Abstract
Alcohol use disorder (AUD) is one of the foremost public health problems. Alcohol is also frequently co-abused with cocaine. There is a huge unmet need for the treatment of AUD and/or cocaine co-abuse. We recently demonstrated that skin grafts generated from mouse epidermal stem cells that had been engineered by CRISPR-mediated genome editing could be transplanted onto mice as a gene delivery platform. Here, we show that expression of the glucagon-like peptide-1 (GLP1) gene delivered by epidermal stem cells attenuated development and reinstatement of alcohol-induced drug-taking and seeking as well as voluntary oral alcohol consumption. GLP1 derived from the skin grafts decreased alcohol-induced increase in dopamine levels in the nucleus accumbens. In exploring the potential of this platform in reducing concurrent use of drugs, we developed a novel co-grafting procedure for both modified human butyrylcholinesterase (hBChE)- and GLP1-expressing cells. Epidermal stem cell-derived hBChE and GLP1 reduced acquisition of drug-taking and toxicity induced by alcohol and cocaine co-administration. These results imply that cutaneous gene delivery through skin transplants may add a new option to treat drug abuse and co-abuse.
Highlights
Alcohol use disorder (AUD) is a chronic brain disease and one of the foremost public health problems [1]
GLP1 receptors (GLP1R) activation, either by glucagon-like peptide-1 (GLP1) or GLP1R agonists, is able to attenuate the rewarding effects of alcohol [19, 20]
Following a priming i.p. alcohol injection (0.5 g/kg), GWT mice but not GGLP1 mice exhibited a preference for the alcohol-paired environment (Fig. 1b), indicating that GLP1 produced by the skin grafts can prevent the reinstatement of drug-seeking induced by alcohol
Summary
Alcohol use disorder (AUD) is a chronic brain disease and one of the foremost public health problems [1]. The lifetime prevalence of occurrence of comorbid alcoholism in cocaine abusers is 60–85% [3, 4]. Concurrent use of alcohol and cocaine produces cocaethylene which inhibits the dopamine (DA) transporter and produces euphoria [5], and it has cardiotoxic effects by blocking cellular sodium. These authors contributed : Qingyao Kong, Yuanyuan Li channels with a potency that is equal to or greater than cocaine [6, 7]. There is a huge unmet need for the treatment of AUD and/or cocaine co-abuse
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