IMR Press / JIN / Volume 22 / Issue 3 / DOI: 10.31083/j.jin2203076
Open Access Original Research
Cognitive Enhancer Donepezil Attenuates Heroin-Seeking Behavior Induced by Cues in Rats
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1 Zhejiang Provincial Key Lab of Addiction, Ningbo University School of Medicine, 315211 Ningbo, Zhejiang, China
2 Lab of Behavioral Neuroscience, Ningbo Addiction Research and Treatment Center, Key Laboratory of Addiction Research of Zhejiang Province, Ningbo Kangning Hospital, Ningbo University School of Medicine, 315211 Ningbo, Zhejiang, China
3 The Affiliated Hospital of Medical School, Ningbo University, 315211 Ningbo, Zhejiang, China
*Correspondence: (Wenhua Zhou)
J. Integr. Neurosci. 2023, 22(3), 76;
Submitted: 15 August 2022 | Revised: 18 October 2022 | Accepted: 21 October 2022 | Published: 16 May 2023
Copyright: © 2023 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.

Purpose: Opioid use disorder is a significant global problem. Chronic heroin use is associated with impairment of cognitive function and conscious control ability. The cholinergic system can be disrupted following heroin administration, indicating that activation of the cholinergic system may prevent chronic heroin misuse. Donepezil as an inhibitor of cholinesterase has been reported to clinically improve cognition and attention. In this study, the inhibition of heroin self-administration and heroin-seeking behaviours by donepezil were evaluated in rats. Methods: Rats were trained to self-administer heroin every four hours for 14 consecutive days under a fixed ratio 1 (FR1) reinforcement schedule, then underwent withdrawal for two weeks. A progressive ratio schedule was then used to evaluate the relative motivational value of heroin reinforcement. After withdrawal, a conditioned cue was introduced for the reinstatement of heroin-seeking behaviour. Donepezil (0.3–3 mg/kg, i.p.) was used during both the FR1 heroin self-administration and progressive ratio schedules. Immunohistochemistry was used to investigate the mechanism of action of donepezil in the rat brain. Results: Pre-treatment with high dose donepezil (3 mg/kg) but not low doses (0.3–1 mg/kg) significantly inhibited heroin self-administration under the FR1 schedule. Donepezil decreased motivation values under the progressive ratio schedule in a dose-dependent manner. All doses of donepezil (1–3 mg/kg) decreased the reinstatement of heroin seeking induced by cues. Correlation analysis indicated that the inhibition of donepezil on heroin-seeking behaviour was positively correlated with an increased expression of dopamine receptor 1 (D1R) and dopamine receptor 2 (D2R) in the nucleus accumbens (NAc) and increased expression of choline acetyltransferase (ChAT) in the ventral tegmental area (VTA). Conclusions: The present study demonstrated that donepezil could inhibit heroin intake and heroin-seeking behaviour. Further, donepezil could regulate dopamine receptors in the NAc via an increase of acetylcholine. These results suggested that donepezil could be developed as a potential approach for the treatment of heroin misuse.

drug use disorder
cholinesterase inhibitor
81671321/National Nature Science Foundation
2017YFC1310403/National Key Research and Development Program of China Grant
ZJDKF202003/Foundation of Key Laboratory of Addiction Research of Zhejiang Province
00-F06/Zhejiang Medical and Health Leading Academic Discipline Project
Fig. 1.
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