Endocannabinoid system, stress and HPA axis.

Prenatal neurodevelopment is dependent on precise functioning of multiple signalling pathways in the brain, including those mobilised by glucocorticoids (GC) and endocannabinoids (eCBs). Prenatal exposure to drugs of abuse, including opioids, alcohol, cocaine and cannabis, has been shown to not only impact GC signalling, but also alter functioning of the hypothalamic-pituitary-adrenal (HPA) axis. Such exposures can have long-lasting neurobehavioural consequences, including alterations in the stress response in the offspring. Furthermore, cannabis contains cannabinoids that signal via the eCB pathway, which is linked to some components of GC signalling in the adult brain. Given that GCs are frequently used in pregnancy to prevent complications of prematurity, and also that rates of cannabis use in pregnancy are increasing, the likelihood of foetal co-exposure to these compounds is high and may have additional implications for long-term neurodevelopment. Here, we present a discussion of GC signalling and the HPA axis, as well as the effects of prenatal drug exposure on these pathways and the stress response, and we explore the interactions between GC and EC signalling in the developing brain and potential for neurodevelopmental consequences.

Prenatal drug exposure and neurodevelopmental programming of glucocorticoid signalling.

The therapeutic benefits of the current medications for patients with psychiatric disorders contrast with a great variety of adverse effects. The endocannabinoid system (ECS) components have gained high interest as potential new targets for treating psychiatry diseases because of their neuromodulator role, which is essential to understanding the regulation of many brain functions. This article reviewed the molecular alterations in ECS occurring in different psychiatric conditions. The methods used to identify alterations in the ECS were also described. We used a translational approach. The animal models reproducing some behavioral and/or neurochemical aspects of psychiatric disorders and the molecular alterations in clinical studies in post-mortem brain tissue or peripheral tissues were analyzed. This article reviewed the most relevant ECS changes in prevalent psychiatric diseases such as mood disorders, schizophrenia, autism, attentional deficit, eating disorders (ED), and addiction. The review concludes that clinical research studies are urgently needed for two different purposes: (1) To identify alterations of the ECS components potentially useful as new biomarkers relating to a specific disease or condition, and (2) to design new therapeutic targets based on the specific alterations found to improve the pharmacological treatment in psychiatry.

/pdf/molecular-alterations-of-the-endocannabinoid-system-in-2aohjacn.pdf

Molecular Alterations of the Endocannabinoid System in Psychiatric Disorders

Marijuana is a widely used recreational drug with increasing legalization worldwide for medical purposes. Most experimental studies use either synthetic or plant-derived cannabinoids to investigate the effect of cannabinoids on anxiety and cognitive functions. The aim of this study was to mimic real life situations where young people smoke cannabis regularly to relax from everyday stress. Therefore, we exposed young adult male NMRI mice to daily stress and concomitant marijuana smoke for 2 months and investigated the consequences on physiology, behavior and adult hippocampal neurogenesis. Animals were restrained for 6-h/day for 5-days a week. During the stress, mice were exposed to cannabis smoke for 2 × 30 min/day. We burned 2 "joints" (2 × 0.8 g marijuana) per occasion in a whole body smoking chamber. Cannabinoid content of the smoke and urine samples was measured by HPLC and SFC-MS/MS. Body weight gain was recorded daily and we did unrestrained, whole body plethysmography to investigate pulmonary functions. The cognitive performance of the animals was evaluated by the novel object recognition and Y maze tests. Anxietyrelated spontaneous locomotor activity and self-grooming were assessed in the open field test (OFT). Adult neurogenesis was quantified post mortem in the hippocampal dentate gyrus. The proliferative activity of the precursor cells was detected by the use of the exogenous marker 5-bromo-20-deoxyuridine. Treatment effects on maturing neurons were studied by the examination of doublecortin-positive neurons. Both stress and cannabis exposure significantly reduced body weight gain. Cannabis smoke had no effect on pulmonary functions, but stress delayed the maturation of several lung functions. Neither stress, nor cannabis smoke affected the cognitive functioning of the animals. Results of the OFT revealed that cannabis had a mild anxiolytic effect and markedly increased self-grooming behavior. Stress blocked cell proliferation in the dentate gyrus, but cannabis had no effect on this parameter. Marijuana smoke however had a pronounced impact on doublecortin-positive neurons influencing their number, morphology and migration. In summary, we report here that long-term stress in combination with cannabis smoke exposure can alter several health-related measures, but the present experimental design could not reveal any interaction between these two treatment factors except for body weight gain.

/pdf/long-term-stress-and-concomitant-marijuana-smoke-exposure-okqv40e648.pdf

Long-Term Stress and Concomitant Marijuana Smoke Exposure Affect Physiology, Behavior and Adult Hippocampal Neurogenesis.

Autism spectrum disorder (ASD) pathophysiology is not completely understood; however, altered inflammatory response and glutamate signaling have been reported, leading to the investigation of molecules targeting the immune-glutamatergic system in ASD treatment. Palmitoylethanolamide (PEA) is a naturally occurring saturated N-acylethanolamine that has proven to be effective in controlling inflammation, depression, epilepsy, and pain, possibly through a neuroprotective role against glutamate toxicity. Here, we systematically reviewed all human and animal studies examining PEA and its biobehavioral correlates in ASD. Studies indicate altered serum/brain levels of PEA and other endocannabinoids (ECBs)/acylethanolamines (AEs) in ASD. Altered PEA signaling response to social exposure and altered expression/activity of enzymes responsible for the synthesis and catalysis of ECBs/AEs, as well as downregulation of the peroxisome proliferator activated receptor-α (PPAR-α) and cannabinoid receptor target GPR55 mRNA brain expression, have been reported. Stress and exposure to exogenous cannabinoids may modulate ECBs/AEs levels and expression of candidate genes for neuropsychiatric disorders, with implications for ASD. Limited research suggests that PEA supplementation reduces overall autism severity by improving language and social and nonsocial behaviors. Potential neurobiological underpinnings include modulation of immune response, neuroinflammation, neurotrophy, apoptosis, neurogenesis, neuroplasticity, neurodegeneration, mitochondrial function, and microbiota activity, possibly through peroxisome proliferator-activated receptor-α (PPAR-α) activation.

Palmitoylethanolamide and Its Biobehavioral Correlates in Autism Spectrum Disorder: A Systematic Review of Human and Animal Evidence.

INTRODUCTION Vulnerability to psychiatric manifestations is achieved by the influence of genetic and environment including stress and cannabis consumption. Here, we used a psychosocial stress model based on resident-intruder confrontations to study the brain corticostriatal-function, since deregulation of corticostriatal circuitries has been reported in many psychiatric disorders. CB1 receptors are widely expressed in the central nervous system and particularly, in both cortex and striatum brain structures. AIMS AND METHODS The investigation presented here is addressed to assess the impact of repeated stress following acute cannabinoid exposure on behavior and corticostriatal brain physiology by assessing mice behavior, the concentration of endocannabinoid and endocannabinoid-like molecules and changes in the transcriptome. RESULTS Stressed animals urinated frequently; showed exacerbated scratching activity, lower striatal N-arachidonylethanolamine (AEA) levels and higher cortical expression of cholinergic receptor nicotinic alpha 6. The cannabinoid agonist WIN55212.2 diminished locomotor activity while the inverse agonist increased the distance travelled in the center of the open field. Upon CB1 activation, N-oleoylethanolamide and N-palmitoylethanolamide, two AEA congeners that do not interact directly with cannabinoid receptors, were enhanced in the striatum. The co-administration with both cannabinoids induced an up-regulation of striatal FK506 binding protein 5. The inverse agonist in controls reversed the effects of WIN55212.2 on motor activity. When Rimonabant was injected under stress, the cortical levels of 2-arachidonoylglycerol were maximum. The agonist and the antagonist influenced the cortical expression of cholinergic receptor nicotinic alpha 6 and serotonin transporter neurotransmitter type 4 in opposite directions, while their co-administration tended to produce a null effect under stress. CONCLUSIONS The endocannabinoid system had a direct effect on serotoninergic neurotransmission and glucocorticoid signaling. Cholinergic receptor nicotinic alpha-6 was shown to be deregulated in response to stress and following synthetic cannabinoid drugs thus could confer vulnerability to cannabis addiction and psychosis. Targeting the receptors of endocannabinoids and endocannabinoid-like mediators might be a valuable option for treating stress-related neuropsychiatric symptoms.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cns.12810

Effects of repeated long-term psychosocial stress and acute cannabinoid exposure on mouse corticostriatal circuitries: Implications for neuropsychiatric disorders.

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Effects of repeated long-term psychosocial stress and acute cannabinoid exposure on mouse corticostriatal circuitries: Implications for neuropsychiatric disorders.