Abstract
Phytocannabinoids are psychotropic substances ofcannabis with the ability to bind endocannabinoid (eCB) receptors that regulate synaptic activity in the central nervous system (CNS). Synthetic cannabinoids (SCs) are synthetic analogs of Δ9-tetrahydrocannabinol (Δ9-THC), the psychotropic compound of cannabis, acting as agonists of eCB receptor CB1. SC is an easily available and popular alternative to cannabis, and their molecular structure is always changing, increasing the hazard for the general population. The popularity of cannabis and its derivatives may lead, and often does, to a child’s exposure to cannabis both in utero and through breastfeeding by a drug-consuming mother. Prenatal exposure to cannabis has been associated with an altered rate of mental development and significant changes in nervous system functioning. However, the understanding of mechanisms of its action on developing the human CNS is still lacking. We investigated the effect of continuous exposure to cannabinoids on developing human neurons, mimicking the prenatal exposure by drug-consuming mother. Two human induced pluripotent stem cells (hiPSC) lines were induced to differentiate into neuronal cells and exposed for 37 days to cannabidiol (CBD), Δ9-THC, and two SCs, THJ-018 and EG-018. Both Δ9-THC and SC, at 10 μM, promote precocious neuronal and glial differentiation, while CBD at the same concentration is neurotoxic. Neurons exposed to Δ9-THC and SC show abnormal functioning of voltage-gated calcium channels when stimulated by extracellular potassium. In sum, all studied substances have a profound impact on the developing neurons, highlighting the importance of thorough research on the impact of prenatal exposure to natural and SC.
Highlights
Phytocannabinoids, such as ∆9-THC, are substances found in cannabis that can bind to the endocannabinoid system receptors, which regulate a variety of physiological processes in the human body, such as synaptic activity in the central nervous system (CNS), and analgesic and metabolic effects in the peripheric nervous system, PNS (Pertwee, 2008; Wu et al, 2011; Metz and Stickrath, 2015)
The ratio between the concentration of a lipophilic drug in the fat tissue and plasma at a steady-state can reach a value of 3–4 digits undermining the measured drug concentration found by blood analysis. ∆9-THC is a partial agonist of Cannabinoid receptors 1 (CB1) and many of its effects on CNS were shown to be mediated by CB1 (Pertwee, 2008)
Exposure to ∆9-THC and Synthetic cannabinoids (SCs) differentially impacted the expression levels of CNR1 and CNR2 supporting the view that both receptors might be involved in the neurogenesis
Summary
Phytocannabinoids, such as ∆9-THC, are substances found in cannabis that can bind to the endocannabinoid (eCB) system receptors, which regulate a variety of physiological processes in the human body, such as synaptic activity in the central nervous system (CNS), and analgesic and metabolic effects in the peripheric nervous system, PNS (Pertwee, 2008; Wu et al, 2011; Metz and Stickrath, 2015). Prenatal exposure to cannabinoids acting as agonists of CB1 and CB2 receptors can produce long-lasting effects on eCB signaling affecting motor activity, verbal development, nociception, drug-seeking behavior and other processes (reviewed in Broyd et al, 2016; Richardson et al, 2016; Grant et al, 2018). Due to their lipophilic nature, phytocannabinoids can permeate cellular membranes passing from drug-consuming mothers’ bloodstream into foetal tissues (Grotenhermen, 2003). There is an urgent need for a better understanding of the impact of these substances on human brain development, especially due to the contemporary trend of increasing cannabis use
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