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

Maria Ellgren, Sabrina M Spano, Yasmin L. Hurd

Neuropsychopharmacology March 2007 DOI: 10.1038/sj.npp.1301127 (opens in new tab)

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AI-extracted from the abstract
Characteristics Preclinical animal study (randomized controlled experiment) Peer reviewed
Population Long-Evans male rats exposed to THC or vehicle during adolescence (postnatal days 28-49) and tested for heroin self-administration from young adulthood (PND 57) into full adulthood (PND 102)
Interventions Delta-9-tetrahydrocannabinol (THC) heroin
Dose THC 1.5 mg/kg intraperitoneally every third day; heroin 30 µg/kg/infusion during acquisition and maintenance, with dose-response testing at 7.5, 15, 30, 60, and 100 µg/kg/injection
Duration THC exposure during postnatal days 28-49; heroin self-administration assessed from PND 57 to PND 102
Measures Heroin self-administration behavior (fixed ratio-1; 3-h sessions), preproenkephalin mRNA expression, mu opioid receptor (muOR) GTP-coupling
Topics Cannabis
Key findings Adolescent THC exposure in male rats led to persistently higher heroin self-administration across acquisition and maintenance phases, and to altered endogenous opioid systems, including increased preproenkephalin mRNA in the nucleus accumbens shell and potentiated mu opioid receptor GTP-coupling in mesolimbic and nigrostriatal regions. The authors argue these results support the gateway hypothesis, suggesting adolescent cannabis exposure produces enduring changes in hedonic processing that enhance opiate intake.

Abstract

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.

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Study Year Design Participants
Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB1 and Serotonin 5-HT2A Receptors Mice 2015 Preclinical study
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Long-term hippocampal interneuronopathy drives sex-dimorphic spatial memory impairment induced by prenatal THC exposure Mice prenatally exposed to THC, including conditional CB1R knockout mice 2020 Animal experimental study
Chronic cannabis promotes pro-hallucinogenic signaling of 5-HT2A receptors through Akt/mTOR pathway Mice exposed to chronic THC early in life 2018 Animal experimental study
Effects of cannabinoid drugs on the deficit of prepulse inhibition of startle in an animal model of schizophrenia: the SHR strain Spontaneously hypertensive rats (SHRs) and Wistar rats 2014 Animal experimental study

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