TA₁ agonists attenuate extended‐access cocaine self‐administration and yohimbine‐induced reinstatement of cocaine‐seeking

Abstract

Trace amine‐associated receptor 1 (TAAR1) is the best‐characterized sub‐family of receptors of trace amines. As a modulator of dopaminergic system, TAAR1 has been shown to play a critical role in regulating the rewarding properties of drugs of abuse such as cocaine. In our previous studies, we demonstrated that TAAR1 agonists were able to reduce cocaine intake and cue‐ and drug‐induced reinstatements of cocaine‐seeking under short‐access conditions. However, compared to the extended access of cocaine self‐administration model, the short‐access model could not mimic some core properties of addiction, such as escalation, compulsive motivation, and incubation of cocaine‐seeking. Furthermore, it remains unclear whether activation of TAAR1 would affect stress‐induced reinstatement of cocaine‐seeking. Here, we investigated the effects of TAAR1 partial agonist RO5263397 on the extended access of cocaine self‐administration. We also assessed the effects of the selective TAAR1 full agonist RO5166017 on the yohimbine‐induced reinstatement of cocaine‐seeking. We found that the TAAR1 partial agonist RO5263397 attenuated the escalation, break point, and cue‐seeking behavior in the extended access of cocaine self‐administration model. We also found that RO5166017 reduced yohimbine‐induced reinstatement of cocaine‐seeking and yohimbine‐potentiated cue‐induced reinstatement of cocaine seeking, indicating that activation of TAAR1 decreased the stress‐induced reinstatement of cocaine‐seeking. Taken together, our results suggest that TAAR1 is a promising therapeutic target for the treatment of cocaine addiction. Support or Funding Information This work was supported by the National Institute of Health Grants R21‐DA033426. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Activation of trace amine‐associated receptor 1 attenuates nicotine withdrawal‐related effects

“…We found that rats from ShA group had more infusions than rats from ShA group, which is consistent with previous studies that demonstrate higher drug intake in extended‐access models 31,32 . Moreover, we found that rats with LA of nicotine did not show an escalation of drug intake as compared with studies that utilized extended‐access of cocaine self‐administration, 39–42 as shown by relatively stable nicotine infusions during the maintenance phase in LA rats. Consistently, studies have shown that extended‐access of nicotine did not result in increased self‐administration 31,32 .…”

“…For example, studies showed that TAAR1 agonists attenuated stress‐induced hyperthermia 68,69 . In our most recent study, TAAR1 activation was shown to abolish the reinstatement of cocaine seeking induced by yohimbine, 42 a pharmacological stressor that can produce anxiety‐ and stress‐like state by increasing the norepinephrine (NE) and cortisol levels 70 . Thus, it is possible that TAAR1 activation may counteract with the stress‐like state induced by nicotine withdrawal and attenuate negative reinforcement of nicotine addiction.…”

“…31,32 This disparity can be explained by the different pharmacological properties of drug actions. Although the effects of cocaine can be increased by extended self-administration, 42 nicotine acetylcholine receptors (nAChRs) desensitize fast to nicotine exposure in both humans and rats. 43,44 On the other hand, both clinical and preclinical studies show that nicotine dependent subjects tend to maintain a stable daily nicotine intake, which may involve the possible aversion induced by high dose nicotine.…”

Activation of trace amine‐associated receptor 1 selectively attenuates the reinforcing effects of morphine

“…Our recent study showed that activation of TA 1 receptors attenuated the pharmacological stressor yohimbine‐induced reinstatement of cocaine‐seeking behaviour, suggesting that these receptors might regulate stress responses to contribute to drug addiction (Liu, Johnson, et al, 2020). Evidence shows that the brain stress systems regulate negative reinforcement associated with opioid withdrawal (Koob, 2020).…”

Residues of ractopamine, a livestock feed additive, in meat might alleviate misuse of cocaine, nicotine, methamphetamine, and morphine

“…Astonishing supporting evidence came from experiments on rats as shown by one group that TAAR1 agonists efficiently suppressed the rewarding and reinforcing phenomenon of cocaine in self-administration and intracranial self-stimulation models (Pei et al, 2015). In another study, activation of TAAR1 by agonists attenuated extended access cocaine intake, decreased cue-induced cocaine-seeking after prolonged abstinence, and eliminated stress-induced cocaine reinstatement (Liu et al, 2020a).…”