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Marijuana use during adolescence has reached virtually every strata of society. The general population has the perception that marijuana use is safe for mature people and therefore is also safe for developing adolescents. However, both clinical and preclinical research shows that marijuana use, particularly prior to age 16, could have long-term effects on cognition, anxiety and stress-related behaviors, mood disorders and substance abuse. These effects derive from the role of the endocannabinoid system, the endogenous cannabinoid system, in the development of cortex, amygdala, hippocampus and hypothalamus during adolescence. Endocannabinoids are necessary for normal neuronal excitation and inhibition through actions at glutamate and GABA terminals. Synaptic pruning at excitatory synapses and sparing of inhibitory synapses likely results in changes in the balance of excitation/inhibition in individual neurons and within networks; processes which are necessary for normal cortical development. The interaction between prefrontal cortex (PFC), amygdala and hippocampus is responsible for emotional memory, anxiety-related behaviors and drug abuse and all utilize the endogenous cannabinoid system to maintain homeostasis. Also, endocannabinoids are required for fast and slow feedback in the normal stress response, processes which mature during adolescence. Therefore, exogenous cannabinoids, such as marijuana, have the potential to alter the course of development of each of these major systems (limbic, hypothalamic-pituitary-adrenal (HPA) axis and neocortex) if used during the critical period of brain development, adolescence. This article is part of a Special Issue entitled SI: Adolescent plasticity . [ABSTRACT FROM AUTHOR]

Recent research has demonstrated that the endogenous cannabinoid system is central to the brain's response to stress. As part of an ongoing collaboration, we sought to examine the effects of prenatal and early postnatal rearing and housing conditions on developing endocannabinoid systems. We compare brain cannabinoid receptors (CBR) in offspring of either prenatal vehicle intubated or non-treated dams (Experiment 1) or in rats derived from a vendor and shipped at weaning to a collaborating lab (Experiment 2). From postnatal day (PND) 23, all rats were either housed in isolated conditions or enriched conditions with 3 rats/cage and a variety of stimulus objects changed twice a week. All rats underwent 5 days of handling as controls for a behavior study and all rats were sacrificed at approximately PND48–50 within 2 hours of the last behavioral test. All brains were processed together for CB1 receptor binding using 3 H CP55,940 in prefrontal cortex, striatum, amygdala and hippocampus. Conditions in the two labs were as similar as possible since the two studies were intentionally designed to be comparable and contemporary. Results show that 1) comparing offspring of non-treated dams to offspring of dams receiving daily vehicle intubations, males show decreased CB1 binding in most brain regions while females only showed alterations in the hippocampus and these were increases in the offspring of the vehicle-intubated dams. 2) When comparing offspring of non-treated dams in NY with those derived from a vendor, shipped and maintained in the collaborating lab, this latter group showed reduced CB1 binding in prefrontal cortex in males and increased binding in all four brain regions in females. Therefore, overall, both prenatal handling (intubations) and being vendor-derived, shipped and maintained in a collaborating facility reduced CB1 receptors in males and increased them in females in key limbic brain regions. Effects of environmental enrichment or isolation were minor with only the prefrontal cortex showing an increase in binding in the isolated animals that were offspring of the vehicle-intubated dams. These results support the ideas that prenatal/early postnatal conditions produce different effects in males and females and override the effects of enrichment/isolation on cannabinoid receptors. Behavioral responses to cannabinoid challenges would therefore be expected to vary depending on sex, prenatal/early postnatal history and postweaning conditions of the rats. Since exogenous cannabinoids act through the CBR, the present data may provide a molecular basis for discrepant behavioral effects reported across various labs in the literature as well as sex differences seen following stress and/or manipulation of the cannabinoid system. [ABSTRACT FROM AUTHOR]

Decades of research have shown the robust behavioral, structural, and molecular effects of environmental enrichment (EE) which predominantly improves neuropathological conditions. However, systematic examination of age and sex influences in response to EE is limited. Examine the use of EE and evaluate where sex differences (or similarities) are described and whether critical developmental periods are addressed. A critical examination of review articles about EE will establish a framework for the context of the findings of EE-induced effects, improve the impact of future EE studies and improve translatability. Narrative, systematic reviews (not original reports) and meta-analyses of any animal species published during 2011 to 2021. Clinical and farming studies were excluded. Indexed review articles in Pubmed and Psychinfo. Most studies examine EE during adulthood such as following an injury or following repeated addictive drug exposure. However, in various genetic models of disease states, little attention is paid to effects of EE at different ages. Only some reviews acknowledge that sex differences exist even when the disease state under study is known to be sexually dimorphic. Identified issues include lack of systematic reporting; status of the "control group" (i.e., isolation or pair housing); the use and reporting of proper statistical analyses. Reviews have concluded that EE is most effective when administered early in life but that EE during adulthood is certainly effective. Too few review studies have compared sexes for the effects of EE to make a statement about sex differences. Overall, articles reflect a lack of integration of information on age and sex differences in response to EE. Future studies of EE should examine both sexes and consider critical periods of the lifespan in the experimental models to facilitate the adequate translation of EE as a non-pharmaceutical intervention. • A scoping review on environmental enrichment(EE), sex differences and lifespan • Reviews generally did not present interactions of age and sex in response to EE. • Inconsistent reporting on age and sex differences in response to EE was found. • Limitations of studies include: control issues, improper statistics, inadequate reporting. • In various disease models, reviews show that EE is generally beneficial. [ABSTRACT FROM AUTHOR]

Abstract: Research suggests that the use and abuse of marijuana can be especially harmful if it occurs during adolescence, a period of vast developmental changes throughout the brain. Due to the localization of cannabinoid receptors within the limbic system and the established effects of cannabinoids on emotional states and anxiety levels of rats and humans, we studied the sex- and dose-related effects of Δ9-tetrahydrocannabinol (THC, the main psychoactive component in marijuana) on behavior and anxiety during spontaneous withdrawal. Male and female Sprague Dawley rats were administered 2, 7.5 or 15mg/kg THC or vehicle from postnatal day 35–41 (approximating mid-adolescence in humans). Locomotor activity and anxiety-related behaviors were measured during drug administration and abstinence. THC caused significant dose-dependent locomotor depression during drug administration. Locomotor depression initially abated upon drug cessation, but re-emerged by the end of the abstinence period and was greater in female than male rats. We found sensitization to the locomotor-depressing effects of THC in middle- and high-dose rats and the subsequent development of tolerance in high-dose rats. The high dose of THC increased anxiety-like behaviors while the low dose decreased anxiety-like behaviors during drug administration, with females more sensitive to the anxiogenic effects of THC than males. During abstinence, females were again especially sensitive to the anxiogenic effects of THC. This study demonstrates sexually-dimorphic effects of THC on anxiety-related behaviors and locomotor activity during and after THC administration during adolescence. This information may be useful in the development of therapeutic approaches for the treatment of marijuana withdrawal in adolescents. [Copyright &y& Elsevier]

Repeated cocaine administration results in a progressive sensitization of behavior which typically occurs more readily in female rats than in males. Our recent studies of rats undergoing surgical procedures revealed that following anesthesia, females sensitized less than males receiving identical repeated cocaine injections. Since isoflurane acts primarily by increasing the effects of the inhibitory neurotransmitter γ-amino butyric acid (GABA) and reducing the effects of the excitatory amino acid glutamate, these amino acids may play more prominent roles in sensitization to cocaine in females than previously understood. In order to examine the effects of isoflurane on cocaine-sensitization, we administered cocaine (15mg/kg i.p) or saline to adult male and female Sprague–Dawley rats for 9 days; on day 10, half of the rats were subjected to isoflurane anesthesia and the other half did not receive anesthesia. On day 11, rats were given their last dose of either cocaine or saline. We recorded behaviors for 1h on days 1, 9 and 11. Locomotor activity and stereotyped behaviors were quantified using photo beam monitors and the scoring of video tapes, respectively. Results indicated that a single exposure to isoflurane significantly dampens the stereotypic behavior associated with repeated cocaine administration in females but not in males. They further suggest that either GABA or glutamate play more prominent roles in cocaine-sensitization behavior in females than in males. [Copyright &y& Elsevier]

Abstract: Methylphenidate (Ritalin; MPD) is one of the most commonly prescribed drugs in childhood and adolescence and many clinical studies have documented its efficacy. Due to the limitations of conducting invasive research in humans, animal models can be beneficial for studying drug effects. However, few animal studies have demonstrated the effects of methylphenidate on cognitive processes. The objective of this study was to find a dose of methylphenidate that was effective in improving performance on a spatial working memory cognitive task when administered orally to periadolescent rats. Therefore, we dosed subjects with methylphenidate at 1 or 3 mg/kg/day via gastric intubation from postnatal day 22 to 59 and assessed the effects of the drug on performance on the radial arm maze each day. To enhance performance overall, a second experiment was conducted where the subjects were moderately food restricted (to 90% of the free-feeding weight). Results of Experiment 1 show that during the first week of testing only the 3 mg/kg MPD-treated males showed improved performance (entries prior to repeated entry) when ad lib fed and housed in pairs while the same dose significantly improved performance in both males and females under conditions of food-restriction and individual housing in Experiment 2. MPD also produced a pattern of increased errors and arms entered during the first week, especially in Experiment 2. MPD increased locomotor activity when tested at postnatal day 60 in both experiments. The data suggest that 3 mg/kg oral methylphenidate improves performance on a spatial cognitive task only early in treatment in the rat. While males show improvement under conditions of both high and low motivation, females only show MPD effects when highly motivated. Hypothetically, methylphenidate may improve radial arm maze performance through increased attention and improved spatial working memory and/or alterations in locomotion, reactivity to novelty or anxiety. Regardless, the study supports the utility of the rat as a suitable model to examine the effects of low dose oral MPD. [Copyright &y& Elsevier]

Abstract: Clinical and animal data point toward deficits in attention and arousal after prenatal cocaine exposure. Since methylphenidate (MPD) is widely used to treat attention disorders, we wanted to determine whether prenatal cocaine (PC) exposure affects the behavioral response to MPD in young rats of both sexes. Pregnant dams received 60 mg/kg of cocaine or vehicle from gestational days 8–22 by intragastric intubations. After delivery, litters were culled to 10 (5 males, 5 females) and fostered. On a single day between PND 41–44 locomotion was recorded in a Plexiglas box within an Accuscan activity monitor after receiving a single injection of 10 mg/kg intraperitoneally of MPD or saline. Rats were also videotaped for analysis of stereotyped behavior. Results showed that MPD administration enhanced locomotion compared to saline injected groups. PC exposure in male rats did not have any effect on the locomotor response to MPD compared to prenatal controls. However, PC-exposed males showed a lower amount of time spent in low intensity stereotypy compared to prenatal control males and both groups of females that received MPD. PC exposure in female rats that received MPD dampened the locomotor response compared to prenatal control females that also received MPD. In conclusion PC exposure dampens the behavioral response to MPD differentially in males and females with an apparent selectivity of locomotion in females and stereotyped behavior in males. [Copyright &y& Elsevier]

Sex differences in both the endocannabinoid system and stress responses have been established for decades. While there is ample evidence that the sexes respond differently to stress and that the endocannabinoid system is involved in this response, what is less clear is whether the endocannabinoid system mediates this response to stress differently in both sexes. Also, do the sexes respond similarly to exogenous cannabinoids (CBs) following stress? Can the administration of exogenous CBs normalize the effects of stress and if so, does this happen similarly in male and female subjects? This review will attempt to delineate the stress induced neurochemical alterations in the endocannabinoid system and the resulting behavioral changes across periods of development: prenatal, early neonatal or adolescent in males and females. Within this frame work, we will then examine the neurochemical and behavioral effects of exogenous CBs and illustrate that the response to CBs is determined by the stress history of the animal. The theoretical framework for this endeavor relates to the established effects of adverse childhood experiences (ACE) in increasing substance abuse, depression and anxiety and the possibility that individuals with high ACE scores may consume cannabinoids to "self-medicate". Overall, we see that while there are instances where exogenous cannabinoids "normalize" the adverse effects produced by early stress, this normalization does not occur in all animal models with any sort of consistency. The most compelling report where CB administration appears to normalize behaviors altered by early stress, shows minimal differences between the sexes (Alteba et al., 2016). This is in stark contrast to the majority of studies on early stress and the endocannabinoid system where both sexes are included and show quite divergent, in fact opposite, effects in males and females. Frequently there is a disconnect between neurochemical changes and behavioral changes and often, exogenous CBs have greater effects in stressed animals compared to non-stressed controls. This report as well as others reviewed here do support the concept that the effects of exogenous CBs are different in individuals experiencing early stress and that these differences are not equal in males and females. However, due to the wide variety of stressors used and the range of ages when the stress is applied, additional careful studies are warranted to fully understand the interactive effects of stress and the endocannabinoid system in males and females. In general, the findings do not support the statement that CB self-administration is an effective treatment for the adverse behavioral effects of early maltreatment in either males or females. Certainly this review should draw the attention of clinicians working with children, adolescents and adults exposed to early trauma and provide some perspective on the dysregulation of the endocannabinoid system in the response to trauma, the complex actions of exogenous CBs based on stress history and the unique effects of these factors in men and women. • Sex differences in the response of the endocannabinoid system to early life stress. • The sexes do not respond similarly to exogenous cannabinoids following stress. • Exogenous cannabinoids can normalize the effects of stress in a few cases. [ABSTRACT FROM AUTHOR]

Adolescents who use marijuana are more likely to exhibit anxiety, depression, and other mood disorders, including psychotic-like symptoms. Additionally, the age at onset of use and the stress history of the individual can affect responses to cannabis. To examine the effect of early life experience on adolescent Δ-9-tetrahydrocannabinol (THC) exposure, we exposed adolescent (postnatal day (P) 29–38) male and female rats, either shipped from a supplier or born in our vivarium, to once daily injections of 3 mg/kg THC. Our findings suggest that males are more sensitive to the anxiolytic and antidepressant effects of THC, as measured by the elevated plus maze (EPM) and forced swim test (FST), respectively, than females. Exposure to the FST increased plasma corticosterone levels, regardless of drug treatment or origin and females had higher levels than males overall. Shipping increased THC responses in females (acoustic startle habituation) and in males (latency to immobility in FST). No significant effects of THC or shipping on pre-pulse inhibition were observed. Due to differences in timing of puberty in males and females during the P29–38 period of THC treatment, we also dosed female rats between P21–30 (pre-puberty) and male rats between P39–48 (puberty). Pre-pubertal animals showed reductions in anxiety on the EPM, an effect that was not seen in animals treated during puberty. These results suggest that both sexes are more susceptible to changes in emotional behavior when THC exposure occurs just prior to the onset of puberty. Within the animals dosed from P29–38, THC increased cannabinoid receptor 1 (CB1R) mRNA expression and tended to decrease CP55,940 stimulated [ 35 S]GTPγS binding in the central amygdala only of females. Therefore, early stress enhances THC responses in males (in FST) and females (ASR habituation), THC alters CB1R expression and function in females only and prepubescent rats are generally more responsive to THC than pubertal rats. In summary, THC and stress interact with the developing endocannabinoid system in a sex specific manner during the peri-pubertal period. [ABSTRACT FROM AUTHOR]

Marijuana use by adolescents has been on the rise since the early 1990s. With recent legalization and decriminalization acts passed, cannabinoid exposure in adolescents will undoubtedly increase. Human studies are limited in their ability to examine underlying changes in brain biochemistry making rodent models valuable. Studies in adult and adolescent animals show region and sex specific downregulation of the cannabinoid 1 (CB1) receptor following chronic cannabinoid treatment. However, although sex-dependent changes in behavior have been observed during the drug abstinence period following adolescent cannabinoid exposure, little is known about CB1 receptor expression during this critical time. In order to characterize CB1 receptor expression following chronic adolescent Δ-9-tetrahydrocannabinol (THC) exposure, we used [ 3 H] CP55,940 binding to assess CB1 receptor expression in the dentate gyrus and areas CA1, CA2, and CA3 of the hippocampus in both male and female adolescent rats at both 24 h and 2 weeks post chronic THC treatment. Consistent with other reported findings, we found downregulation of the CB1 receptor in the hippocampal formation at 24 h post treatment. While this downregulation persisted in both sexes following two weeks of abstinence in the CA2 region, in females, this downregulation also persisted in areas CA1 and CA3. Expression in the dentate gyrus returned to the normal range by two weeks. These data suggest that selective regions of the hippocampus show persistent reductions in CB1 receptor expression and that these reductions are more widespread in female compared to male adolescents. [ABSTRACT FROM AUTHOR]

Abstract: Research suggests that not only is marijuana use prevalent among women of reproductive age, but a significant number of women continue to use marijuana and its derivatives throughout pregnancy. Many studies have shown, in both humans and animals, that marijuana exposure during adolescence and adulthood is detrimental to normal cognition and memory. In this study, we examined the effects of daily intravenous injections of 0.15mg/kg Δ9-tetrahydrocannabinol (THC), given to pregnant dams throughout gestation, on cognitive function in the offspring. Offspring were exposed to three tests: a passive avoidance test at postnatal day (PND) 22, an active place avoidance test at PND 45, and an attention task at PND 60, which assessed learning and long-term memory, spatial working memory and prediction, and attention, respectively. Other offspring were also given a 1mg/kg amphetamine challenge at PND 60. Passive avoidance testing showed that prenatal THC had no effect on acquisition but interfered with consolidation during retention testing. The active place avoidance task showed no treatment-related effects on acquisition but a significant treatment effect was observed in reversal performance in males. The attention task showed that a smaller percentage of THC-exposed rats completed the test, although the failure rate of both groups was quite high. Finally, THC exposed animals, both male and female, showed a dampened locomotor response to amphetamine, but females were more active than males overall. These results suggest that prenatal THC exposure has effects on certain aspects of cognitive function in rats from weaning to adulthood. These effects suggest that prenatal marijuana exposure could also alter cognitive function in humans and therefore have an impact on school performance and dampen responses to psychostimulants as well. [Copyright &y& Elsevier]