle group. RO5166017 (10 mg·kg−1, i.p.) blocked yohimbine‐induced reinstatement of cocaine‐seeking. Data are expressed as mean ± SEM; *P < 0.05, significantly different as indicated; n = 8–9 per group

To further confirm the role of TAAR1 activation in stress‐induced cocaine relapse, we assessed the effect of a TAAR1 full agonist RO5166017 on yohimbine‐induced reinstatement of cocaine‐seeking. The two groups of rats (n = 8 per group) showed no difference in cocaine self‐administration (Figure 4d) or extinction (Figure 4e) baselines. Two‐way repeated‐measures ANOVA was conducted to analyse the reinstatement results, revealing a significant effect in the responding on the active lever but not on the inactive lever. Post hoc analysis showed that yohimbine‐induced reinstatement of cocaine‐seeking, which was prevented by RO5166017 (Figure 4f). Taken together, these results indicate that activation of TAAR1 disrupts yohimbine‐induced reinstatement of cocaine‐seeking.

4. DISCUSSION

Although significant advances have been achieved on understanding the neurobiology of drug addiction, there is currently no FDA‐approved medicine to treat cocaine use disorder. Nonetheless, extensive evidence supports a key role of the dopaminergic system in regulating cocaine use disorder (Volkow & Morales, 2015). Therefore, modulators of the dopaminergic system such as TAAR1 agonists could be potential treatments for cocaine use disorder.

TAAR1 is a well‐characterized GPCR that modulates the dopaminergic system (Revel et al., 2011). In rodents and humans, TAAR1 is expressed in the dopaminergic system extensively including the ventral tegmental area (VTA) and its projecting areas such as dorsal and ventral striatum and prefrontal cortex (PFC) (Borowsky et al., 2001; Liu et al., 2017). Indeed, our previous study showed that TAAR1 in the VTA, nucleus accumbens (NAc) and PFC all contribute to cue‐ and drug‐induced reinstatement of cocaine‐seeking (Liu et al., 2017). A growing number of mechanistic studies have indicated a critical role of TAAR1 in dopamine transmission (Borowsky et al., 2001; Gainetdinov et al., 2018; Revel et al., 2011). in vitro studies showed that activation of TAAR1 reduces the activity of dopaminergic neurons in the VTA and decreases dopamine transmission in the striatum (Pei et al., 2014; Revel et al., 2011). In addition, knockout of TAAR1 enhanced the firing rate of dopaminergic neurons (Pei et al., 2014). One of our recent studies also showed that the TAAR1 agonist RO5166017 reduced striatal dopamine release induced by electrical stimulation in the VTA in vivo (Liu et al., 2018). Although the precise mechanisms of TAAR1 in modulating dopamine transmission remain unclear, there is evidence that TAAR1 may interact with dopamine D2 receptors (both presynaptic and postsynaptic) to inhibit dopamine release within the synaptic cleft and the signalling pathways associated with dopamine receptors‐ (Espinoza et al., 2015; Leo et al., 2014). Consistent with the neurobiological evidence, other results show that activation of TAAR1 inhibited the behavioural effects of several drugs of abuse including cocaine (Achat‐Mendes, Lynch, Sullivan, Vallender, & Miller, 2012; Liu et al., 2018; Pei et al., 2014; Revel, Meyer, et al., 2012; Sukhanov et al., 2018; Thorn et al., 2014). Activation of TAAR1 attenuates acute cocaine‐induced hyperactivity and chronic cocaine‐induced behavioural sensitization (Thorn et al., 2014). In the short‐access intravenous cocaine self‐administration model, the TAAR1 agonist RO5203648 reduced cocaine intake in rats (Revel, Moreau, et al., 2012). However, although these studies indicated a critical role of TAAR1 in regulating cocaine use disorder, more studies are in need to examine the translational values of TAAR1 agonists in more reliable preclinical models of such a complex disease.

Compulsive drug use, one of the criteria of addiction, can be modelled by extended‐access cocaine self‐administration procedures (Ahmed & Koob, 1998; Hyman & Malenka, 2001). Compared to the short‐access self‐administration procedure, extended access to cocaine self‐administration resulted in a compulsive phenotype such as enhanced cue‐ and drug‐induced reinstatement of cocaine‐seeking and resistance to concomitant punishment (Kippin, Fuchs, & See, 2006; Mantsch et al., 2008; Pelloux, Everitt, & Dickinson, 2007). Thus, the extended‐access cocaine self‐administration procedure may be a more suitable preclinical model of cocaine use disorder. Consistent with our previous findings using short‐access cocaine self‐administration procedure (Thorn et al., 2014), the present study showed that activation of TAAR1 attenuated cocaine‐related behaviours in the extended‐access model including cocaine intake, cocaine binge and cue‐induced cocaine‐seeking behaviour. Nevertheless, it is important to note that, although our previous study showed that RO5263397 dose‐dependently attenuated cue‐ and drug‐induced reinstatement of cocaine‐seeking in a short‐access model (Thorn et al., 2014), a complete dose–response effect of RO5263397 on cocaine self‐administration in a long‐access model is required to provide reliable evidence that RO5263397 could attenuate the effects of cocaine under long‐access conditions. Pretreatment with RO5263397 consistently produced about 50% decrease in cocaine intake in the 10‐day maintenance phase of extended access to cocaine self‐administration, suggesting that chronic treatment with RO5263397 did not develop tolerance. Drug addiction is also characterized by a high rate of relapse (Kauer & Malenka, 2007) and the incubation of craving after abstinence has been linked to a high rate of drug relapse (Dong et al., 2017; Guillem & Ahmed, 2018; Li, Caprioli, & Marchant, 2015). Similar to previous studies (Conrad et al., 2008; Dong et al., 2017; Grimm, Hope, Wise, & Shaham, 2001), we observed that cue‐induced cocaine‐seeking was markedly increased after long‐term abstinence. Although we did not examine the role of TAAR1 in the development of incubation, that is, administering TAAR1 agonists during the abstinence period, we demonstrated that activation of TAAR1 was able to attenuate cocaine craving even after prolonged abstinence. Furthermore, RO5263397 also attenuated a binge use of cocaine, and the effect of RO5263397 persisted during the 12 h of cocaine binge. Interestingly, the effect of a single dose of RO5263397 treatment persisted longer than the half‐life of the drug. However, although RO5263397 may be metabolized during the last several hours (Revel et al., 2013), activation of TAAR1 by RO5263397 may lead to a long‐term alteration of its downstream signalling pathways and neural plasticity to produce a long‐lasting effect (Kauer & Malenka, 2007; Liu & Li, 2018).

Many factors, such as cocaine‐associated cues, cocaine itself and stress, could induce cocaine relapse (Shaham et al., 2003). Our previous study showed that activation of TAAR1 attenuated cue‐ and drug‐induced reinstatement (Thorn et al., 2014). Consistent with these results, we found that activation of TAAR1 also reduced yohimbine‐induced reinstatement of cocaine‐seeking in the present study. In the present study, yohimbine was able to induce reinstatement of cocaine‐seeking after different extinction procedures. The effect of TAAR1 activation on yohimbine‐induced reinstatement of cocaine‐seeking was not dependent on the extinction paradigm as activation of TAAR1 attenuated yohimbine‐induced reinstatement after two different extinction paradigms. Both RO5263397 and RO5166017 attenuated yohimbine‐induced reinstatement of cocaine‐seeking, which is consistent with our previous findings that the effects of RO5263397 and RO5166017 on cocaine‐ and nicotine‐associated behaviours were similar to each other (Liu et al., 2018; Pei et al., 2014; Thorn et al., 2014). With this consideration, we did not test both agonists in all experiments in the present study. Although the full agonist RO5166017 attenuated, while the partial agonist RO5263397 increased, the firing rate of dopaminergic neurons in the VTA (Revel et al., 2011; Revel et al., 2013), reducing dopamine release in the NAc might be a common mechanism underlying their effects on drug addiction. Our previous study showed that RO5166017 decreased dopamine release in the NAc by using in vivo fast‐scan cyclic voltammetry in rats (Liu et al., 2018). Another study showed that RO5263397 reduced methamphetamine‐triggered dopamine release in slices of rat NAc by using in vitro fast‐scan cyclic voltammetry (Pei, Asif‐Malik, Hoener, & Canales, 2017). The activity of VTA and NAc neurons regulate many functions and behaviours, such as rewarding process, affective states and cognition processes that would affect the effectiveness of pharmacological treatment (Conio et al., 2019; Polter & Kauer, 2014). Thus, the mechanical and behavioural similarity and differences between TAAR1 partial and full agonists might affect their clinical use.

Various neural mechanisms may explain the role of TAAR1 in yohimbine‐induced reinstatement of cocaine‐seeking. Yohimbine is a pharmacological stressor that is widely used in neuropsychological experiments (Anker & Carroll, 2010; Le et al., 2005; Lee et al., 2004). Administration of yohimbine induces an anxiety‐ and stress‐like state, such as an increase in the levels of noradrenaline by antagonizing the presynaptic adrenergic autoreceptors, increases in cortisol levels and hyper‐arousal (Bremner, Krystal, Southwick, & Charney, 1996a, 1996b; Moran‐Santa Maria, McRae‐Clark, Baker, Ramakrishnan, & Brady, 2014). A possible explanation is that activation of TAAR1 may counteract yohimbine‐induced stress‐like state, as a previous study showed that TAAR1 agonists attenuated stress‐induced hyperthermia (Revel et al., 2011). It is assumed that the dose–response curve of yohimbine‐induced reinstatement of drug‐seeking would be an inverted U‐shape. Because of the anti‐stress properties of TAAR1 agonists, we believe that TAAR1 agonists inhibited but did not potentiate, the effect of yohimbine. An alternative explanation may be that TAAR1 negatively regulates impulsivity. Impulsivity is an important factor that attributes to relapse vulnerability (Pattij & De Vries, 2013). Previous studies showed that yohimbine‐induced impulsivity may contribute to drug relapse (Sun et al., 2010). Our recent study showed that RO5263397 reduced methamphetamine‐induced premature responses in a rat five‐choice serial reaction time task, indicating that the activation of TAAR1 reduces drug‐induced impulsivity (Xue, Siemian, Johnson, Zhang, & Li, 2018). Therefore, TAAR1 activation may prevent yohimbine‐induced relapse by inhibiting yohimbine‐induced impulsivity. It should be noted that yohimbine‐ and stress‐induced reinstatement is a complicated process and also depends on other neurotransmitter systems such as the glutamatergic and κ opioid systems (Funk, Tamadon, Coen, Fletcher, & Le, 2019; Mantsch et al., 2016). The inhibitory effects of TAAR1 agonists on yohimbine‐induced reinstatement may not be generalizable to physical stressors. Besides, the effects of TAAR1 agonists on yohimbine‐induced reinstatement would be different in the cocaine self‐administration model under long‐access conditions. More studies are in need to investigate the effects of TAAR1 agonists on cocaine relapse induced by physical stressors and its underlying neural mechanisms.

A limitation of the present study is that we did not assess the pharmacological selectivity of the TAAR1 agonists on cocaine‐related behaviours. However, previous studies have clearly addressed this issue. in vitro studies showed that, in HEK293 cells expressing TAAR1, the maximal cAMP level triggered by RO5166017 was similar to that triggered by β‐phenylethylamine, the endogenous agonist of TAAR1, while cAMP levels triggered by RO5263397 was lower, suggesting that RO5263017 is a full agonist and RO5263397 is a partial agonist (Revel, Moreau, et al., 2012; Revel et al., 2013). RO5263397 and RO5166017 are both highly selective at TAAR1 with a very low affinity at other receptors (Revel et al., 2011; Revel et al., 2013). RO5166017 selectively attenuated cocaine‐induced hyperactivity in wild‐type mice but not TAAR1 knockout mice (Revel et al., 2011). Our previous study also showed that RO5263397 at the same dose of that we used in the present study attenuated cue‐ and drug‐induced reinstatement of methamphetamine‐seeking and cocaine‐seeking, without affecting locomotion or cue‐induced reinstatement of sucrose‐seeking, suggesting that RO5263397 did not produce locomotor or operant responding deficits (Jing, Zhang, & Li, 2014; Thorn et al., 2014). Thus, it is likely that the inhibitory effects of TAAR1 agonists on abuse‐related behaviours of drugs are not because of non‐specific behavioural disruption. However, the role of TAAR1 in regulating hedonic and affective states remains unclear. Previous studies showed that activation of TAAR1 by its ligand 3‐iodothyronamine (T(1)AM) might affect food intake bidirectionally, which was dependent on the doses and administration routes of T(1)AM and species (Dhillo et al., 2009; Manni et al., 2012; Rutigliano, Accorroni, & Zucchi, 2017). Nevertheless, the TAAR1 full agonist RO5256390 blocked compulsive‐like eating of palatable food but did not affect the intake of regular chow (Ferragud et al., 2017). Thus, more studies are required to draw firm conclusions about the contribution of non‐specific behavioural disruption to the inhibitory effects of TAAR1 agonists on abuse‐related behaviours of drugs. Besides, although we showed that in our previous study RO5263397 did not induce conditioned place aversion in naive rats (Thorn et al., 2014), we acknowledged that RO5263397 would produce aversive effects in rats self‐administrating cocaine under long‐access conditions. Another concern of this study is that we only used a single dose of TAAR1 agonist. However, our previous study has demonstrated dose‐dependent effects of RO5263397 and RO5166017 in drug abuse‐associated behaviours (Liu et al., 2018; Thorn et al., 2014). It also should be noted that animals were individually housed and maintained in an environment of non‐enrichment in the present study. The mechanisms of cocaine self‐administration under such conditions might be different from cocaine addiction in a natural environment (Mesa‐Gresa, Ramos‐Campos, & Redolat, 2013; Venniro, Caprioli, & Shaham, 2016).

In conclusion, we found that activation of TAAR1 attenuated cocaine intake, cocaine binge and cue‐induced cocaine‐seeking after abstinence in the extended‐access cocaine self‐administration model. Activation of TAAR1 also prevented yohimbine‐induced reinstatement of cocaine‐seeking. Although the TAAR1 partial agonist RO5263397 only partly blocked cocaine intake and did not prevent cocaine escalation, the present study further supports the critical role of TAAR1 in regulating cocaine‐related behaviours and suggests that TAAR1 agonists are promising pharmacological interventions to treat cocaine use disorder and relapse.

ACKNOWLEDGEMENT

This work was supported by the National Institutes of Health National Institute on Drug Abuse (Grants R21DA040777 and R01DA047967). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

AUTHOR CONTRIBUTIONS

J.L. and J.‐X.L. designed the study and prepared the manuscript; J.L., B.J., R.W., R.S., J.V. and Q.Z. performed all the behavioural studies; Y.Z. provided the TAAR1 agonists. All authors read and approved the final version of the manuscript.

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

DECLARATION OF TRANSPARENCY AND SCIENTIFIC RIGOUR

This Declaration acknowledges that this paper adheres to the principles for transparent reporting and scientific rigour of preclinical research as stated in the BJP guidelines for Design & Analysis, and Animal Experimentation, and as recommended by funding agencies, publishers and other organizations engaged with supporting research.

Liu J, Johnson B, Wu R, et al. TAAR1 agonists attenuate extended‐access cocaine self‐administration and yohimbine‐induced reinstatement of cocaine‐seeking. Br J Pharmacol. 2020;177:3403–3414. 10.1111/bph.15061

REFERENCES

  1. Achat‐Mendes, C. , Lynch, L. J. , Sullivan, K. A. , Vallender, E. J. , & Miller, G. M. (2012). Augmentation of methamphetamine‐induced behaviors in transgenic mice lacking the trace amine‐associated receptor 1. Pharmacology, Biochemistry, and Behavior, 101, 201–207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ahmed, S. H. , & Koob, G. F. (1998). Transition from moderate to excessive drug intake: Change in hedonic set point. Science, 282, 298–300. Alex GPCR [DOI] [PubMed] [Google Scholar]
  3. Anker, J. J. , & Carroll, M. E. (2010). Reinstatement of cocaine seeking induced by drugs, cues, and stress in adolescent and adult rats. Psychopharmacology, 208, 211–222. 10.1007/s00213-009-1721-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Borowsky, B. , Adham, N. , Jones, K. A. , Raddatz, R. , Artymyshyn, R. , Ogozalek, K. L. , … Gerald, C. (2001). Trace amines: Identification of a family of mammalian G protein‐coupled receptors. Proceedings of the National Academy of Sciences of the United States of America, 98, 8966–8971. 10.1073/pnas.151105198 [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bremner, J. D. , Krystal, J. H. , Southwick, S. M. , & Charney, D. S. (1996a). Noradrenergic mechanisms in stress and anxiety: I. Preclinical studies. Synapse, 23, 28–38. [DOI] [PubMed] [Google Scholar]
  6. Bremner, J. D. , Krystal, J. H. , Southwick, S. M. , & Charney, D. S. (1996b). Noradrenergic mechanisms in stress and anxiety: II. Clinical studies. Synapse, 23, 39–51. [DOI] [PubMed] [Google Scholar]
  7. Conio, B. , Martino, M. , Magioncalda, P. , Escelsior, A. , Inglese, M. , Amore, M. , & Northoff, G. (2020). Opposite effects of dopamine and serotonin on resting‐state networks: Review and implications for psychiatric disorders. Molecular Psychiatry, 25(1), 82–93. [DOI] [PubMed] [Google Scholar]
  8. Conrad, K. L. , Tseng, K. Y. , Uejima, J. L. , Reimers, J. M. , Heng, L. J. , Shaham, Y. , … Wolf, M. E. (2008). Formation of accumbens GluR2‐lacking AMPA receptors mediates incubation of cocaine craving. Nature, 454, 118–121. 10.1038/nature06995 [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Curtis, M. J. , Alexander, S. , Cirino, G. , Docherty, J. R. , George, C. H. , Giembycz, M. A. , … Ahluwalia, A. (2018). Experimental design and analysis and their reporting II: Updated and simplified guidance for authors and peer reviewers. British Journal of Pharmacology, 175, 987–993. 10.1111/bph.14153 [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dhillo, W. S. , Bewick, G. A. , White, N. E. , Gardiner, J. V. , Thompson, E. L. , Bataveljic, A. , … Bloom, S. R. (2009). The thyroid hormone derivative 3‐iodothyronamine increases food intake in rodents. Diabetes, Obesity & Metabolism, 11, 251–260. 10.1111/j.1463-1326.2008.00935.x [DOI] [PubMed] [Google Scholar]
  11. Dong, Y. , Taylor, J. R. , Wolf, M. E. , & Shaham, Y. (2017). Circuit and synaptic plasticity mechanisms of drug relapse. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 37, 10867–10876. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Edwards, S. , & Koob, G. F. (2013). Escalation of drug self‐administration as a hallmark of persistent addiction liability. Behavioural Pharmacology, 24, 356–362. 10.1097/FBP.0b013e3283644d15 [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Erb, S. , Shaham, Y. , & Stewart, J. (1996). Stress reinstates cocaine‐seeking behavior after prolonged extinction and a drug‐free period. Psychopharmacology, 128, 408–412. 10.1007/s002130050150 [DOI] [PubMed] [Google Scholar]
  14. Espinoza, S. , Ghisi, V. , Emanuele, M. , Leo, D. , Sukhanov, I. , Sotnikova, T. D. , … Gainetdinov, R. R. (2015). Postsynaptic D2 dopamine receptor supersensitivity in the striatum of mice lacking TAAR1. Neuropharmacology, 93, 308–313. 10.1016/j.neuropharm.2015.02.010 [DOI] [PubMed] [Google Scholar]
  15. Ferragud, A. , Howell, A. D. , Moore, C. F. , Ta, T. L. , Hoener, M. C. , Sabino, V. , & Cottone, P. (2017). The trace amine‐associated receptor 1 agonist RO5256390 blocks compulsive, binge‐like eating in rats. Neuropsychopharmacology, 42, 1458–1470. 10.1038/npp.2016.233 [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Funk, D. , Tamadon, S. , Coen, K. , Fletcher, P. J. , & Le, A. D. (2019). Kappa opioid receptors mediate yohimbine‐induced increases in impulsivity in the 5‐choice serial reaction time task. Behavioural Brain Research, 359, 258–265. 10.1016/j.bbr.2018.11.006 [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gainetdinov, R. R. , Hoener, M. C. , & Berry, M. D. (2018). Trace amines and their receptors. Pharmacological Reviews, 70, 549–620. 10.1124/pr.117.015305 [DOI] [PubMed] [Google Scholar]
  18. Gancarz‐Kausch, A. M. , Adank, D. N. , & Dietz, D. M. (2014). Prolonged withdrawal following cocaine self‐administration increases resistance to punishment in a cocaine binge. Scientific Reports, 4, 6876. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Grandy, D. K. (2007). Trace amine‐associated receptor 1—Family archetype or iconoclast? Pharmacology & Therapeutics, 116, 355–390. 10.1016/j.pharmthera.2007.06.007 [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Grimm, J. W. , Hope, B. T. , Wise, R. A. , & Shaham, Y. (2001). Neuroadaptation. Incubation of cocaine craving after withdrawal. Nature, 412, 141–142. 10.1038/35084134 [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Guillem, K. , & Ahmed, S. H. (2018). Incubation of accumbal neuronal reactivity to cocaine cues during abstinence predicts individual vulnerability to relapse. Neuropsychopharmacology, 43, 1059–1065. 10.1038/npp.2017.224 [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Harding, S. D. , Sharman, J. L. , Faccenda, E. , Southan, C. , Pawson, A. J. , Ireland, S. , … NC‐IUPHAR . (2018). The IUPHAR/BPS Guide to PHARMACOLOGY in 2018: Updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY. Nucleic Acids Research, 46, D1091–D1106. 10.1093/nar/gkx1121 [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hyman, S. E. , & Malenka, R. C. (2001). Addiction and the brain: The neurobiology of compulsion and its persistence. Nature Reviews Neuroscience, 2, 695–703. 10.1038/35094560 [DOI] [PubMed] [Google Scholar]
  24. Jing, L. , Zhang, Y. , & Li, J. X. (2014). Effects of the trace amine associated receptor 1 agonist RO5263397 on abuse‐related behavioral indices of methamphetamine in rats. The International Journal of Neuropsychopharmacology, 18, pyu060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kauer, J. A. , & Malenka, R. C. (2007). Synaptic plasticity and addiction. Nature Reviews Neuroscience, 8, 844–858. 10.1038/nrn2234 [DOI] [PubMed] [Google Scholar]
  26. Kilkenny, C. , Browne, W. , Cuthill, I. C. , Emerson, M. , & Altman, D. G. (2010). Animal research: Reporting in vivo experiments: The ARRIVE guidelines. British Journal of Pharmacology, 160, 1577–1579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kippin, T. E. , Fuchs, R. A. , & See, R. E. (2006). Contributions of prolonged contingent and noncontingent cocaine exposure to enhanced reinstatement of cocaine seeking in rats. Psychopharmacology, 187, 60–67. 10.1007/s00213-006-0386-3 [DOI] [PubMed] [Google Scholar]
  28. Koob, G. F. , & Volkow, N. D. (2010). Neurocircuitry of addiction. Neuropsychopharmacology, 35, 217–238. 10.1038/npp.2009.110 [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Le, A. D. , Harding, S. , Juzytsch, W. , Funk, D. , & Shaham, Y. (2005). Role of alpha‐2 adrenoceptors in stress‐induced reinstatement of alcohol seeking and alcohol self‐administration in rats. Psychopharmacology, 179, 366–373. 10.1007/s00213-004-2036-y [DOI] [PubMed] [Google Scholar]
  30. Lee, B. , Tiefenbacher, S. , Platt, D. M. , & Spealman, R. D. (2004). Pharmacological blockade of α2‐adrenoceptors induces reinstatement of cocaine‐seeking behavior in squirrel monkeys. Neuropsychopharmacology, 29, 686–693. 10.1038/sj.npp.1300391 [DOI] [PubMed] [Google Scholar]
  31. Leo, D. , Mus, L. , Espinoza, S. , Hoener, M. C. , Sotnikova, T. D. , & Gainetdinov, R. R. (2014). Taar1‐mediated modulation of presynaptic dopaminergic neurotransmission: Role of D2 dopamine autoreceptors. Neuropharmacology, 81, 283–291. 10.1016/j.neuropharm.2014.02.007 [DOI] [PubMed] [Google Scholar]
  32. Li, X. , Caprioli, D. , & Marchant, N. J. (2015). Recent updates on incubation of drug craving: A mini‐review. Addiction Biology, 20, 872–876. 10.1111/adb.12205 [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Liu, J. F. , & Li, J. X. (2018). TAAR1 in addiction: Looking beyond the tip of the iceberg. Frontiers in Pharmacology, 9, 279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Liu, J. F. , Seaman, R. Jr. , Siemian, J. N. , Bhimani, R. , Johnson, B. , Zhang, Y. , … Li, J. X. (2018). Role of trace amine‐associated receptor 1 in nicotine's behavioral and neurochemical effects. Neuropsychopharmacology, 43, 2435–2444. 10.1038/s41386-018-0017-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Liu, J. F. , Siemian, J. N. , Seaman, R. Jr. , Zhang, Y. , & Li, J. X. (2017). Role of TAAR1 within the subregions of the mesocorticolimbic dopaminergic system in cocaine‐seeking behavior. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 37, 882–892. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Liu, J. F. , Thorn, D. A. , Zhang, Y. , & Li, J. X. (2016). Effects of trace amine‐associated receptor 1 agonists on the expression, reconsolidation, and extinction of cocaine reward memory. The International Journal of Neuropsychopharmacology, 19, pyw009 10.1093/ijnp/pyw009 [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Manni, M. E. , De Siena, G. , Saba, A. , Marchini, M. , Dicembrini, I. , Bigagli, E. , … Raimondi, L. (2012). 3‐Iodothyronamine: A modulator of the hypothalamus‐pancreas‐thyroid axes in mice. British Journal of Pharmacology, 166, 650–658. 10.1111/j.1476-5381.2011.01823.x [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Mantsch, J. R. , Baker, D. A. , Francis, D. M. , Katz, E. S. , Hoks, M. A. , & Serge, J. P. (2008). Stressor‐ and corticotropin releasing factor‐induced reinstatement and active stress‐related behavioral responses are augmented following long‐access cocaine self‐administration by rats. Psychopharmacology, 195, 591–603. 10.1007/s00213-007-0950-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Mantsch, J. R. , Baker, D. A. , Funk, D. , Le, A. D. , & Shaham, Y. (2016). Stress‐induced reinstatement of drug seeking: 20 years of progress. Neuropsychopharmacology, 41, 335–356. 10.1038/npp.2015.142 [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. McGrath, J. C. , & Lilley, E. (2015). Implementing guidelines on reporting research using animals (ARRIVE etc.): New requirements for publication in BJP . British Journal of Pharmacology, 172, 3189–3193. 10.1111/bph.12955 [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Mesa‐Gresa, P. , Ramos‐Campos, M. , & Redolat, R. (2013). Enriched environments for rodents and their interaction with nicotine administration. Current Drug Abuse Reviews, 6, 191–200. 10.2174/187447370603140401224222 [DOI] [PubMed] [Google Scholar]
  42. Moran‐Santa Maria, M. M. , McRae‐Clark, A. , Baker, N. L. , Ramakrishnan, V. , & Brady, K. T. (2014). Yohimbine administration and cue‐reactivity in cocaine‐dependent individuals. Psychopharmacology, 231, 4157–4165. 10.1007/s00213-014-3555-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Pattij, T. , & De Vries, T. J. (2013). The role of impulsivity in relapse vulnerability. Current Opinion in Neurobiology, 23, 700–705. 10.1016/j.conb.2013.01.023 [DOI] [PubMed] [Google Scholar]
  44. Pei, Y. , Asif‐Malik, A. , Hoener, M. , & Canales, J. J. (2017). A partial trace amine‐associated receptor 1 agonist exhibits properties consistent with a methamphetamine substitution treatment. Addiction Biology, 22, 1246–1256. 10.1111/adb.12410 [DOI] [PubMed] [Google Scholar]
  45. Pei, Y. , Lee, J. , Leo, D. , Gainetdinov, R. R. , Hoener, M. C. , & Canales, J. J. (2014). Activation of the trace amine‐associated receptor 1 prevents relapse to cocaine seeking. Neuropsychopharmacology, 39, 2299–2308. 10.1038/npp.2014.88 [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Pelloux, Y. , Everitt, B. J. , & Dickinson, A. (2007). Compulsive drug seeking by rats under punishment: Effects of drug taking history. Psychopharmacology, 194, 127–137. 10.1007/s00213-007-0805-0 [DOI] [PubMed] [Google Scholar]
  47. Polter, A. M. , & Kauer, J. A. (2014). Stress and VTA synapses: Implications for addiction and depression. The European Journal of Neuroscience, 39, 1179–1188. 10.1111/ejn.12490 [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Revel, F. G. , Meyer, C. A. , Bradaia, A. , Jeanneau, K. , Calcagno, E. , Andre, C. B. , … Hoener, M. C. (2012). Brain‐specific overexpression of trace amine‐associated receptor 1 alters monoaminergic neurotransmission and decreases sensitivity to amphetamine. Neuropsychopharmacology, 37, 2580–2592. 10.1038/npp.2012.109 [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Revel, F. G. , Moreau, J. L. , Gainetdinov, R. R. , Bradaia, A. , Sotnikova, T. D. , Mory, R. , … Hoener, M. C. (2011). TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity. Proceedings of the National Academy of Sciences of the United States of America, 108, 8485–8490. 10.1073/pnas.1103029108 [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Revel, F. G. , Moreau, J. L. , Gainetdinov, R. R. , Ferragud, A. , Velazquez‐Sanchez, C. , Sotnikova, T. D. , … Hoener, M. C. (2012). Trace amine‐associated receptor 1 partial agonism reveals novel paradigm for neuropsychiatric therapeutics. Biological Psychiatry, 72, 934–942. 10.1016/j.biopsych.2012.05.014 [DOI] [PubMed] [Google Scholar]
  51. Revel, F. G. , Moreau, J. L. , Pouzet, B. , Mory, R. , Bradaia, A. , Buchy, D. , … Hoener, M. C. (2013). A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic‐ and antidepressant‐like activity, improve cognition and control body weight. Molecular Psychiatry, 18, 543–556. 10.1038/mp.2012.57 [DOI] [PubMed] [Google Scholar]
  52. Rutigliano, G. , Accorroni, A. , & Zucchi, R. (2017). The case for TAAR1 as a modulator of central nervous system function. Frontiers in Pharmacology, 8, 987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Shaham, Y. , Shalev, U. , Lu, L. , de Wit, H. , & Stewart, J. (2003). The reinstatement model of drug relapse: History, methodology and major findings. Psychopharmacology, 168, 3–20. 10.1007/s00213-002-1224-x [DOI] [PubMed] [Google Scholar]
  54. Shepard, J. D. , Bossert, J. M. , Liu, S. Y. , & Shaham, Y. (2004). The anxiogenic drug yohimbine reinstates methamphetamine seeking in a rat model of drug relapse. Biological Psychiatry, 55, 1082–1089. 10.1016/j.biopsych.2004.02.032 [DOI] [PubMed] [Google Scholar]
  55. Sukhanov, I. , Dorofeikova, M. , Dolgorukova, A. , Dorotenko, A. , & Gainetdinov, R. R. (2018). Trace amine‐associated receptor 1 modulates the locomotor and sensitization effects of nicotine. Frontiers in Pharmacology, 9, 329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Sun, H. , Green, T. A. , Theobald, D. E. , Birnbaum, S. G. , Graham, D. L. , Zeeb, F. D. , … Winstanley, C. A. (2010). Yohimbine increases impulsivity through activation of cAMP response element binding in the orbitofrontal cortex. Biological Psychiatry, 67, 649–656. 10.1016/j.biopsych.2009.11.030 [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Thorn, D. A. , Jing, L. , Qiu, Y. , Gancarz‐Kausch, A. M. , Galuska, C. M. , Dietz, D. M. , … Li, J. X. (2014). Effects of the trace amine‐associated receptor 1 agonist RO5263397 on abuse‐related effects of cocaine in rats. Neuropsychopharmacology, 39, 2309–2316. 10.1038/npp.2014.91 [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Venniro, M. , Caprioli, D. , & Shaham, Y. (2016). Animal models of drug relapse and craving: From drug priming‐induced reinstatement to incubation of craving after voluntary abstinence. Progress in Brain Research, 224, 25–52. 10.1016/bs.pbr.2015.08.004 [DOI] [PubMed] [Google Scholar]
  59. Volkow, N. D. , & Morales, M. (2015). The brain on drugs: From reward to addiction. Cell, 162, 712–725. 10.1016/j.cell.2015.07.046 [DOI] [PubMed] [Google Scholar]
  60. Xue, Z. , Siemian, J. N. , Johnson, B. N. , Zhang, Y. , & Li, J. X. (2018). Methamphetamine‐induced impulsivity during chronic methamphetamine treatment in rats: Effects of the TAAR 1 agonist RO5263397. Neuropharmacology, 129, 36–46. 10.1016/j.neuropharm.2017.11.012 [DOI] [PMC free article] [PubMed] [Google Scholar]

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