Cognitive Enhancer Donepezil Attenuates Heroin-Seeking Behavior Induced by Cues in Rats.

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.

The effect of electroacupuncture on extinction responding of heroin-seeking behavior and FosB expression in the nucleus accumbens core.

Augmentation of extinction with learning enhancing therapy may offer an effective strategy to combat heroin relapse. Our lab previously found that electroacupuncture (EA) not only significantly reduced cue-induced reinstatement of heroin seeking but also exhibited a promoting effect on the ability of learning and memory. In the present study, we further investigated the effects of EA on the extinction of heroin-seeking behavior in rats with a history of intravenous heroin self-administration. We trained Sprague-Dawley rats to nose-poke for i.v. heroin either daily for 4h or 25 infusions for 14 consecutive days; then the rats underwent 7 daily 3h extinction sessions in the operant chamber. To assess EA's effects on the extinction response of heroin-associated cues, 2Hz EA was administered 1h before each of the 7 extinction sessions. We also applied immunohistochemistry to detect FosB-positive nuclei in the nucleus accumbens core. We found that EA treatment facilitated the extinction response of heroin seeking but did not alter the locomotor activity in an open field testing environment. EA stimulation attenuated the FosB expression in the core of the nucleus accumbens, a brain region involved in the learning and execution of motor responses. Altogether, these results suggest that EA may provide a novel nonpharmacological approach to enhance extinction learning when combined with extinction therapy for the treatment of heroin addiction.

Electroacupuncture suppresses discrete cue-evoked heroin-seeking and fos protein expression in the nucleus accumbens core in rats.

Relapse to drug seeking was studied using a rodent model of reinstatement induced by exposure to drug-related cues. Here, we used intravenous drug self-administration procedures in rats to further investigate the beneficial effects of electroacupuncture (EA) on heroin-seeking behavior in a reinstatement model of relapse. We trained Sprague-Dawley rats to nose-poke for i.v. heroin either daily for 4 h or 25 infusions for 14 consecutive days. Then the rats were abstinent from heroin for two weeks. 2 Hz EA stimulation was conducted once daily for 14 days during heroin abstinence. We tested these animals for contextual and discrete cue-induced reinstatement of active responses. We also applied immunohistochemistry to detect Fos-positive nuclei in the nucleus accumbens (NACc) core and shell after reinstatement test. We found that active responses elicited by both contextual cues and discrete cues were high in the rats trained with heroin than in saline controls. EA treatment significantly reduced active responses elicited by discrete cues. EA stimulation attenuated Fos expression in the core but not the shell of the NACc. Altogether, these results highlight the therapeutic benefit of EA in preventing relapse to drug addiction.