Prenatal Cannabinoid Exposure Research Articles

The impact of prenatal alcohol, synthetic cannabinoid and co-exposure on behavioral adaptations in adolescent offspring and alcohol self-administration in adulthood

Prenatal exposure to alcohol or cannabinoids can produce enduring neurobiological, cognitive, and behavioral changes in the offspring. Furthermore, prenatal co-exposure to alcohol and cannabinoids induces malformations in brain regions associated with reward and stress-related circuitry. This study examined the effects of co-exposure to alcohol and the synthetic cannabinoid (SCB) CP55,940 throughout gastrulation and neurulation in rats on basal corticosterone levels and a battery of behavioral tests during adolescence and alcohol self-administration in adulthood. Importantly, we find that prenatal alcohol exposure (PAE) caused lower baseline corticosterone levels in adolescent males and females. Co-exposure to alcohol + CP produced hyperactivity during open field test in males, but not females. During the two-bottle choice alcohol-drinking procedure, prenatal cannabinoid exposed male and female adolescent rats drank more alcohol than their vehicle-exposed controls. In adulthood, female rats treated with prenatal cannabinoid exposure (PCE), showed an overall total increase in alcohol intake during alcohol self-administration; but this was not found in males. When the reinforcer was changed to a 1% sucrose solution, male rats exposed to PCE, showed a reduced self-administration compared to vehicle-exposed males, potentially indicative of an anhedonic response. This lower self-administration persisted when 20% alcohol was reintroduced to the sucrose solution. Lastly, following an abstinence period, there were no changes due to prenatal drug exposure in either males or females. Overall, these data suggest lasting consequences of prenatal alcohol and cannabinoid exposure during adolescence and adulthood in male and female rats.

The impact of recreational cannabinoid legalization on utilization in a pregnant population.

Marijuana potency and utilization both continue to increase across the United States. While the overall prevalence of cannabinoid utilization during pregnancy has been surveyed in various studies, the direct impact of changing governmental policies on pregnancy use is less characterized. Thus, we aimed to investigate how the legalization of recreational cannabinoid products impacted use during pregnancy in the state of New Mexico. Participants who had a live birth during two study epochs were included: pre-legalization (Epoch 1: 1 January 2019-31 March 2021) and post-legalization (Epoch 2: 1 November 2021-30 November 2022). Participants were further divided into case group [prenatal cannabinoid exposure (PCE)] vs. control (no PCE), with cases being identified by documented self-report or a positive laboratory toxicology test for cannabinoid use during pregnancy. A total of 1,191 maternal/infant dyads were included in Epoch 1, and 378 maternal/infant dyads were included in Epoch 2. In Epoch 1, 788 dyads were controls with 403 cases, while Epoch 2 had 292 controls and 86 cases. Interestingly there was a significant decrease in self-report or positive laboratory toxicology tests in Epoch 2 compared to Epoch 1. Infants born following PCE in both Epoch groups were more commonly born via Cesarean section, had significantly smaller birth weight, length, and head circumference as well as significantly lower Apgar scores at 1 and 5 min. The finding of decreased reported cannabinoid use in the post-legalization group is contradictory to previous studies which have shown increased rates of cannabinoid use after legalization. This could be due to multiple factors including changes in screening practices, the COVID-19 pandemic, and lack of commercialization of THC products. Additional studies are needed to further characterize how changing governmental policies impacts utilization during pregnancy.

Prenatal cannabinoid exposure and early language development

Prenatal cannabinoid exposure and early language development

Prenatal Cannabinoid Exposure Elicits Memory Deficits Associated with Reduced PSA-NCAM Expression, Altered Glutamatergic Signaling, and Adaptations in Hippocampal Synaptic Plasticity.

Cannabis is now one of the most commonly used illicit substances among pregnant women. This is particularly concerning since developmental exposure to cannabinoids can elicit enduring neurofunctional and cognitive alterations. This study investigates the mechanisms of learning and memory deficits resulting from prenatal cannabinoid exposure (PCE) in adolescent offspring. The synthetic cannabinoid agonist WIN55,212-2 was administered to pregnant rats, and a series of behavioral, electrophysiological, and immunochemical studies were performed to identify potential mechanisms of memory deficits in the adolescent offspring. Hippocampal-dependent memory deficits in adolescent PCE animals were associated with decreased long-term potentiation (LTP) and enhanced long-term depression (LTD) at hippocampal Schaffer collateral-CA1 synapses, as well as an imbalance between GluN2A- and GluN2B-mediated signaling. Moreover, PCE reduced gene and protein expression of neural cell adhesion molecule (NCAM) and polysialylated-NCAM (PSA-NCAM), which are critical for GluN2A and GluN2B signaling balance. Administration of exogenous PSA abrogated the LTP deficits observed in PCE animals, suggesting PSA mediated alterations in GluN2A- and GluN2B- signaling pathways may be responsible for the impaired hippocampal synaptic plasticity resulting from PCE. These findings enhance our current understanding of how PCE affects memory and how this process can be manipulated for future therapeutic purposes.

Prenatal cannabinoid exposure: why expecting individuals should take a pregnancy pause from using cannabinoid products.

Cannabinoid use in all populations is increasing as legalization across the United States continues. Concerningly, there is a lack of caution provided by medical providers to pregnant individuals as to the impact the use of cannabinoids could have on the developing fetus. Research continues in both the preclinical and clinical areas, and is severely needed, as the potency of delta-9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis, has increased dramatically since the initial studies were completed. Thus far, clinical studies raise compelling evidence for short term memory deficits, impulse control issues, and attention deficiencies following prenatal cannabinoid exposure (PCE). These changes may be mediated through epigenetic modifications that not only impact the current offspring but could carry forward to future generations. While additional studies are needed, a pregnancy pause from cannabinoid products should be strongly recommended by providers to ensure the optimal health and well-being of our future generations.

Effects of prenatal cannabinoid exposure.

Effects of prenatal cannabinoid exposure.

Influence of prenatal cannabinoid exposure on early development and beyond.

Public perception surrounding whether cannabis use is harmful during pregnancy often diverges greatly from the recommendations of doctors and healthcare providers. In contrast to the medical guidance of abstinence before, during, and after pregnancy, many women of reproductive age believe cannabis use during pregnancy is associated with little potential harm. Legalization and social cues support public perceptions that cannabis use during pregnancy is safe. Moreover, pregnant women may consider cannabis to be a safe alternative for treating pregnancy related ailments, including morning sickness. Compounding the problem is a lack of medical and federal guidance on safe, low, or high-risk levels of cannabis use. These issues mirror the continuing debate surrounding alcohol use and health, in particular, whether there are safe or lower risk levels of alcohol consumption during pregnancy. Clinical studies to date suffer from several limitations. First, most human studies are correlative in nature, meaning that causal associations cannot be made between in utero cannabis exposure and health and behavioral outcomes later in life. Due to obvious ethical constraints, it is not possible to randomly assign pregnant mothers to cannabis or other drug exposure conditions-a requirement needed to establish causality. In addition, clinical studies often lack quantitative information on maternal exposure (i.e., dose, frequency, and duration), include a small number of individuals, lack replication of outcome measures across cohorts, rely on self-report to establish maternal drug use, and suffer from unmeasured or residual confounding factors. Causal associations between maternal cannabis exposure and offspring outcomes are possible in preclinical cohorts but there is a large amount of heterogeneity across study designs and developmental differences between rodents and humans may limit translatability. In this review, we summarize research from human and preclinical models to provide insight into potential risks associated with prenatal cannabinoid exposure (PCE). Finally, we highlight gaps in knowledge likely to contribute to the growing divide between medical guidance and public attitudes regarding cannabis use during pregnancy.

Effects of prenatal synthetic cannabinoid exposure on the cerebellum of adolescent rat offspring

Cannabis is the most commonly used illicit drug worldwide. Recently, cannabis use among young pregnant women has greatly increased. However, prenatal cannabinoid exposure leads to long-lasting cognitive, motor, and behavioral deficits in the offspring and alterations in neural circuitry through various mechanisms. Although these effects have been studied in the hippocampus, the effects of prenatal cannabinoid exposure on the cerebellum are not well elucidated. The cerebellum plays an important role in balance and motor control, as well as cognitive functions such as attention, language, and procedural memories. The aim of this study was to investigate the effects of prenatal cannabinoid exposure on the cerebellum of adolescent offspring. Pregnant rats were treated with synthetic cannabinoid agonist WIN55,212-2, and the offspring were evaluated for various cerebellar markers of oxidative stress, mitochondrial function, and apoptosis. Additionally, signaling proteins associated with glutamate dependent synaptic plasticity were examined. Administration of WIN55,212-2 during pregnancy altered markers of oxidative stress by significantly reducing oxidative stress and nitrite content. Mitochondrial Complex I and Complex IV activities were also enhanced following prenatal cannabinoid exposure. With regard to apoptosis, pP38 levels were significantly increased, and proapoptotic factor caspase-3 activity, pERK, and pJNK levels were significantly decreased. CB1R and GluA1 levels remained unchanged; however, GluN2A was significantly reduced. There was a significant decrease in MAO activity although tyrosine hydroxylase activity was unaltered. Our study indicates that the effects of prenatal cannabinoid exposure on the cerebellum are unique compared to other brain regions by enhancing mitochondrial function and promoting neuronal survival. Further studies are required to evaluate the mechanisms by which prenatal cannabinoid exposure alters cerebellar processes and the impact of these alterations on behavior.

Prenatal Cannabinoid Exposure: Emerging Evidence of Physiological and Neuropsychiatric Abnormalities.

Clinical reports of cannabis use prevalence during pregnancy vary widely from 3% to upwards of 35% in North America; this disparity likely owing to underestimates from self-reporting in many cases. The rise in cannabis use is mirrored by increasing global legalization and the overall perceptions of safety, even during pregnancy. These trends are further compounded by a lack of evidence-based policy and guidelines for prenatal cannabis use, which has led to inconsistent messaging by healthcare providers and medically licensed cannabis dispensaries regarding prenatal cannabis use for treatment of symptoms, such as nausea. Additionally, the use of cannabis to self-medicate depression and anxiety during pregnancy is a growing medical concern. This review aims to summarize recent findings of clinical and preclinical data on neonatal outcomes, as well as long-term physiological and neurodevelopmental outcomes of prenatal cannabis exposure. Although many of the outcomes under investigation have produced mixed results, we consider these data in light of the unique challenges facing cannabis research. In particular, the limited longitudinal clinical studies available have not previously accounted for the exponential increase in (-)-Δ9– tetrahydrocannabinol (Δ9–THC; the psychoactive compound in cannabis) concentrations found in cannabis over the past two decades. Polydrug use and the long-term effects of individual cannabis constituents [Δ9–THC vs. cannabidiol (CBD)] are also understudied, along with sex-dependent outcomes. Despite these limitations, prenatal cannabis exposure has been linked to low birth weight, and emerging evidence suggests that prenatal exposure to Δ9–THC, which crosses the placenta and impacts placental development, may have wide-ranging physiological and neurodevelopmental consequences. The long-term effects of these changes require more rigorous investigation, though early reports suggest Δ9–THC increases the risk of cognitive impairment and neuropsychiatric disease, including psychosis, depression, anxiety, and sleep disorders. In light of the current trends in the perception and use of cannabis during pregnancy, we emphasize the social and medical imperative for more rigorous investigation of the long-term effects of prenatal cannabis exposure.

Prenatal Cannabinoid Exposure Impacts Offspring's Health in Sickle Mice

Cannabis use is rising amongst pregnant women. An estimated 4% of pregnant women in the United States use cannabis, but, in California approximately 20% of 18-24-year-old pregnant women in a study cohort reported using cannabis (Young-Wolff et al JAMA 2017). Cannabis and cannabinoid use are relatively higher in patients with sickle cell disease (SCD) compared to the general population, perhaps due to pain. Majority of SCD patients in the Western world are on hydroxyurea (HU), which improves survival. However, HU is not prescribed to SCD patients who become pregnant, which may increase the likelihood of cannabinoid use to control pain. This may have devastating consequences as even a single dose of synthetic- (CP 55940) or phyto-cannabinoids (cannabidiol or Δ9-tetrahydrocannabinol) when administered to pregnant C57BL/6 mice on day 8 of gestation produced developmental changes in the offspring. (Fish et al Sci. Rep. 2019). Thus, we hypothesized that cannabinoid use during pregnancy will have teratogenic effects on the offspring's health in SCD. Using humanized transgenic Berkeley sickle (HbSS) and hemizygous (HbAS) mice and control mice expressing normal human hemoglobin A (HbAA), we examined the effect of chronic maternal cannabinoid exposure on the health outcomes of their offsprings. We paired hemizygous AS Berkeley females (homozygous SS Berkeley females do not breed well) with homozygous SS Berkeley males, while AA control mice were paired with each other. Females were treated with HU (i.p., 50 mg/kg/day) for two weeks prior to pairing with a male. Female mice were then treated with CP55940 (CP; i.p., 0.3 mg/kg/day) or vehicle (Veh; 2% DMSO in sterile saline) during breeding until the pups were born (~3 weeks). A subset of females were left untreated to assess baseline measures. At birth, we recorded: [a] litter size, [b] body weight, [c] body size (crown to rump length), [d] right and left eye diameters, and [e] front- and hind-limb lengths. High-resolution digital images were acquired to quantify these parameters. At P21 pups were weighed and euthanized then their organs were collected, weighed, and fixed in formalin. Observations at birth: Use of HU in AS females yielded a larger mean litter size than those of untreated AS females (8.5 vs 5.5 pups/litter). No difference in mean litter size of AA mice treated with HU was observed. The body weight between offspring of AA mice treated with HU+Veh and HU+CP was not significantly different. However, in both the offspring of AA mice and AS/SS mice treated with HU+CP, we observed a ~20% decrease in body weight compared to the untreated AA (p<0.001) and AS/SS (p<0.001) offspring. We observed a similar 20% decrease in body weight between the offspring of AA mice treated with HU+Veh and untreated AA offspring (20%, p<0.001), while no decrease in body weight was observed between AS/SS offspring treated with HU+Veh and untreated AS/SS offspring. Taken together, these data show that maternal cannabinoid treatment leads to a significant decrease in the body weight of offspring. Observations at post-natal day 21: Significant decreases in mean body size (5%, p<0.01) and right eye diameters (8%, p<0.01 & 7%, p<0.05) were seen in the offspring of AA mice treated with HU+CP compared to HU+Veh. Offspring of AS/SS mice treated with HU+CP showed reduced mean body size (~9%, p<0.001), reduced right and left eye diameters (20%, p<0.001 & 19%, p<0.001 respectively), and reduced front and hind limb lengths (21%, p<0.001 & 16%, p<0.001 respectively) compared to those treated with HU+ Veh. In addition, the offspring of AS/SS mice treated with HU+CP had about a 20% decrease in the ratio of brain to body weight compared to HU+Veh treated AS/SS mice (p<0.001). No significant differences in mean litter size, body weight, front and hind limb length and brain weight to body weight ratio were observed between offspring of AA mice treated with HU+Veh and HU+CP. Our data suggest that development/growth of the offspring's body and brain may be hindered by pre-natal cannabinoid exposure and that chronic parental cannabinoid use during pregnancy has a more substantial adverse impact on offspring's health in sickle mice than in control mice. Our data raise concern for cannabinoid use during pregnancy in SCD, which may have adverse effects on the offspring's health and therefore requires monitoring in prospective clinical studies. Disclosures Gupta: CSL Behring: Honoraria; Tautona Group: Honoraria; Novartis: Honoraria; Grifols: Research Funding; 1910 Genetics: Research Funding; Cyclerion: Research Funding.

Mesolimbic dopamine dysregulation as a signature of information processing deficits imposed by prenatal THC exposure

Cannabis is the illicit drug most widely used by pregnant women worldwide. Its growing acceptance and legalization have markedly increased the risks of child psychopathology, including psychotic-like experiences, which lowers the age of onset for a first psychotic episode. As the majority of patients with schizophrenia go through a premorbid condition long before this occurs, understanding neurobiological underpinnings of the prodromal stage of the disease is critical to improving illness trajectories and therapeutic outcomes. We have previously shown that male rat offspring prenatally exposed to Δ9-tetrahydrocannabinol (THC), a rat model of prenatal cannabinoid exposure (PCE), exhibit extensive molecular and synaptic changes in dopaminergic neurons of the ventral tegmental area (VTA), converging on a hyperdopaminergic state. This leads to a silent psychotic-like endophenotype that is unmasked by a single exposure to THC. Here, we further characterized the VTA dopamine neuron and sensorimotor gating functions of PCE rats exposed to acute stress or a challenge of the D2 receptor agonist apomorphine, by using in vivo single-unit extracellular recordings and Prepulse Inhibition (PPI) analyses. At pre-puberty, PCE male rat offspring display a reduced population activity of VTA dopamine neurons in vivo, the majority of which are tonically active. PCE male progeny also exhibit enhanced sensitivity to dopamine D2 (DAD2) receptor activation and a vulnerability to acute stress, which is associated with compromised sensorimotor gating functions. This data extends our knowledge of the multifaceted sequelae imposed by PCE in the mesolimbic dopamine system of male pre-adolescent rats, which renders a neural substrate highly susceptible to subsequent challenges that may trigger psychotic-like outcomes.

Prenatal Cannabinoid Exposure Mediated Cognitive Deficits in the Offspring: Elucidation of the Mechanism and Identifying Therapeutic Targets

Cannabinoid is currently one of the most commonly used recreational drugs in the world with an approximate user of 22.2 million. As more and more states in the US are legalizing the use of cannabinoid, the rate of cannabinoid use is increasing specially in pregnant women. The active ingredient of cannabis is delta‐9‐tetrahydrocannabinol (THC) which can cross blood placental barrier and may cause enduring alterations in synaptic circuitry of the fetal brain. The aim of our study is to investigate the mechanism of learning and memory deficits in case of prenatal cannabinoid exposure (PCE) in the adolescent offspring. An osmotic pump filled with either vehicle or the cannabinoid receptor full agonist WIN55,212‐2 (2 mg/kg body weight/day) was implanted subcutaneously in Gestational Day‐3 to deliver the drug at a constant rate until the pups were born. Open field test was performed to see the effect of PCE on locomotor activity which revealed no abnormality in the general motor activity. Contextual fear conditioning test indicated a significantly reduced freezing behavior in the PCE group compared to the vehicle exposed group. Hippocampus based spatial memory test Morris water maze showed that during the trial period, PCE animals exhibit no preference for any particular quadrant while control animals had an increased preference for the quadrant where the hidden platform was present during the training period. Electrophysiological experiments were performed on the Schaffer collateral pathway of acute hippocampal slices to measure synaptic plasticity. Impairment in both long term potentiation (LTP) and long‐term depression (LTD), which are important parameters of synaptic plasticity, were observed. These impairments were associated with downstream changes in the glutamatergic signaling. An increase in cannabinoid receptor type 1(CB1) expression followed by reduced neural cell adhesion molecule (NCAM) and its active form polysialylated NCAM (PSA‐NCAM) expression have been observed in the hippocampus of PCE animals. Interestingly, restoration of PSA‐NCAM activity restored the LTP deficits observed in PCE animals. Thus, based on the previous studies and our current data, it can be postulated that, the observed cognitive deficits in the PCE animals might be partly due to an imbalance in glutamate receptors mediated neurotransmission influenced by NCAM/PSA NCAM. Understanding this specific NCAM/PSA‐NCAM interdependent signaling cascade will lead to an identification of a specific therapeutic target to improve gestational cannabinoid exposure mediated memory deficits.

Prenatal THC exposure raises kynurenic acid levels in the prefrontal cortex of adult rats

Cannabis remains one of the most widely used illicit drugs during pregnancy. The main psychoactive component of marijuana (Δ9-tetrahydrocannabinol, THC) is correlated with untoward physiological effects in the offspring. Neurobehavioral and cognitive impairments have been reported in longitudinal studies on children and adolescents prenatally exposed to marijuana, and a link to psychiatric disorders has been proposed. Interestingly, the deleterious effects of prenatal cannabis use are similar to those observed in adult rats prenatally exposed to (L)-kynurenine, the direct bioprecursor of the neuroactive metabolite kynurenic acid (KYNA). We therefore investigated whether alterations in KYNA levels in the rat brain might play a role in the long-term consequences of prenatal cannabinoid exposure. Pregnant Wistar rats were treated daily with THC [5 mg/kg, p.o.] from gestational day (GD)5 through GD20. Using in vivo microdialysis in the medial prefrontal cortex, adult animals were then used to determine the extracellular levels of KYNA and glutamate. Compared to controls, extracellular basal KYNA levels were higher, and basal glutamate levels were lower, in prenatally THC-exposed rats. These rats also showed abnormal short-term memory. Following an additional acute challenge with a low dose of kynurenine (5 mg/kg i.p.) in adulthood, the increase in extracellular KYNA levels in the mPFC was more pronounced in in prenatally THC-exposed rats. These effects could be causally related to the cognitive dysfunction seen in prenatally THC-exposed rats. In the translational realm, these experiments raise the prospect of prevention of KYNA neosynthesis as a promising novel approach to combat some of the detrimental long-term effects of prenatal cannabis use.

Mechanism of Prenatal Cannabinoid Exposure Mediated Memory Loss in Adolescent Offspring: Opportunities for Identifying Therapeutic Target

Cannabis use during pregnancy has increased by 62% from 2002 through 2014 and is now the most commonly used illicit drug during pregnancy, in part due to its ability to reduce morning sickness during pregnancy. Several studies have demonstrated that neural network activity which underlies typical cognitive and behavioral processes can be altered by prenatal cannabinoid exposure (PCE) leading to a long lasting effects on adult behavior. Here, we have investigated the impact of PCE in adolescent offspring in hippocampus dependent learning and memory via performing a series of behavioral, electrophysiological and immunochemical studies. An osmotic pump filled with either vehicle or the cannabinoid receptor full agonist WIN55, 212–2 (2 mg/kg body weight/day) was implanted subcutaneously in gestational day 4, which delivered the drug at a constant rate until the pups were born. Contextual Fear Conditioning and Morris Water Maze test were performed to investigate the hippocampus based memory revealing significant learning deficits in the PCE group. To investigate the mechanisms behind observed behavioral deficits, electrophysiological experiments were performed on acute hippocampal slices. Reduced long‐term potentiation and enhanced and long term depression were observed in the PCE group demonstrating impaired synaptic plasticity. To identify alterations in the downstream signaling cascade involved in glutamatergic neurotransmission, immunoblotting experiment was performed. Immunoblotting data showed increased Cannabinoid Receptor Type 1(CB1) expression along with reduced Neural Cell Adhesion Molecule (NCAM) expression. NCAM is important for maintaining proper neuronal connections, and it modulates NMDA mediated glutamatergic neurotransmission. Based on our data, we hypothesize that a reduction in NCAM may be responsible for the learning and memory deficits observed in PCE animals and can be used as a therapeutic target to ameliorate the cognitive deficits in PCE offspring.Support or Funding InformationNo Available Funding SourceThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Sex-dependent effects of in utero cannabinoid exposure on cortical function.

Cannabinoids can cross the placenta, thus may interfere with fetal endocannabinoid signaling during neurodevelopment, causing long-lasting deficits. Despite increasing reports of cannabis consumption during pregnancy, the protracted consequences of prenatal cannabinoid exposure (PCE) remain incompletely understood. Here, we report sex-specific differences in behavioral and neuronal deficits in the adult progeny of rat dams exposed to low doses of cannabinoids during gestation. In males, PCE reduced social interaction, ablated endocannabinoid long-term depression (LTD) and heightened excitability of prefrontal cortex pyramidal neurons, while females were spared. Group 1 mGluR and endocannabinoid signaling regulate emotional behavior and synaptic plasticity. Notably, sex-differences following PCE included levels of mGluR1/5 and TRPV1R mRNA. Finally, positive allosteric modulation of mGlu5 and enhancement of anandamide levels restored LTD and social interaction in PCE adult males. Together, these results highlight marked sexual differences in the effects of PCE and introduce strategies for reversing detrimental effects of PCE.

Endocannabinoids via CB1receptors act as neurogenic niche cues during cortical development

During brain development, neurogenesis is precisely regulated by the concerted action of intrinsic factors and extracellular signalling systems that provide the necessary niche information to proliferating and differentiating cells. A number of recent studies have revealed a previously unknown role for the endocannabinoid (ECB) system in the control of embryonic neuronal development and maturation. Thus, the CB(1) cannabinoid receptor in concert with locally produced ECBs regulates neural progenitor (NP) proliferation, pyramidal specification and axonal navigation. In addition, subcellularly restricted ECB production acts as an axonal growth cone signal to regulate interneuron morphogenesis. These findings provide the rationale for understanding better the consequences of prenatal cannabinoid exposure, and emphasize a novel role of ECBs as neurogenic instructive cues involved in cortical development. In this review the implications of altered CB(1)-receptor-mediated signalling in developmental disorders and particularly in epileptogenesis are briefly discussed.

Cannabis use and cognitive dysfunction

Byline: Amresh. Shrivastava, Megan. Johnston, Ming. Tsuang This review considers the effects of cannabis on cognitive functioning, in both short and long term. Although the general impression supported by many studies is that cannabis causes cognitive decline, particularly with long-term usage, some research suggests that this may not be the case. Nevertheless, certain specific neuropsychological parameters have been found to be affected. Most commonly and consistently reported are response time, prolongation of word viewing time, basic oculomotor deficit, residual verbal memory and executive functioning. The pathways to cognitive dysfunction are given particular focus, including the role of the central nervous system (CNS) cannabinoid system. Finally, the psychiatric effects of cannabis are considered in light of the idea that cognitive function may be the common denominator in the association between cannabis and psychotic disorders. Effect of Cannabis on Cognition Cannabis is one of the most commonly abused illicit drugs. The World Health Organization [sup][1] reports that almost 3% of the world's adult population abuses cannabis, with many more individuals reporting less frequent use. Adolescents in particular consume high levels of cannabis, starting generally between 12 and 16 years of age. This is an important factor from a psychiatric and developmental point of view. [sup][2] Cannabis use is of important consideration in light of its recognized acute and long-term health effects. [sup][1],[3] Active compounds of cannabis, called cannabidols, have 64 active isomers, each having different effects on human health and behavior. Only one metabolite, tetrahydrocannabinol (THC), is reported to be an active metabolite responsive for its effects. [sup][4] Studies show that it induces both psychical and physical dependencies, [sup][5] but the perception of withdrawal is weak on account of its slow elimination. [sup][6] There is a widely held belief that cannabis is inert to the brain, [sup][7] and although the psychological consequences are quite evident, the population at large seems unconvinced. There is much debate about the nature of cannabis dependence, as it is considered non-addicting due to the absence of a withdrawal state. This presumption has also been proved wrong. [sup][6] The general impression supported by many studies is that cannabis causes cognitive decline, particularly with long-term usage. Majority of studies have suggested a significant cognitive decline in cannabis abusers compared to non-abusers and healthy controls. [sup][8],[9],[10] A report by Bartholomew et al. [sup][11] suggested that cannabis use has a detrimental effect on prospective memory ability in young adults but users may not be aware of these deficits. Cannabis is known to produce substantial acute effects on human cognition and visuomotor skills. Many recent studies additionally revealed rather long-lasting effects on basic oculomotor control, especially after chronic use. [sup][12] Even so, it is still unknown to what extent these deficits play a role in everyday tasks that strongly rely on an efficient saccade system, such as reading. Cannabis has a negative impact on cognition; however, the current body of research literature does not provide evidence of significant, long-term effects due to cannabis use. Several acute effects are noted and some are suggestive of negative mental health consequences. [sup][13] Evidence from both animal and human studies suggests that the severity of the effects of cannabis use on cognitive development is dependent on the age when cannabis use begins. [sup][14] One possible explanation is that those who begin cannabis use early in adolescence are more likely to become heavily dependent. It is plausible that chronic cannabis abuse will then interfere with educational and vocational training. From a more biological perspective, however, use of cannabis during critical developmental periods in the still maturing brain may induce persistent alterations in brain structure and brain function. …

The endocannabinoid system and the regulation of neural development: potential implications in psychiatric disorders

During brain development, functional neurogenesis is achieved by the concerted action of various steps that include the expansion of progenitor cells, neuronal specification, and establishment of appropriate synapses. Brain patterning and regionalization is regulated by a variety of extracellular signals and morphogens that, together with neuronal activity, orchestrate and regulate progenitor proliferation, differentiation, and neuronal maturation. In the adult brain, CB(1) cannabinoid receptors are expressed at very high levels in selective areas and are engaged by endocannabinoids, which act as retrograde messengers controlling neuronal function and preventing excessive synaptic activity. In addition, the endocannabinoid system is present at early developmental stages of nervous system formation. Recent studies have provided novel information on the role of this endogenous neuromodulatory system in the control of neuronal specification and maturation. Thus, cannabinoid receptors and locally produced endocannabinoids regulate neural progenitor proliferation and pyramidal specification of projecting neurons. CB(1) receptors also control axonal navigation, migration, and positioning of interneurons and excitatory neurons. Loss of function studies by genetic ablation or pharmacological blockade of CB(1) receptors interferes with long-range subcortical projections and, likewise, prenatal cannabinoid exposure induces different functional alterations in the adult brain. Potential implications of these new findings, such as the participation of the endocannabinoid system in the pathogenesis of neurodevelopmental disorders (e.g., schizophrenia) and the regulation of neurogenesis in brain depression, are discussed herein.

Neurobiological consequences of maternal cannabis on human fetal development and its neuropsychiatric outcome

Despite the high prevalence of marijuana use among pregnant women and adolescents, the impact of cannabis on the developing brain is still not well understood. However, growing evidence supports that the endocannabinoid system plays a major role in CNS patterning in structures relevant for mood, cognition, and reward, such as the mesocorticolimbic system. It is thus clear that exposure to cannabis during early ontogeny is not benign and potential compensatory mechanisms that might be expected to occur during neurodevelopment appear insufficient to eliminate vulnerability to neuropsychiatric disorders in certain individuals. Both human longitudinal cohort studies and animal models strongly emphasize the long-term influence of prenatal cannabinoid exposure on behavior and mental health. This review provides an overview of the endocannabinoid system and examines the neurobiological consequences of cannabis exposure in pregnancy and early life by addressing its impact on the development of neurotransmitters systems relevant to neuropsychiatric disorders and its association with these disorders later in life. It posits that studying in utero cannabis exposure in association with genetic mutations of neural systems that have strong relationships to endocannabinoid function, such as the dopamine, opioid, glutamate, and GABA, might help to identify individuals at risk. Such data could add to existing knowledge to guide public health platform in regard to the use of cannabis and its derivatives during pregnancy.

Prenatal Cannabinoid Exposure Down- Regulates Glutamate Transporter Expressions (GLAST and EAAC1) in the Rat Cerebellum

Efficient reuptake of synaptically released glutamate is essential for preventing glutamate receptor overstimulation and neuronal death. Glutamate transporters play a vital role in removing extracellular glutamate from the synaptic cleft. This study analyzed the expression of the glial (GLAST) and neuronal (EAAC1) subtypes of glutamate transporter in the cerebellum of male and female offspring exposed pre- and postnatally to Δ⁹-tetrahydrocannabinol (THC, the main component of marijuana). Pregnant rats were administered saline or THC from gestational day 5 to postnatal day 20 (PD20). The expression of glutamate transporters was examined at PD20, PD30 and PD70 (10 and 50 days after THC withdrawal) to analyze the short- and long-term effects of prenatal THC exposure. The expression of the glutamate transporter GLAST in astroglial cells and EAAC1 in Purkinje neurons decreased in THC-exposed offspring compared to controls. This reduction was observed at all ages but mainly in males. Moreover, the glial glutamate transporter level in THC-exposed rats (quantified by Western blot) was lower than in control rats. These results suggest that THC exposure during cerebellar development may alter the glutamatergic system not only during the period of drug exposure but in the postnatal stage following withdrawal. The down-regulation reported here might reflect an abnormal maturation of the glutamatergic neuron-glia circuitry.