Adolescent nicotine exposure induces long-term, sex-specific disturbances in mood and anxiety-related behavioral, neuronal and molecular phenotypes in the mesocorticolimbic system.

The majority of lifetime smokers begin using nicotine during adolescence, a critical period of brain development wherein neural circuits critical for mood, affect and cognition are vulnerable to drug-related insults. Specifically, brain regions such as the medial prefrontal cortex (mPFC), the ventral tegmental area (VTA), nucleus accumbens (NAc) and hippocampus, are implicated in both nicotine dependence and pathological phenotypes linked to mood and anxiety disorders. Clinical studies report that females experience higher rates of mood/anxiety disorders and are more resistant to smoking cessation therapies, suggesting potential sex-specific responses to nicotine exposure and later-life neuropsychiatric risk. However, the potential neural and molecular mechanisms underlying such sex differences are not clear. In the present study, we compared the impacts of adolescent nicotine exposure in male vs. female rat cohorts. We performed a combination of behavioral, electrophysiological and targeted protein expression analyses along with matrix assisted laser deionization imaging (MALDI) immediately post-adolescent exposure and later in early adulthood. We report that adolescent nicotine exposure induced long-lasting anxiety/depressive-like behaviors, disrupted neuronal activity patterns in the mPFC-VTA network and molecular alterations in various neural regions linked to affect, anxiety and cognition. Remarkably, these phenotypes were only observed in males and/or were expressed in the opposite direction in females. These findings identify a series of novel, sex-selective biomarkers for adolescent nicotine-induced neuropsychiatric risk, persisting into adulthood.

Cannabidiol Exposure During Gestation Leads to Adverse Cardiac Outcomes Early in Postnatal Life in Male Rat Offspring.

Introduction: Studies indicate that ∼7% of pregnant individuals in North America consume cannabis in pregnancy. Pre-clinical studies have established that maternal exposure to Δ9-tetrahydrocannabinol (THC; major psychoactive component in cannabis) leads to fetal growth restriction and impaired cardiac function in offspring. However, the effects of maternal exposure to cannabidiol (CBD; major non-euphoric constituent) on cardiac outcomes in offspring remain unknown. Therefore, our objective is to investigate the functional and underlying molecular impacts in the hearts of offspring exposed to CBD in pregnancy. Methods: Pregnant Wistar rats were exposed to either 3 or 30 mg/kg CBD or vehicle control i.p. daily from gestational day 6 to term. Echocardiography was used to assess cardiac function in male and female offspring at postnatal day (PND) 21. Furthermore, quantitative polymerase chain reaction (qPCR), immunoblotting, and bulk RNA-sequencing (RNA-seq) were performed on PND21 offspring hearts. Results: Despite no differences in the heart-to-body weight ratio, both doses of CBD led to reduced cardiac function exclusively in male offspring at 3 weeks of age. Underlying this, significant alterations in the expression of the endocannabinoid system (ECS; e.g., decreased cannabinoid receptor 2) were observed. In addition, bulk RNA-seq data demonstrated transcriptional pathways significantly enriched in mitochondrial function/metabolism as well as development. Conclusion: Collectively, we demonstrated for the first time that gestational exposure to CBD, a constituent perceived as safe, leads to early sex-specific postnatal cardiac deficits and alterations in the cardiac ECS in offspring.

Inhibition of fatty acid binding protein-5 in the basolateral amygdala induces anxiolytic effects and accelerates fear memory extinction.

RATIONALE: The endocannabinoid (eCB) system critically controls anxiety and fear-related behaviours. Anandamide (AEA), a prominent eCB ligand, is a hydrophobic lipid that requires chaperone proteins such as Fatty Acid Binding Proteins (FABPs) for intracellular transport. Intracellular AEA transport is necessary for degradation, so blocking FABP activity increases AEA neurotransmission. OBJECTIVE: To investigate the effects of a novel FABP5 inhibitor (SBFI-103) in the basolateral amygdala (BLA) on anxiety and fear memory. METHODS: We infused SBFI-103 (0.5 µg-5 µg) to the BLA of adult male Sprague Dawley rats and ran various anxiety and fear memory behavioural assays, neurophysiological recordings, and localized molecular signaling analyses. We also co-infused SBFI-103 with the AEA inhibitor, LEI-401 (3 µg and 10 µg) to investigate the potential role of AEA in these phenomena. RESULTS: Acute intra-BLA administration of SBFI-103 produced strong anxiolytic effects across multiple behavioural tests. Furthermore, animals exhibited acute and long-term accelerated associative fear memory extinction following intra-BLA FABP5 inhibition. In addition, BLA FABP5 inhibition induced strong modulatory effects on putative PFC pyramidal neurons along with significantly increased gamma oscillation power. Finally, we observed local BLA changes in the phosphorylation activity of various anxiety- and fear memory-related molecular biomarkers in the PI3K/Akt and MAPK/Erk signaling pathways. At all three levels of analyses, we found the functional effects of SBFI-103 depend on availability of the AEA ligand. CONCLUSIONS: These findings demonstrate a novel intra-BLA FABP5 signaling mechanism regulating anxiety and fear memory behaviours, neuronal activity states, local anxiety-related molecular pathways, and functional AEA modulation.

Gestational exposure to cannabidiol leads to glucose intolerance in 3-month-old male offspring.

Reports in North America suggest that up to 20% of young women (18-24 years) use cannabis during pregnancy. This is concerning given clinical studies indicate that maternal cannabis use is associated with fetal growth restriction and dysglycemia in the offspring. Preclinical studies demonstrated that prenatal exposure to Δ9-tetrahydrocannabinol, the main psychoactive component of cannabis, in rat dams led to female-specific deficits in ß-cell mass and glucose intolerance/insulin resistance. Yet to date, the contributions of cannabidiol (CBD), the primary nonpsychoactive compound in cannabis, remain elusive. This study aimed to define the effects of in utero cannabidiol (CBD) exposure on postnatal glucose regulation. Pregnant Wistar rat dams received daily intraperitoneal injections of either a vehicle solution or 3 mg/kg of CBD from gestational day (GD) 6 to parturition. CBD exposure did not lead to observable changes in maternal or neonatal outcomes; however, by 3 months of age male CBD-exposed offspring exhibited glucose intolerance despite no changes in pancreatic ß/α-cell mass. Transcriptomic analysis on the livers of these CBD-exposed males revealed altered gene expression of circadian rhythm clock machinery, which is linked to systemic glucose intolerance. Furthermore, alterations in hepatic developmental and metabolic processes were also observed, suggesting gestational CBD exposure has a long-lasting detrimental effect on liver health throughout life. Collectively, these results indicate that exposure to CBD alone in pregnancy may be detrimental to the metabolic health of the offspring later in life.

Sex-Dependent Synergism of an Edible THC: CBD Formulation in Reducing Anxiety and Depressive-like Symptoms Following Chronic Stress.

Cannabis has shown therapeutic potential in mood and anxiety-related pathologies. However, the two primary constituents of cannabis, cannabidiol (CBD) and Δ-9-tetrahydrocannabinol (THC) produce distinct effects on molecular pathways in neural circuits associated with affective disorders. Moreover, it has been proposed that the combination of THC: and CBD may have unique synergistic properties. In the present study, the effects of a 1:100 THC: CBD ratio edible formulation were tested in behavioural, neuronal and molecular assays for anxiety and depressive-like endophenotypes. Adult male and female Sprague-Dawley rats were stressed for 14 days. Then, for three weeks, open field, elevated plus maze, light/dark box, social interaction, sucrose preference, and the forced swim test were performed 90 minutes after acute consumption of CBD (30 mg/kg), THC (0.3 mg/kg), or 1:100 combination of THC:CBD. After behavioural tests, in vivo, neuronal electrophysiological analyses were performed in the ventral tegmental area and prefrontal cortex (PFC). Furthermore, western-blot experiments examined the expression of biomarkers associated with mood and anxiety disorders, including protein kinase B (Akt), glycogen synthase kinase-3 (GSK-3), BDNF, mTOR, D1, and D2 receptor in nucleus accumbens (NAc) and PFC.Edible THC:CBD produces significant anxiolytic and antidepressant effects only in stressed male rats. In most cases, the combination of THC and CBD had stronger effects than either phytochemical alone. These synergistic effects are associated with alterations in Akt/GSK3 and D2-R expression in NAc and BDNF expression in PFC. Furthermore, THC:CBD reverses chronic stress-induced alterations in PFC neuronal activity. These findings demonstrate a novel synergistic potential for THC:CBD edible formulations in stress-related pathologies.

Prenatal THC exposure induces long-term, sex-dependent cognitive dysfunction associated with lipidomic and neuronal pathology in the prefrontal cortex-hippocampal network.

With increasing maternal cannabis use, there is a need to investigate the lasting impact of prenatal exposure to Δ9-tetrahydrocannabinol (THC), the main psychotropic compound in cannabis, on cognitive/memory function. The endocannabinoid system (ECS), which relies on polyunsaturated fatty acids (PUFAs) to function, plays a crucial role in regulating prefrontal cortical (PFC) and hippocampal network-dependent behaviors essential for cognition and memory. Using a rodent model of prenatal cannabis exposure (PCE), we report that male and female offspring display long-term deficits in various cognitive domains. However, these phenotypes were associated with highly divergent, sex-dependent mechanisms. Electrophysiological recordings revealed hyperactive PFC pyramidal neuron activity in both males and females, but hypoactivity in the ventral hippocampus (vHIPP) in males, and hyperactivity in females. Further, cortical oscillatory activity states of theta, alpha, delta, beta, and gamma bandwidths were strongly sex divergent. Moreover, protein expression analyses at postnatal day (PD)21 and PD120 revealed primarily PD120 disturbances in dopamine D1R/D2 receptors, NMDA receptor 2B, synaptophysin, gephyrin, GAD67, and PPARα selectively in the PFC and vHIPP, in both regions in males, but only the vHIPP in females. Lastly, using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS), we identified region-, age-, and sex-specific deficiencies in specific neural PUFAs, namely docosahexaenoic acid (DHA) and arachidonic acid (ARA), and related metabolites, in the PFC and hippocampus (ventral/dorsal subiculum, and CA1 regions). This study highlights several novel, long-term and sex-specific consequences of PCE on PFC-hippocampal circuit dysfunction and the potential role of specific PUFA signaling abnormalities underlying these pathological outcomes.

Identification of a novel fatty acid binding protein-5-CB2 receptor-dependent mechanism regulating anxiety behaviors in the prefrontal cortex.

The endocannabinoid (eCB) system represents a promising neurobiological target for novel anxiolytic pharmacotherapies. Previous clinical and preclinical evidence has revealed that genetic and/or pharmacological manipulations altering eCB signaling modulate fear and anxiety behaviors. Water-insoluble eCB lipid anandamide requires chaperone proteins for its intracellular transport to degradation, a process that requires fatty acid-binding proteins (FABPs). Here, we investigated the effects of a novel FABP-5 inhibitor, SBFI-103, on fear and anxiety-related behaviors using rats. Acute intra-prelimbic cortex administration of SBFI-103 induced a dose-dependent anxiolytic response and reduced contextual fear expression. Surprisingly, both effects were reversed when a cannabinoid-2 receptor (CB2R) antagonist, AM630, was co-infused with SBFI-103. Co-infusion of the cannabinoid-1 receptor antagonist Rimonabant with SBFI-103 reversed the contextual fear response yet showed no reversal effect on anxiety. Furthermore, in vivo neuronal recordings revealed that intra-prelimbic region SBFI-103 infusion altered the activity of putative pyramidal neurons in the basolateral amygdala and ventral hippocampus, as well as oscillatory patterns within these regions in a CB2R-dependent fashion. Our findings identify a promising role for FABP5 inhibition as a potential target for anxiolytic pharmacotherapy. Furthermore, we identify a novel, CB2R-dependent FABP-5 signaling pathway in the PFC capable of strongly modulating anxiety-related behaviors and anxiety-related neuronal transmission patterns.

Cannabis in Adolescence: Lasting Cognitive Alterations and Underlying Mechanisms.

Cannabis consumption during adolescence is an area of particular concern, owing to changes in the social and political perception of the drug, and presents a scientific, medical, and economic challenge. Major social and economic interests continue to push toward cannabis legalization as well as pharmaceutical development. As a result, shifting perceptions of both legal and illicit cannabis use across the population have changed the collective evaluation of the potential dangers of the product. The wave of cannabis legalization therefore comes with new responsibility to educate the public on potential risks and known dangers associated with both recreational and medical cannabis. Among these is the risk of long-term cognitive and psychological consequences, particularly following early-life initiation of use, compounded by high-potency and/or synthetic cannabis, and heavy/frequent use of the drug. Underlying these cognitive and psychiatric consequences are lasting aberrations in the development of synaptic function, often secondary to epigenetic changes. Additional factors such as genetic risk and environmental influences or nondrug toxic insults during development are also profound contributors to these long-term functional alterations following adolescent cannabis use. Preclinical studies indicate that exposure to cannabinoids during specific windows of vulnerability (e.g., adolescence) impacts neurodevelopmental processes and behavior by durably changing dendritic structure and synaptic functions, including those normally mediated by endogenous cannabinoids and neuronal circuits.

Adolescent Δ-9-tetrahydrocannabinol exposure induces differential acute and long-term neuronal and molecular disturbances in dorsal vs. ventral hippocampal subregions.

Chronic exposure to Δ-9-tetrahydrocannabinol (THC) during adolescence is associated with long-lasting cognitive impairments and enhanced susceptibility to anxiety and mood disorders. Previous evidence has revealed functional and anatomical dissociations between the posterior vs. anterior portions of the hippocampal formation, which are classified as the dorsal and ventral regions in rodents, respectively. Notably, the dorsal hippocampus is critical for cognitive and contextual processing, whereas the ventral region is critical for affective and emotional processing. While adolescent THC exposure can induce significant morphological disturbances and glutamatergic signaling abnormalities in the hippocampus, it is not currently understood how the dorsal vs. ventral hippocampal regions are affected by THC during neurodevelopment. In the present study, we used an integrative combination of behavioral, molecular, and neural assays in a neurodevelopmental rodent model of adolescent THC exposure. We report that adolescent THC exposure induces long-lasting memory deficits and anxiety like-behaviors concomitant with a wide range of differential molecular and neuronal abnormalities in dorsal vs. ventral hippocampal regions. In addition, using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS), we show for the first time that adolescent THC exposure induces significant and enduring dysregulation of GABA and glutamate levels in dorsal vs. ventral hippocampus. Finally, adolescent THC exposure induced dissociable dysregulations of hippocampal glutamatergic signaling, characterized by differential glutamatergic receptor expression markers, profound alterations in pyramidal neuronal activity and associated oscillatory patterns in dorsal vs. ventral hippocampal subregions.

Maternal Delta-9-Tetrahydrocannabinol Exposure Induces Abnormalities of the Developing Heart in Mice.

Introduction: Cannabis is increasingly being consumed by pregnant women for recreational purposes as well as for its antiemetic and anxiolytic effects despite limited studies on its safety during pregnancy. Importantly, phytocannabinoids found in cannabis can pass through the placenta and enter the fetal circulation. Recent reports suggest gestational cannabis use is associated with negative fetal outcomes, including fetal growth restriction and perinatal intensive care, however, the effects of delta-9-tetrahydrocannabinol (THC) on fetal heart development remains to be elucidated. Materials and Methods: We aimed to determine the outcomes of maternal THC exposure on fetal heart development in mice by administering 0, 5, or 10 mg/kg/day of THC orally to C57BL/6 dams starting at embryonic day (E)3.5. Offspring were collected at E12.5 for molecular analysis, at E17.5 to analyze cardiac morphology or at postnatal day (PND)21 to assess heart function. Results: Maternal THC exposure in E17.5 fetuses resulted in an array of cardiac abnormalities with an incidence of 44% and 55% in the 5 and 10 mg/kg treatment groups, respectively. Maternal THC exposure in offspring resulted in ventricular septal defect, higher semilunar valve volume relative to orifice ratio, and higher myocardial wall thickness. Notably, cell proliferation within the ventricular myocardium was increased, and expression of multiple cardiac transcription factors was downregulated in THC-exposed E12.5 fetuses. Furthermore, heart function was compromised with lower left ventricular ejection fraction, fractional shortening, and cardiac output in PND21 pups exposed to THC compared to controls. Discussion: The results show that maternal THC exposure during gestation induces myocardial hyperplasia and semilunar valve thickening in the fetal heart and postnatal cardiac dysfunction. Our study suggests that maternal cannabis consumption may induce abnormalities in the developing heart and cardiac dysfunction in postnatal life.

Prenatal THC Exposure Induces Sex-Dependent Neuropsychiatric Endophenotypes in Offspring and Long-Term Disruptions in Fatty-Acid Signaling Pathways Directly in the Mesolimbic Circuitry.

Despite increased prevalence of maternal cannabis use, little is understood regarding potential long-term effects of prenatal cannabis exposure (PCE) on neurodevelopmental outcomes. While neurodevelopmental cannabis exposure increases the risk of developing affective/mood disorders in adulthood, the precise neuropathophysiological mechanisms in male and female offspring are largely unknown. Given the interconnectivity of the endocannabinoid (ECb) system and the brain's fatty acid pathways, we hypothesized that prenatal exposure to Δ9-tetrahydrocannabinol (THC) may dysregulate fetal neurodevelopment through alterations of fatty-acid dependent synaptic and neuronal function in the mesolimbic system. To investigate this, pregnant Wistar rats were exposed to vehicle or THC (3 mg/kg) from gestational day (GD)7 until GD22. Anxiety-like, depressive-like, and reward-seeking behavior, electrophysiology, and molecular assays were performed on adult male/female offspring. Imaging of fatty acids using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) was performed at prepubescence and adulthood. We report that PCE induces behavioral, neuronal, and molecular alterations in the mesolimbic system in male and female offspring, resembling neuropsychiatric endophenotypes. Additionally, PCE resulted in profound dysregulation of critical fatty acid pathways in the developing brain lipidome. Female progeny exhibited significant alterations to fatty acid levels at prepubescence but recovered from these deficits by early adulthood. In contrast, males exhibited persistent fatty acid deficits into adulthood. Moreover, both sexes maintained enduring abnormalities in glutamatergic/GABAergic function in the nucleus accumbens (NAc). These findings identify several novel long-term risks of maternal cannabis use and demonstrate for the first time, sex-related effects of maternal cannabinoid exposure directly in the developing neural lipidome.

Anxiety and cognitive-related effects of Δ 9-tetrahydrocannabinol (THC) are differentially mediated through distinct GSK-3 vs. Akt-mTOR pathways in the nucleus accumbens of male rats.

RATIONALE: Δ9-tetrahydrocannabinol (THC) is the primary psychoactive compound in cannabis and is responsible for cannabis-related neuropsychiatric side effects, including abnormal affective processing, cognitive and sensory filtering deficits and memory impairments. A critical neural region linked to the psychotropic effects of THC is the nucleus accumbens shell (NASh), an integrative mesocorticolimbic structure that sends and receives inputs from multiple brain areas known to be dysregulated in various disorders, including schizophrenia and anxiety-related disorders. Considerable evidence demonstrates functional differences between posterior vs. anterior NASh sub-regions in the processing of affective and cognitive behaviours influenced by THC. Nevertheless, the neuroanatomical regions and local molecular pathways responsible for these psychotropic effects are not currently understood. OBJECTIVES: The objectives of this study were to characterize the effects of intra-accumbens THC in the anterior vs. posterior regions of the NASh during emotional memory formation, sensorimotor gating and anxiety-related behaviours. METHODS: We performed an integrative series of translational behavioural pharmacological studies examining anxiety, sensorimotor gating and fear-related associative memory formation combined with regionally specific molecular signalling analyses in male Sprague Dawley rats. RESULTS: We report that THC in the posterior NASh causes distortions in emotional salience attribution, impaired sensory filtering and memory retention and heightened anxiety, through a glycogen-synthase-kinase-3 (GSK-3)-ß-catenin dependent signalling pathway. In contrast, THC in the anterior NASh produces anxiolytic effects via modulation of protein kinase B (Akt) phosphorylation states. CONCLUSIONS: These findings reveal critical new insights into the neuroanatomical and molecular mechanisms associated with the differential neuropsychiatric side effects of THC in dissociable nucleus accumbens sub-regions.

Functional interactions between cannabinoids, omega-3 fatty acids, and peroxisome proliferator-activated receptors: Implications for mental health pharmacotherapies.

Cannabis contains a plethora of phytochemical constituents with diverse neurobiological effects. Cannabidiol (CBD) is the main non-psychotropic component found in cannabis that is capable of modulating mesocorticolimbic DA transmission and may possess therapeutic potential for several neuropsychiatric disorders. Emerging evidence also suggests that, similar to CBD, omega-3 polyunsaturated fatty acids may regulate DA transmission and possess therapeutic potential for similar neuropsychiatric disorders. Although progress has been made to elucidate the mechanisms underlying the therapeutic properties of CBD and omega-3s, it remains unclear through which receptor mechanisms they may produce their purported effects. Peroxisome proliferator-activated receptors are a group of nuclear transcription factors with multiple isoforms. PPARγ is an isoform activated by both CBD and omega-3, whereas the PPARα isoform is activated by omega-3. Interestingly, the activation of PPARγ and PPARα with selective agonists has been shown to decrease mesocorticolimbic DA activity and block neuropsychiatric symptoms similar to CBD and omega-3s, raising the possibility that CBD and omega-3s produce their effects through PPAR signaling. This review will examine the relationship between CBD, omega-3s, and PPARs and how they may be implicated in the modulation of mesocorticolimbic DAergic abnormalities and associated neuropsychiatric symptoms.

Reversing the Psychiatric Effects of Neurodevelopmental Cannabinoid Exposure: Exploring Pharmacotherapeutic Interventions for Symptom Improvement.

Neurodevelopmental exposure to psychoactive compounds in cannabis, specifically THC, is associated with a variety of long-term psychopathological outcomes. This increased risk includes a higher prevalence of schizophrenia, mood and anxiety disorders, and cognitive impairments. Clinical and pre-clinical research continues to identify a wide array of underlying neuropathophysiological sequelae and mechanisms that may underlie THC-related psychiatric risk vulnerability, particularly following adolescent cannabis exposure. A common theme among these studies is the ability of developmental THC exposure to induce long-term adaptations in the mesocorticolimbic system which resemble pathological endophenotypes associated with these disorders. This narrative review will summarize recent clinical and pre-clinical evidence that has elucidated these THC-induced developmental risk factors and examine how specific pharmacotherapeutic interventions may serve to reverse or perhaps prevent these cannabis-related risk outcomes.

In Utero Exposure to Δ9-Tetrahydrocannabinol Leads to Postnatal Catch-Up Growth and Dysmetabolism in the Adult Rat Liver.

The rates of gestational cannabis use have increased despite limited evidence for its safety in fetal life. Recent animal studies demonstrate that prenatal exposure to Δ9-tetrahydrocannabinol (Δ9-THC, the psychoactive component of cannabis) promotes intrauterine growth restriction (IUGR), culminating in postnatal metabolic deficits. Given IUGR is associated with impaired hepatic function, we hypothesized that Δ9-THC offspring would exhibit hepatic dyslipidemia. Pregnant Wistar rat dams received daily injections of vehicular control or 3 mg/kg Δ9-THC i.p. from embryonic day (E) 6.5 through E22. Exposure to Δ9-THC decreased the liver to body weight ratio at birth, followed by catch-up growth by three weeks of age. At six months, Δ9-THC-exposed male offspring exhibited increased visceral adiposity and higher hepatic triglycerides. This was instigated by augmented expression of enzymes involved in triglyceride synthesis (ACCα, SCD, FABP1, and DGAT2) at three weeks. Furthermore, the expression of hepatic DGAT1/DGAT2 was sustained at six months, concomitant with mitochondrial dysfunction (i.e., elevated p66shc) and oxidative stress. Interestingly, decreases in miR-203a-3p and miR-29a/b/c, both implicated in dyslipidemia, were also observed in these Δ9-THC-exposed offspring. Collectively, these findings indicate that prenatal Δ9-THC exposure results in long-term dyslipidemia associated with enhanced hepatic lipogenesis. This is attributed by mitochondrial dysfunction and epigenetic mechanisms.

Exposure to Δ9-tetrahydrocannabinol during rat pregnancy leads to impaired cardiac dysfunction in postnatal life.

BACKGROUND: Cannabis use in pregnancy leads to fetal growth restriction (FGR), but the long-term effects on cardiac function in the offspring are unknown, despite the fact that fetal growth deficits are associated with an increased risk of developing postnatal cardiovascular disease. We hypothesize that maternal exposure to Δ9-tetrahydrocannabinol (Δ9-THC) during pregnancy will impair fetal development, leading to cardiac dysfunction in the offspring. METHODS: Pregnant Wistar rats were randomly selected and administered 3 mg/kg of Δ9-THC or saline as a vehicle daily via intraperitoneal injection from gestational days 6 to 22, followed by echocardiogram analysis of cardiac function on offspring at postnatal days 1 and 21. Heart tissue was harvested from the offspring at 3 weeks for molecular analysis of cardiac remodelling. RESULTS: Exposure to Δ9-THC during pregnancy led to FGR with a significant decrease in heart-to-body weight ratios at birth. By 3 weeks, pups exhibited catch-up growth associated with significantly greater left ventricle anterior wall thickness with a decrease in cardiac output. Moreover, these Δ9-THC-exposed offsprings exhibited increased expression of collagen I and III, decreased matrix metallopeptidase-2 expression, and increased inactivation of glycogen synthase kinase-3ß, all associated with cardiac remodelling. CONCLUSIONS: Collectively, these data suggest that Δ9-THC-exposed FGR offspring undergo postnatal catch-up growth concomitant with cardiac remodelling and impaired cardiac function early in life. IMPACT: To date, the long-term effects of perinatal Δ9-THC (the main psychoactive component) exposure on the cardiac function in the offspring remain unknown. We demonstrated, for the first time, that exposure to Δ9-THC alone during rat pregnancy results in significantly smaller hearts relative to body weight. These Δ9-THC-exposed offsprings exhibited postnatal catch-up growth concomitant with cardiac remodelling and impaired cardiac function. Given the increased popularity of cannabis use in pregnancy along with rising Δ9-THC concentrations, this study, for the first time, identifies the risk of perinatal Δ9-THC exposure on early postnatal cardiovascular health.

Imaging of Neurotransmitters and Small Molecules in Brain Tissues Using Laser Desorption/Ionization Mass Spectrometry Assisted with Zinc Oxide Nanoparticles.

Inorganic nanostructured materials such as silicon, carbon, metals, and metal oxides have been explored as matrices of low-background signals to assist the laser desorption/ionization (LDI) mass spectrometric (MS) analysis of small molecules, but their applications for imaging of small molecules in biological tissues remain limited in the literature. Titanium dioxide is one of the known nanoparticles (NP) that can effectively assist LDI MS imaging of low molecular weight molecules (LMWM). TiO2 NP is commercially available as dispersions, which can be applied using a chemical solution sprayer. However, aggregation of NP can occur in the dispersions, and the aggregated NP can slowly clog the sprayer nozzle. In this work, the use of zinc oxide (ZnO) NP for LDI MS imaging is investigated as a superior alternative due to its dissolution in acidic pH. ZnO NP was found to deliver similar or better results in the imaging of LMWM in comparison to TiO2 NP. The regular acid washes were effective in minimizing clogging and maintaining high reproducibility. High-quality images of mouse sagittal and rat coronal tissue sections were obtained. Ions were detected predominately as Na+ or K+ adducts in the positive ion mode. The number of LMWM detected with ZnO NP was similar to that obtained with TiO2 NP, and only a small degree of specificity was observed.

Could Cannabidiol Be a Treatment for Coronavirus Disease-19-Related Anxiety Disorders?

Coronavirus disease-19 (COVID-19)-related anxiety and post-traumatic stress symptoms (PTSS) or post-traumatic stress disorder (PTSD) are likely to be a significant long-term issue emerging from the current pandemic. We hypothesize that cannabidiol (CBD), a chemical isolated from Cannabis sativa with reported anxiolytic properties, could be a therapeutic option for the treatment of COVID-19-related anxiety disorders. In the global over-the-counter CBD market, anxiety, stress, depression, and sleep disorders are consistently the top reasons people use CBD. In small randomized controlled clinical trials, CBD (300-800 mg) reduces anxiety in healthy volunteers, patients with social anxiety disorder, those at clinical high risk of psychosis, in patients with Parkinson's disease, and in individuals with heroin use disorder. Observational studies and case reports support these findings, extending to patients with anxiety and sleep disorders, Crohn's disease, depression, and in PTSD. Larger ongoing trials in this area continue to add to this evidence base with relevant patient cohorts, sample sizes, and clinical end-points. Pre-clinical studies reveal the molecular targets of CBD in these indications as the cannabinoid receptor type 1 and cannabinoid receptor type 2 (mainly in fear memory processing), serotonin 1A receptor (mainly in anxiolysis) and peroxisome proliferator-activated receptor gamma (mainly in the underpinning anti-inflammatory/antioxidant effects). Observational and pre-clinical data also support CBD's therapeutic value in improving sleep (increased sleep duration/quality and reduction in nightmares) and depression, which are often comorbid with anxiety. Together these features of CBD make it an attractive novel therapeutic option in COVID-related PTSS that merits investigation and testing through appropriately designed randomized controlled trials.

Exploring the impact of adolescent exposure to cannabinoids and nicotine on psychiatric risk: insights from translational animal models.

Adolescence represents a highly sensitive period of mammalian neurodevelopment wherein critical synaptic and structural changes are taking place in brain regions involved in cognition, self-regulation and emotional processing. Importantly, neural circuits such as the mesocorticolimbic pathway, comprising the prefrontal cortex, sub-cortical mesolimbic dopamine system and their associated input/output centres, are particularly vulnerable to drug-related insults. Human adolescence represents a life-period wherein many individuals first begin to experiment with recreational drugs such as nicotine and cannabis, both of which are known to profoundly modulate neurochemical signalling within the mesocorticolimbic pathway and to influence both long-term and acute neuropsychiatric symptoms. While a vast body of epidemiological clinical research has highlighted the effects of adolescent exposure to drugs such as nicotine and cannabis on the developing adolescent brain, many of these studies are limited to correlative analyses and rely on retrospective self-reports from subjects, making causal interpretations difficult to discern. The use of pre-clinical animal studies can avoid these issues by allowing for precise temporal and dose-related experimental control over drug exposure during adolescence. In addition, such animal-based research has the added advantage of allowing for in-depth molecular, pharmacological, genetic and neuronal analyses of how recreational drug exposure may set up the brain for neuropsychiatric risk. This review will explore some of the advantages and disadvantages of these models, with a focus on the common, divergent and synergistic effects of adolescent nicotine and cannabis exposure on neuropsychiatric risk.