阻断 D3 受体可防止社交应激和可卡因引发的可卡因 CPP 复吸引起的中脑边缘多巴胺能回路中 DAT 和 D3R 表达的变化。

Blockade of D3 receptor prevents changes in DAT and D3R expression in the mesolimbic dopaminergic circuit produced by social stress- and cocaine prime-induced reinstatement of cocaine-CPP.

机构信息

Group of Cellular and Molecular Pharmacology, Department of Pharmacology, University of Murcia, Campus de Ciencias de la Salud, Murcia, Spain.

Murcia Research Institute of Health Sciences (IMIB), Avda. Buenavista, Murcia, Spain.

出版信息

J Psychopharmacol. 2020 Nov;34(11):1300-1315. doi: 10.1177/0269881120936468. Epub 2020 Jul 10.

DOI:10.1177/0269881120936468

PMID:32648812

Abstract

BACKGROUND

Cocaine may cause persistent changes in the brain, which are more apparent in DA transporter (DAT) and DA receptor availability within the nucleus accumbens (NAc). On the other hand, the DA D3 receptor (D3R) has emerged as a promising pharmacotherapeutic target for substance use disorders.

AIMS

This study aims to assess the impact of selective D3R antagonism on DAT and D3R after reinstatement of cocaine preference (CPP) induced by an acute session of social defeat stress (SDS) and a cocaine prime in mice after a period of abstinence.

METHODS

Male mice were conditioned with 25 mg/kg of cocaine for 4 days. After 60 days of extinction training mice were pretreated with the selective D3R antagonist SB-277011A before the re-exposure to a priming dose of cocaine or to a single SDS session. CPP scores were determined and levels of DAT, D3R, phospho Akt (pAkt) and phospho mTOR (pmTOR) were assessed in the NAc shell.

RESULTS

An increase in DAT and D3R expression was seen in the NAc after both a cocaine prime- and SDS-induced reinstatement of CPP. Pretreatment with SB-277011A blocked elevated DAT and D3R expression as well as SDS-induced reinstatement. By contrast, the blockade of D3R did not modified the cocaine prime-induced CPP. Changes in DAT and D3R expression do not seem to occur via the canonic pathway involving Akt/mTOR.

CONCLUSIONS

Our results suggest that the selective D3R antagonist ability to inhibit DAT and D3R up-regulation could represent a possible mechanism for its behavioral effects in cocaine-memories reinstatement induced by social stress.

摘要

背景

可卡因可能会导致大脑发生持久变化，在伏隔核（NAc）中多巴胺转运体（DAT）和多巴胺受体的可及性方面更为明显。另一方面，多巴胺 D3 受体（D3R）已成为治疗物质使用障碍的有希望的药物治疗靶点。

目的

本研究旨在评估选择性 D3R 拮抗剂对可卡因偏好复燃（CPP）后 DAT 和 D3R 的影响，可卡因偏好复燃由急性社交挫败应激（SDS）和一段禁欲期后的可卡因引发。

方法

雄性小鼠用 25mg/kg 的可卡因进行 4 天的条件训练。在 60 天的消退训练后，用选择性 D3R 拮抗剂 SB-277011A 预处理，然后再次暴露于可卡因引发剂量或单次 SDS 中。测定 CPP 评分，并评估 NAc 壳内的 DAT、D3R、磷酸化 Akt（pAkt）和磷酸化 mTOR（pmTOR）水平。

结果

可卡因引发和 SDS 引发 CPP 复燃后，NAc 中 DAT 和 D3R 的表达增加。SB-277011A 预处理可阻断 DAT 和 D3R 的表达上调以及 SDS 诱导的 CPP 复燃。相反，D3R 阻断剂不改变可卡因引发的 CPP。DAT 和 D3R 表达的变化似乎不通过涉及 Akt/mTOR 的经典途径发生。