Smaga Irena, Wydra Karolina, Piechota Marcin, Caffino Lucia, Fumagalli Fabio, Sanak Marek, Filip Małgorzata
Maj Institute of Pharmacology Polish Academy of Sciences, Department of Drug Addiction Pharmacology, Smętna 12, PL 31-343 Kraków, Poland.
Maj Institute of Pharmacology Polish Academy of Sciences, Department of Drug Addiction Pharmacology, Smętna 12, PL 31-343 Kraków, Poland.
Prog Neuropsychopharmacol Biol Psychiatry. 2021 Jul 13;109:110248. doi: 10.1016/j.pnpbp.2021.110248. Epub 2021 Jan 22.
Cocaine use disorder develops in part due to the strong associations formed between drugs and the stimuli associated with drug use. Recently, treatment strategies including manipulations of drug-associated memories have been investigated, and the possibility of interfering with N-methyl-d-aspartate (NMDA)-mediated neurotransmission may represent an important option. The aim of this study was to examine the significance of the NMDA receptor subunit GluN2B at the molecular level (the expression of the GluN2B subunit, the Grin2B gene and the association of GluN2B with postsynaptic density protein 95 (PSD95)) in the brain structures of rats with a history of cocaine self-administration after i) cocaine abstinence with extinction training or ii) cocaine abstinence without instrumental tasks, as well as at the pharmacological level (peripheral or intracranial administration of CP 101,606, a GluN2B subunit antagonist during the cocaine- or cue-induced reinstatement). The GluN2B subunit levels and the GluN2B/PSD95 complex levels were either increased in the ventral hippocampus (vHIP) with higher levels of Grin2B gene expression in the HIP or decreased in the dorsal striatum (dSTR) after cocaine abstinence with extinction training. Moreover, CP 101,606, a GluN2B subunit antagonist, administered peripherally, attenuated the reinstatement of active lever presses induced by a priming dose of cocaine or by drug-associated conditioned stimuli, while injection into the vHIP reduced the cocaine- or cue with the subthreshold dose of cocaine-induced reinstatement. In cocaine abstinence without instrumental tasks, an increase in the GluN2B subunit levels and the level of the GluN2B/PSD95 complex in the dSTR was observed in rats that had previously self-administered cocaine. In conclusion, cocaine abstinence with extinction training seems to be associated with the up-regulation of the hippocampal GluN2B subunits, which seems to control cocaine-seeking behavior.
可卡因使用障碍的形成部分归因于药物与药物使用相关刺激之间形成的强烈关联。最近，包括操纵与药物相关记忆在内的治疗策略已被研究，而干扰N-甲基-D-天冬氨酸（NMDA）介导的神经传递的可能性可能是一个重要选择。本研究的目的是在分子水平上（GluN2B亚基的表达、Grin2B基因的表达以及GluN2B与突触后致密蛋白95（PSD95）的关联）检查NMDA受体亚基GluN2B在有可卡因自我给药史的大鼠脑结构中的意义，这些大鼠在以下两种情况下：i）可卡因戒断并进行消退训练，或ii）可卡因戒断但无操作性任务，以及在药理学水平上（在可卡因或线索诱导的复吸期间外周或颅内给予GluN2B亚基拮抗剂CP 101,606）。在进行消退训练的可卡因戒断后，腹侧海马（vHIP）中GluN2B亚基水平和GluN2B/PSD95复合物水平升高，海马中Grin2B基因表达水平也较高，而背侧纹状体（dSTR）中这些水平则降低。此外，外周给予GluN2B亚基拮抗剂CP 101,606可减弱由可卡因引发剂量或药物相关条件刺激诱导的主动压杆复吸，而注射到vHIP中可降低可卡因或线索与阈下剂量可卡因诱导的复吸。在无操作性任务的可卡因戒断中，在先前自我给药可卡因的大鼠中观察到dSTR中GluN2B亚基水平和GluN2B/PSD95复合物水平升高。总之，可卡因戒断并进行消退训练似乎与海马GluN2B亚基的上调有关，这似乎控制着觅药行为。
