Efficacy of N-acetylcysteine in the prevention of alcohol relapse-like drinking: Study in long-term ethanol-experienced male rats.

Alcohol use disorders are chronic and highly relapsing disorders, thus alcoholic patients have a high rate of recidivism for drug use even after long periods of abstinence. The literature points to the potential usefulness of N-acetylcysteine (NAC) in the management of several substance use disorders probably due to its capacity to restore brain homeostasis of the glutamate system disrupted in addiction. However, there is little evidence in the case of alcohol. The aim of this study was to explore the potential anti-relapse efficacy of NAC using the alcohol deprivation effect (ADE) model in long-term experienced rats. Two experiments were performed in male Wistar rats to: (a) test the efficacy of NAC to prevent relapse and (b) discriminate the best administration schedule (intermittent vs. continuous) for NAC. In the first experiment, animals were implanted with mini-osmotic pumps delivering 0 or 1 mg/hr NAC during 14 days. In a second experiment, rats received 0, 60, or 100 mg/kg once daily by subcutaneous injection. The efficacy to prevent ADE was evaluated in both experiments. NAC subcutaneously administered, either by continuous infusion or by intermittent injections regimen, is able to block the ADE. The best results were obtained after using 60 mg/kg NAC dose. Our findings support the hypothesis that NAC may represent a valuable therapy in the management of alcohol relapse.

Low-dose polypharmacology targeting dopamine D1 and D3 receptors reduces cue-induced relapse to heroin seeking in rats.

Chemical compounds that target dopamine (DA) D1 or D3 receptors have shown promise as potential interventions in animal models of cue-induced relapse. However, undesirable side effects or pharmacodynamic profiles have limited the advancement of new compounds in preclinical studies when administered as independent treatments. In this series of experiments, we explored the effects of coadministration of a D1-receptor partial agonist (SKF 77434) and a D3-receptor antagonist (NGB 2904) in heroin-seeking rats within a "conflict" model of abstinence and cue-induced relapse. Rats were first trained to press a lever to self-administer heroin, and drug delivery was paired contingently with cues (e.g., light and pump noise). Self-initiated abstinence was facilitated by applying electrical current to the flooring in front of the levers. Lastly, a relapse response was provoked by noncontingent presentation of conditioned cues. Prior to provocation, rats received a systemic injection of SKF 77434, NGB 2904, or a combination of both compounds to assess treatment effects on lever pressing. Results indicated that the coadministration of low (i.e., independently ineffective) doses of both compounds was more effective in reducing cue-induced relapse to heroin seeking than either compound alone, with some evidence of drug synergism. Follow-up studies indicated that this reduction was not due to motoric impairment nor enhanced sensitivity to the electrified flooring and that this treatment did not significantly affect motivation for food. Implications for the treatment of opiate use disorder and recommendations for further research are discussed.

Chloral Hydrate Alters Brain Activation Induced by Methamphetamine-Associated Cue and Prevents Relapse.

Methamphetamine is a highly addictive drug and its abuse leads to serious health and social problems. Until now, no effective medications are yet available for the treatment of methamphetamine addiction. Our study reveals that chloral hydrate, a clinical sedative drug, suppresses the seeking desire for methamphetamine. After 5 days of continuous administration (subanesthetic dose 50 mg/kg and 100 mg/kg), methamphetamine-seeking behavior of rats was inhibited in the condition place preference and intravenous self-administration tests. Furthermore, chloral hydrate treatment robustly suppressed cue-induced methamphetamine relapse. The whole brain c-fos immunostaining revealed that chloral hydrate treatment suppressed neuronal activity in the rhomboid thalamic nucleus (Rh), dorsal endopiriform nucleus (dEn), and claustrum (Cl) while enhanced zona incerta (ZI) activity during cue-induced methamphetamine relapse. Therefore, chloral hydrate could remodel neural network activity and serve as a potential medicine to treat methamphetamine addiction.