Maternal cannabis use alters ventral striatal dopamine D2 gene regulation in the offspring.

BACKGROUND: Prenatal cannabis exposure has been linked to addiction vulnerability, but the neurobiology underlying this risk is unknown. METHODS: Striatal dopamine and opioid-related genes were studied in human fetal subjects exposed to cannabis (as well as cigarettes and alcohol). Cannabis-related gene disturbances observed in the human fetus were subsequently characterized with an animal model of prenatal Δ-9-tetrahydrocannabinol (THC) (.15 mg/kg) exposure. RESULTS: Prenatal cannabis exposure decreased dopamine receptor D2 (DRD2) messenger RNA expression in the human ventral striatum (nucleus accumbens [NAc]), a key brain reward region. No significant alterations were observed for the other genes in cannabis-exposed subjects. Maternal cigarette use was associated with reduced NAc prodynorphin messenger RNA expression, and alcohol exposure induced broad alterations primarily in the dorsal striatum of most genes. To explore the mechanisms underlying the cannabis-associated disturbances, we exposed pregnant rats to THC and examined the epigenetic regulation of the NAc Drd2 gene in their offspring at postnatal day 2, comparable to the human fetal period studied, and in adulthood. Chromatin immunoprecipitation of the adult NAc revealed increased 2meH3K9 repressive mark and decreased 3meH3K4 and RNA polymerase II at the Drd2 gene locus in the THC-exposed offspring. Decreased Drd2 expression was accompanied by reduced dopamine D2 receptor (D(2)R) binding sites and increased sensitivity to opiate reward in adulthood. CONCLUSIONS: These data suggest that maternal cannabis use alters developmental regulation of mesolimbic D(2)R in offspring through epigenetic mechanisms that regulate histone lysine methylation, and the ensuing reduction of D(2)R might contribute to addiction vulnerability later in life.

Adolescent cannabis exposure alters opiate intake and opioid limbic neuronal populations in adult rats.

Cannabis use is a hypothesized gateway to subsequent abuse of other drugs such as heroin. We currently assessed whether Delta-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 microg/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 microg/kg/infusion) and greater responding for moderate-low heroin doses (dose-response curve: 7.5, 15, 30, 60, and 100 microg/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, mu opioid receptor (muOR) GTP-coupling was potentiated in mesolimbic and nigrostriatal brainstem regions in THC-pretreated animals. muOR 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.

Endocannabinoid system and opioid addiction: behavioural aspects.

Cannabinoids produce a variety of pharmacological effects very similar to those elicited by opioids. Direct and indirect interactions with opioid system have been proposed to explain some cannabinoid effects such as analgesia and attenuation of opioid-withdrawal syndrome, and evidence has been provided in support to the notion that rewarding properties of cannabinoids and opioids might be functionally linked. In particular, a growing body of studies points to an important role of the endogenous cannabinoid system in the modulation of opioid rewarding and addictive effects. The current review examines progresses in the past few years in the elucidation of cannabinoid-opioid interactions in drug abuse and dependence, focusing on recent findings from behavioural studies using different animal models of addiction. Specifically, here we review data on the behavioural aspects (i.e., drug abuse, dependence, tolerance, sensitization, relapse and drug vulnerability) of the specific, often reciprocal, cross-talk between cannabinoids and opioids with particular reference to the role of the endocannabinoid system in opioid addiction. The potential biochemical mechanisms involved in these pharmacological interactions are discussed together with possible therapeutic implications in the pharmacotherapy of opioid dependence. However, individuation of the precise anatomical substrates and molecular mechanisms of such interaction still remains a complex and challenging field for future research.