The endocannabinoid system during development: emphasis on perinatal events and delayed effects.

The endocannabinoid system (ECS) including its receptors, endogenous ligands ("endocannabinoids"), synthesizing and degradating enzymes, and transporter molecules has been detected from the earliest embryonal stages and throughout pre- and postnatal development; endocannabinoids, notably 2-arachidonoylglycerol, are also present in maternal milk. During three developmental stages, (1) early embryonal, (2) prenatal brain development, and (3) postnatal suckling, the ECS plays an essential role for development and survival. During early gestation, successful embryonal passage through the oviduct and implantation into the uterus require critical enzymatic control of the endocannabinoids. During fetal life, endocannabinoids and the cannabinoid CB(1) receptor are important for brain development, regulating neural progenitor differentiation and guiding axonal migration and synaptogenesis. Postnatally, CB(1) receptor activation by 2-arachidonoylglycerol appears to play a critical role in the initiation of milk suckling in mouse pups, possibly by enabling innervation and/or activation of the tongue muscles. Perinatal manipulation of the ECS, by administering cannabinoids or by maternal marijuana consumption, alters neurotransmitter and behavioral functions in the offspring. Interestingly, the sequelae of prenatal cannabinoids are similar to many effects of prenatal stress, which may suggest that prenatal stress impacts on the ECS and that vice versa prenatal cannabinoid exposure may interfere with the ability of the fetus to cope with the stress. Future studies should further clarify the mechanisms involved in the developmental roles of the ECS and understand better the adverse effects of prenatal exposure, to design strategies for the treatment of conditions including infertility, addiction, and failure-to-thrive.