Abstract
The ABC transporters P-glycoprotein (P-gp, Abcb1) and breast cancer resistance protein (Bcrp, Abcg2) regulate the CNS disposition of many drugs. The main psychoactive constituent of cannabis Δ9-tetrahydrocannabinol (THC) has affinity for P-gp and Bcrp, however it is unknown whether these transporters modulate the brain accumulation of THC and its functional effects on the CNS. Here we aim to show that mice devoid of Abcb1 and Abcg2 retain higher brain THC levels and are more sensitive to cannabinoid-induced hypothermia than wild-type (WT) mice. Abcb1a/b (−/−), Abcg2 (−/−) and wild-type (WT) mice were injected with THC before brain and blood were collected and THC concentrations determined. Another cohort of mice was examined for THC-induced hypothermia by measuring rectal body temperature. Brain THC concentrations were higher in both Abcb1a/b (−/−) and Abcg2 (−/−) mice than WT mice. ABC transporter knockout mice exhibited delayed elimination of THC from the brain with the effect being more prominent in Abcg2 (−/−) mice. ABC transporter knockout mice were more sensitive to THC-induced hypothermia compared to WT mice. These results show P-gp and Bcrp prolong the brain disposition and hypothermic effects of THC and offer a novel mechanism for both genetic vulnerability to the psychoactive effects of cannabis and drug interactions between CNS therapies and cannabis.
Highlights
Cannabis is the most widely used illicit drug in the world and may trigger psychiatric disorders such as psychosis and addiction in genetically vulnerable individuals [1]
Augmented THC-induced hypothermia in Abcb1a/b (2/2) and Abcg2 (2/2) mice. Given that both Abcb1a/b (2/2) and Abcg2 (2/2) mice retained higher concentrations of THC in the brain we proceeded to test whether this had functional consequences by examining whether Abcb1a/b (2/2) and Abcg2 (2/2) mice were more sensitive than WT mice to the hypothermic actions of THC - an effect mediated by the central nervous system (CNS)
We show for the first time that the ABC transporters P-gp and Bcrp regulate the brain disposition and consequent CNSmediated functional effect of the main psychoactive constituent of cannabis, THC
Summary
Cannabis is the most widely used illicit drug in the world and may trigger psychiatric disorders such as psychosis and addiction in genetically vulnerable individuals [1]. Research identifying the exact genes that comprise genetic vulnerability to cannabisinduced brain disorders is in its infancy. ABC transporters are a family of drug efflux pumps that utilize ATP hydrolysis to transport substrates across biological membranes and were originally discovered due to their role in mediating multidrug resistance (MDR) to anti-cancer drugs [8]. They regulate the disposition of many drugs in tissues because they are localised in excretory organs such as the liver, intestine and the blood-brain barrier (BBB) [9,10,11,12]. Bcrp affects brain disposition of drugs [16] and often cooperates with P-gp to extrude compounds from the brain because these transporters share overlapping substrate specificities [17,18,19]
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