Department of Biomedical Sciences, Neuropsychopharmacology Section, University of Cagliari, Cagliari, Italy.
Institute of Neuroscience, Cagliari Section, National Research Council of Italy, Cagliari, Italy.
Neuropharmacology. 2020 Apr;166:107974. doi: 10.1016/j.neuropharm.2020.107974. Epub 2020 Jan 22.
On the basis of epidemiological studies it has been proposed that cannabis use plays a causal role in the abuse of highly addictive drugs (Gateway Hypothesis). However, epidemiological studies are intrinsically unable to provide evidence of causality. Experimental studies can provide this evidence but they are feasible only in animal models and to date such evidence is lacking. In view of the importance of genetic factors in drug abuse, we investigated the influence of adolescent cannabis exposure on adult heroin reinforcement in two inbred rat strains differentially vulnerable to drugs of abuse, addiction prone Lewis (LEW) and addiction resistant Fischer 344 (F344) strains. Male LEW and F344 rats aged six weeks were exposed to increasing Δ-tetrahydrocannabinol (THC) doses, twice a day for 3 days (2, 4, 8 mg/kg, i.p.). At adulthood they were allowed to self-administer heroin (0.025 mg/kg) under both Fixed- (FR) and Progressive- (PR) ratio schedules of responding. Following extinction, responding was reinstated by drug-cues and/or by heroin priming. THC pre-exposure increased responding for heroin and heroin intake under FR-3 and FR-5 as well as PR protocols and increased breaking point in PR schedules in LEW but not F344 rats. Drug cues and heroin priming reinstated responding in LEW and F344, but THC pre-exposure increased reinstatement by priming in LEW rats and by cues in F344 rats. These observations show that in genetically predisposed individuals, adolescent cannabis exposure increases heroin reinforcing properties, thus providing a mechanism for a causal role of adolescent cannabis use in heroin abuse.
基于流行病学研究，人们提出大麻的使用在高度成瘾药物的滥用中起着因果作用（“门户假说”）。然而，流行病学研究本质上无法提供因果关系的证据。实验研究可以提供这种证据，但它们仅在动物模型中可行，而且迄今为止，这种证据还很缺乏。鉴于遗传因素在药物滥用中的重要性，我们研究了青少年大麻暴露对两种对滥用药物易感的近交系大鼠（易成瘾的 Lewis [LEW]和不易成瘾的 Fischer 344 [F344]）成年后海洛因强化的影响。六周龄雄性 LEW 和 F344 大鼠每天两次接受递增的 Δ-四氢大麻酚（THC）剂量，共 3 天（2、4、8mg/kg，ip）。成年后，它们被允许在固定（FR）和递增（PR）比率反应方案下自行服用海洛因（0.025mg/kg）。在消退后，通过药物线索和/或海洛因启动来恢复反应。与 F344 大鼠相比，THC 预暴露增加了 LEW 大鼠在 FR-3 和 FR-5 以及 PR 方案下的海洛因反应和海洛因摄入，并增加了 PR 方案中的突破点。药物线索和海洛因启动恢复了 LEW 和 F344 大鼠的反应，但 THC 预暴露增加了 LEW 大鼠通过启动和 F344 大鼠通过线索恢复的反应。这些观察结果表明，在遗传易感性个体中，青少年大麻暴露增加了海洛因的强化作用，从而为青少年大麻使用在海洛因滥用中起因果作用提供了一种机制。
