¹Department of Clinical Neuroscience, Karolinska Institutet, Psychiatry Section, Stockholm, Sweden

Correspondence: Professor Y Hurd, Mount Sinai School of Medicine, Departments of Psychiatry and Pharmacology and Biological Chemistry, One Gustave Levy Place, Box 1215, New York, NY 10029, USA. Tel: +1 212 659 1740, Fax: +1 212 831 0114, E-mail: Yasmin.Hurd@mssm.edu

Received 26 September 2005; Revised 24 April 2006; Accepted 11 May 2006; Published online 5 July 2006.

Abstract

Cannabis use is a hypothesized gateway to subsequent abuse of other drugs such as heroin. We currently assessed whether -9-tetrahydrocannabinol (THC) exposure during adolescence modulates opiate reinforcement and opioid neural systems in adulthood. Long–Evan male rats received THC (1.5 mg/kg intraperitoneally (i.p.)) or vehicle every third day during postnatal days (PNDs) 28–49. Heroin self-administration behavior (fixed ratio-1; 3-h sessions) was studied from young adulthood (PND 57) into full adults (PND 102). THC-pretreated rats showed an upward shift throughout the heroin self-administration acquisition (30 g/kg/infusion) phase, whereas control animals maintained the same pattern once stable intake was obtained. Heightened opiate sensitivity in THC animals was also evidenced by higher heroin consumption during the maintenance phase (30 and 60 g/kg/infusion) and greater responding for moderate–low heroin doses (dose–response curve: 7.5, 15, 30, 60, and 100 g/kg/injection). Specific disturbance of the endogenous opioid system was also apparent in the brain of adults with adolescent THC exposure. Striatal preproenkephalin mRNA expression was exclusively increased in the nucleus accumbens (NAc) shell; the relative elevation of preproenkephalin mRNA in the THC rats was maintained even after heroin self-administration. Moreover, opioid receptor (OR) GTP-coupling was potentiated in mesolimbic and nigrostriatal brainstem regions in THC-pretreated animals. OR function in the NAc shell was specifically correlated to heroin intake. The current findings support the gateway hypothesis demonstrating that adolescence cannabis exposure has an enduring impact on hedonic processing resulting in enhanced opiate intake, possibly as a consequence of alterations in limbic opioid neuronal populations.