Consequences of Perinatal Cannabis Exposure

Abstract

Cannabis exposure during the perinatal period results in varied and significant consequences in affected offspring. The prevalence of detrimental outcomes of perinatal cannabis exposure is likely to increase in tandem with the broadening of legalization and acceptance of the drug. As such, it is crucial to highlight the immediate and protracted consequences of cannabis exposure on pre- and postnatal development. Here, we identify lasting changes in neurons' learning flexibility (synaptic plasticity) and epigenetic misregulation in animal models of perinatal cannabinoid exposure (using synthetic cannabinoids or active components of the cannabis plant), in addition to significant alterations in social behavior and executive functions. These findings are supported by epidemiological data indicating similar behavioral outcomes throughout life in human offspring exposed to cannabis during pregnancy. Further, we indicate important lingering questions regarding accurate modeling of perinatal cannabis exposure as well as the need for sex- and age-dependent outcome measures in future studies.

Keywords: cannabis; perinatal.

Figure 1:. The perinatal period of sensitivity extends from early pregnancy until weaning.

The perinatal period of sensitivity to cannabis exposure in humans and rodents extends from early gestation through the pre-weaning period. In humans (top), the WHO defines the perinatal period as between gestational week (GW) 22 and 7 days after birth. Robust data indicate significant transfer of cannabinoids through lactation, extending this period of vulnerability to the end of breastfeeding, which varies widely among individuals. For the sake of simplified comparison with animal models, and as a conservative estimate, the breastfeeding window can be considered three months post-birth, which approximately corresponds to the weaning age in rodents. In rats and mice (bottom) the perinatal period begins at neural tube formation (GD10.5-11 and GD9-9.5 in rats and mice, respectively) and extends to white matter development (PND07-10). In rodents, the gestational period approximately corresponds to the first two trimesters of human in utero development, whereas the first week of postnatal life corresponds to the third trimester of human in utero development. Cannabinoid transfer to the developing offspring extends until weaning at PND21.

Figure 2:. The endocannabinoid system (ECS).

The ECS is a complex array of both pre- and post-synaptic receptors, synthesizing and degrading enzymes, and the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Post-synaptic synthesis of AEA and 2-AG by the enzyme NAPE-PLD occurs via a Ca²⁺-dependent process derived from IP3-mediated Ca²⁺ stores, NMDA receptors and voltage-sensitive Ca²⁺ channels (VSCC). AEA and 2-AG both act as agonists at the presynaptic CB1R, while AEA acts as an agonist at both pre- and post-synaptic Transient Receptor Potential Vanniloide 1 (TRPV1) channels. While AEA degradation mediated by FAAH occurs post-synaptically, 2-AG hydrolysis is mediated by MAGL and ABHD6 at the pre- and post-synaptic sites, respectively.

Figure 3:. Consequences of perinatal cannabis exposure in humans and rodents.

The table summarizes consequences of perinatal cannabis exposure in both humans and rodents highlighted in this review. Behavioral outcomes (top row) throughout life (left to right) consistently indicate detrimental effects of perinatal cannabis exposure on cognitive and executive functions and social interactions along with increased risk-taking and impulsive behaviors in rodents and humans. Early onset of drug abuse and increased drug seeking behavior are similarly noted starting in adolescence and into adulthood in both models. Systems-level outcomes (middle row) show similar consistency across age groups. Namely, perinatal cannabis exposure appears to result in a loss of plasticity at adolescence and adulthood in multiple brain regions. Molecular outcomes (bottom row) thus far identified appear to impact largely the opioidergic and dopaminergic systems across all age groups, with the latter being similarly misregulated in humans and rodents at infancy.