Adolescent cannabis exposure increases heroin reinforcement in rats genetically vulnerable to addiction

• Published in: Neuropharmacology Vol. 166; p. 107974
• Main Authors: Lecca, Daniele, Scifo, Andrea, Pisanu, Augusta, Valentini, Valentina, Piras, Giovanna, Sil, Annesha, Cadoni, Cristina, Di Chiara, Gaetano
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-04-2020
• Subjects: Adolescence; Age Factors; Analgesics, Opioid - administration & dosage; Animals; Behavior, Addictive - chemically induced; Behavior, Addictive - genetics; Behavior, Addictive - psychology; Cannabis; Dronabinol - administration & dosage; Gateway hypothesis; Genetic vulnerability; Heroin; Heroin - administration & dosage; Male; Rats; Rats, Inbred F344; Rats, Inbred Lew; Rats, Transgenic; Reinforcement, Psychology; Self Administration; Δ9-tetrahydrocannabinol; Adolescence; Self-administration; PR; FR; F344; THC; SA; Gateway hypothesis; NAc; Genetic vulnerability; Δ9-tetrahydrocannabinol; Heroin; LEW; Δ-tetrahydrocannabinol
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2020.107974

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 Δ9-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.
•Genetic background affects the outcome of adolescent cannabis exposure.•THC exposure increases heroin reinforcing properties in LEW addiction prone rats.•LEW, but not F344 rats, show increased motivation for heroin following THC.•THC exposure increases reinstatement by cues in F344 and by priming in LEW rats.•A common liability mechanism might be at the basis of THC gateway effect.