The Adenosine A2A Receptor Activation in Nucleus Accumbens Suppress Cue-Induced Reinstatement of Propofol Self-administration in Rats

Zhanglei Dong,Han Lin,Bingwu Huang,Qingquan Lian,Chenchen Jiang,Jiangfan Chen,Binbin Wu

doi:10.1007/s11064-021-03238-9

Abstract

Propofol has shown strong addictive properties in rats and humans. Adenosine A2A receptors (A2AR) in the nucleus accumbens (NAc) modulate dopamine signal and addictive behaviors such as cocaine- and amphetamine-induced self-administration. However, whether A2AR can modulate propofol addiction remains unknown. AAV-shA2AR was intra-NAc injected 3 weeks before the propofol self-administration training to test the impacts of NAc A2AR on establishing the self-administration model with fixed ratio 1 (FR1) schedule. Thereafter, the rats were withdrawal from propofol for 14 days and tested cue-induced reinstatement of propofol seeking behavior on day 15. The propofol withdrawal rats received one of the doses of CGS21680 (A2AR agonist, 2.5–10.0 ng/site), MSX-3 (A2AR antagonist, 5.0–20.0 μg/site) or eticlopride (D2 receptor (D2R) antagonist, 0.75–3.0 μg/site) or vehicle via intra-NAc injection before relapse behavior test. The numbers of active and inactive nose-poke response were recorded. Focal knockdown A2AR by shA2AR did not affect the acquisition of propofol self-administration behavior, but enhance cue-induced reinstatement of propofol self-administration compared with the AAV-shCTRLgroup. Pharmacological activation of the A2AR by CGS21680 (≥ 5.0 ng/site) attenuated cue-induced reinstatement of propofol self-administration behavior. Similarly, pharmacological blockade of D2R by eticlopride (0.75–3.0 μg/site) attenuated propofol seeking behavior. These effects were reversed by the administration of MSX-3 (5.0–20.0 μg/site). The A2AR- and D2R-mediated effects on propofol relapse were not confounded by the learning process, and motor activity as the sucrose self-administration and locomotor activity were not affected by all the treatments. This study provides genetic and pharmacological evidence that NAc A2AR activation suppresses cue-induced propofol relapse in rats, possibly by interacting with D2R.

Highlights

Drug use disorder results in global health issues and massive economic losses, and relapse is the severest limitation and barrier to successful drug use disorder treatment after periods of abstinence [1, 2]
Some brain regions are implicated in the development of drug reward, craving and relapse, and the foremost among these regions include a mesolimbic dopaminergic system that projected from the ventral tegmental area to the ventral striatum of nucleus accumbens (NAc), which is considered as the common final pathway of drug reward [14]
We examined the effects of the adenosine A2A receptors (A2AR) in the NAc on propofol self-administration model establishment and the cue-induced reinstatement of propofol self-administration behaviors

Summary

Introduction

Drug use disorder results in global health issues and massive economic losses, and relapse is the severest limitation and barrier to successful drug use disorder treatment after periods of abstinence [1, 2]. Some brain regions are implicated in the development of drug reward, craving and relapse, and the foremost among these regions include a mesolimbic dopaminergic system that projected from the ventral tegmental area to the ventral striatum of nucleus accumbens (NAc), which is considered as the common final pathway of drug reward [14]. Multiple drugs implement their reward effects by increasing the dopamine (DA) level in NAc by promoting DA release or inhibiting DA reuptake [15, 16]. The sucrose self-administration and locomotor activities were tested to identify the specificity of A2AR and D2R on propofol relapse

Materials and Methods

Results

Compliance with ethical standards