Combined exposure to alcohol and cannabis during development: Mechanisms and outcomes

Abstract

Exposure to substances of abuse during pregnancy can have long-lasting effects on offspring. Alcohol is one of the most widely used substances of abuse that leads to the most severe consequences. Recent studies in the United States, Canada, and the United Kingdom showed that between 1% and 7% of all children exhibit signs and symptoms of fetal alcohol spectrum disorder (FASD). Despite preventive campaigns, the rate of children with FASD has not decreased during recent decades. Alcohol consumption often accompanies exposure to such drugs as tobacco, cocaine, opioids, and cannabis. These interactions can be synergistic and exacerbate the deleterious consequences of developmental alcohol exposure. The present review focuses on interactions between alcohol and cannabis exposure and the potential consequences of these interactions.

Keywords: Cannabinoid receptors; Drug interactions; Endocannabinoid system; Fetal alcohol spectrum disorders (FASD); Prenatal drug exposure; Simultaneous alcohol and cannabis exposure.

Figure A. Simplified representation of altered embryonic signaling in the telencephalon after alcohol and cannabinoid exposure.

Alcohol inhibits sonic hedgehog and maintains the Patched repression of Smo, inhibiting the shh signaling. Cannabinoids have a direct inhibition of Smo, while stimulating CB₁ receptors that leads to the formation of heteromers with Smo. The latter mechanism reduces Smo-G_αi protein signaling and stimulates CB₁ receptor-G_αs protein signaling. (Figure adapted from Fish et al. (2019)

Figure B. Local signals in the telencephalon:

Fibroblast Growth Factor (Fgf) and Sonic Hedgehog (Shh) (Figure adapted from Petryk et al. (2015); Geng & Oliver (2009))

Figure C. Ocular and craniofacial morphology are altered in normal, alcohol-exposed, cannabinoid-exposed, and co-exposed mouse embryos.

A) Craniofacial features of a) normal, b) alcohol, c) cannabinoids, and d) combined alcohol and cannabinoids exposed mice. b) Alcohol-exposed mice: narrow eyelid openings and forehead, small midface, short nose (nostril deficiency), hair follicles closer to the midline, long upper lip, philtrum deficiency. c) Cannabinoids-exposed mice: minor to moderate coloboma, small jaws, philtrum deficiency. d) Combined alcohol and cannabinoids exposure: severe eye anomalies (anophthalmia), narrow forehead, small jaws, philtrum deficiency, small nose (nostril deficiency). B) Growth features of drug exposures. e) normal weight and length of control mice. f) Alcohol-exposed mice: reduced weight and length. g) Cannabinoid-exposed mice: reduced weight, no significant change in length. h) Combined alcohol and cannabinoid exposure: reduced body weight and length. (Figure adapted from Fish et al. (2019))

Figure D. Developmental exposure to alcohol and cannabinoids leads to neurobehavioral defects.

a) Alcohol activates gene transcription of GDE1 and NAPE-PLD enzymes 3) Increased AEA levels c) AEA and cannabinoids act through CB1R at pre-synaptic cell membrane d) Enhanced level of CB1R mRNA expression e) CB1-mediated Ca2+ channel inhibition f) Decreased glutamate release g) NMDAR hypofunction h) CDK/pERK/pCREB signaling deficit i) Inhibition of Arc, Rac j) Decreased CREB phosphorylation k) inhibition of Arc, Rac expression. (Figure adapted from Basavarajappa (2019))