Endocannabinoid signaling in the central nervous system.

It is hard to overestimate the influence of the endocannabinoid signaling (ECS) system on central nervous system (CNS) function. In the 40 years since cannabinoids were found to trigger specific cell signaling cascades, studies of the ECS system continue to cause amazement, surprise, and confusion! CB1 cannabinoid receptors are expressed widely in the CNS and regulate cell-cell communication via effects on the release of both neurotransmitters and gliotransmitters. CB2 cannabinoid receptors are difficult to detect in the CNS but seem to "punch above their weight" as compounds targeting these receptors have significant effects on inflammatory state and behavior. Positive and negative allosteric modulators for both receptors have been identified and examined in preclinical studies. Concentrations of the endocannabinoid ligands, N-arachidonoylethanolamine and 2-arachidonoylglycerol (2-AG), are regulated by a combination of enzymatic synthesis and degradation and inhibitors of these processes are available and making their way into clinical trials. Importantly, ECS regulates many essential brain functions, including regulation of reward, anxiety, inflammation, motor control, and cellular development. While the field is on the cusp of preclinical discoveries providing impactful clinical and therapeutic insights into many CNS disorders, there is still much to be learned about this remarkable and versatile modulatory system.

Adolescent THC Treatment Does Not Potentiate the Behavioral Effects in Adulthood of Maternal Immune Activation.

Both in utero exposure to maternal immune activation and cannabis use during adolescence have been associated with increased risk for the development of schizophrenia; however, whether these exposures exert synergistic effects on brain function is not known. In the present study, mild maternal immune activation (MIA) was elicited in mice with prenatal exposure to polyinosinic-polycytidylic acid (poly(I:C)), and ∆9-tetrahydrocannabinol (THC) was provided throughout adolescence in cereal (3 mg/kg/day for 5 days). Neither THC nor MIA pretreatments altered activity in assays used to characterize hyperdopaminergic states in adulthood: amphetamine hyperlocomotion and prepulse inhibition of the acoustic startle reflex. Adolescent THC treatment elicited deficits in spatial memory and enhanced spatial reversal learning in adult female mice in the Morris water maze, while exposure to MIA elicited female-specific deficits in fear extinction learning in adulthood. There were no effects in these assays in adult males, nor were there interactions between THC and MIA in adult females. While doses of poly(I:C) and THC were sufficient to elicit behavioral effects, particularly relating to cognitive performance in females, there was no evidence that adolescent THC exposure synergized with the risk imposed by MIA to worsen behavioral outcomes in adult mice of either sex.

Contribution of the Adenosine 2A Receptor to Behavioral Effects of Tetrahydrocannabinol, Cannabidiol and PECS-101.

The cannabis-derived molecules, ∆9 tetrahydrocannabinol (THC) and cannabidiol (CBD), are both of considerable therapeutic interest for a variety of purposes, including to reduce pain and anxiety and increase sleep. In addition to their other pharmacological targets, both THC and CBD are competitive inhibitors of the equilibrative nucleoside transporter-1 (ENT-1), a primary inactivation mechanism for adenosine, and thereby increase adenosine signaling. The goal of this study was to examine the role of adenosine A2A receptor activation in the effects of intraperitoneally administered THC alone and in combination with CBD or PECS-101, a 4'-fluorinated derivative of CBD, in the cannabinoid tetrad, elevated plus maze (EPM) and marble bury assays. Comparisons between wild-type (WT) and A2AR knock out (A2AR-KO) mice were made. The cataleptic effects of THC were diminished in A2AR-KO; no other THC behaviors were affected by A2AR deletion. CBD (5 mg/kg) potentiated the cataleptic response to THC (5 mg/kg) in WT but not A2AR-KO. Neither CBD nor THC alone affected EPM behavior; their combination produced a significant increase in open/closed arm time in WT but not A2AR-KO. Both THC and CBD reduced the number of marbles buried in A2AR-KO but not WT mice. Like CBD, PECS-101 potentiated the cataleptic response to THC in WT but not A2AR-KO mice. PECS-101 also reduced exploratory behavior in the EPM in both genotypes. These results support the hypothesis that CBD and PECS-101 can potentiate the cataleptic effects of THC in a manner consistent with increased endogenous adenosine signaling.

Meet Your Stress Management Professionals: The Endocannabinoids.

The endocannabinoid signaling system (ECSS) is altered by exposure to stress and mediates and modulates the effects of stress on the brain. Considerable preclinical data support critical roles for the endocannabinoids and their target, the CB1 cannabinoid receptor, in the adaptation of the brain to repeated stress exposure. Chronic stress exposure increases vulnerability to mental illness, so the ECSS has attracted attention as a potential therapeutic target for the prevention and treatment of stress-related psychopathology. We discuss human genetic studies indicating that the ECSS contributes to risk for mental illness in those exposed to severe stress and trauma early in life, and we explore the potential difficulties in pharmacological manipulation of the ECSS.