Scoping review on environmental enrichment: Are critical periods and sex differences adequately studied?

BACKGROUND: 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. OBJECTIVE: 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. ELIGIBILITY CRITERIA: Narrative, systematic reviews (not original reports) and meta-analyses of any animal species published during 2011 to 2021. Clinical and farming studies were excluded. SOURCES OF EVIDENCE: Indexed review articles in Pubmed and Psychinfo. RESULTS: 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. CONCLUSION: 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.

This is your teen brain on drugs: In search of biological factors unique to dependence toxicity in adolescence.

Response variability across the lifespan is an important consideration in toxicology and risk assessment, and the toxic effects of drugs and chemicals during adolescence need more research. This paper summarizes a workshop presented in March 2019, at the Society of Toxicology Annual Meeting in Baltimore, Maryland, that brought together experts in research on drug dependence and toxicity related to nicotine, cannabis, cocaine, and other illicit drugs during adolescence. The goal of the workshop was to address the following issues: (1) Do the effects of adolescent exposure differ from the same exposure in adults? (2) Are there unique biological markers of adolescent brain development? If so, what are they and how reliable are they? (3) Since multiple factors influence substance use disorder, can we disentangle risk factors for abuse and/or toxicity? What are the underlying biological susceptibilities that lead to dependence and neurotoxicity? What are the social, psychosocial and environmental factors that contribute to abuse susceptibilities? This paper reviews drug policy and national trends in adolescent substance use; the public health consequences of e-cigarettes; rat models of adolescent-onset nicotine self-administration and persisting effects of gestational nicotine; sex-dependent effects of delta-9-tetrahydrocannabinol on adolescent brain-behavior relationships; and translational approaches for identifying adolescent risk factors for transition to drug dependence. There is strong evidence that drug exposure prior to adulthood has longer lasting effects on behavior and the underlying neural circuitry. These effects, which are sex-dependent and influenced by stress, may be candidates as predictors of adolescent vulnerability. A major challenge to determining if adolescents have a unique susceptibility to dependence is whether and to what extent the human data allow distinction between the increased risk due to biological immaturity, an underlying biological susceptibility to dependence, or psychosocial and environmental factors for substance dependence. Factors important to consider for development of animal models include the timing and pattern of exposure as it relates to adolescence; age of assessment, and direct comparison with similar effects following exposures to adults to demonstrate that these effects are unique to adolescence. Here we provide a roadmap for further research into what makes adolescent brain development unique.

Sex differences in the interactive effects of early life stress and the endocannabinoid system.

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.

Experience during adolescence shapes brain development: From synapses and networks to normal and pathological behavior.

Adolescence is a period of dramatic neural reorganization creating a period of vulnerability and the possibility for the development of psychopathology. The maturation of various neural circuits during adolescence depends, to a large degree, on one's experiences both physical and psychosocial. This occurs through a process of plasticity which is the structural and functional adaptation of the nervous system in response to environmental demands, physiological changes and experiences. During adolescence, this adaptation proceeds upon a backdrop of structural and functional alterations imparted by genetic and epigenetic factors and experiences both prior to birth and during the postnatal period. Plasticity entails an altering of connections between neurons through long-term potentiation (LTP) (which alters synaptic efficiency), synaptogenesis, axonal sprouting, dendritic remodeling, neurogenesis and recruitment (Skaper et al., 2017). Although most empirical evidence for plasticity derives from studies of the sensory systems, recent studies have suggested that during adolescence, social, emotional, and cognitive experiences alter the structure and function of the networks subserving these domains of behavior. Each of these neural networks exhibits heightened vulnerability to experience-dependent plasticity during the sensitive periods which occur in different circuits and different brain regions at specific periods of development. This report will summarize some examples of adaptation which occur during adolescence and some evidence that the adolescent brain responds differently to stimuli compared to adults and children. This symposium, "Experience during adolescence shapes brain development: from synapses and networks to normal and pathological behavior" occurred during the Developmental Neurotoxicology Society/Teratology Society Annual Meeting in Clearwater Florida, June 2018. The sections will describe the maturation of the brain during adolescence as studied using imaging technologies, illustrate how plasticity shapes the structure of the brain using examples of pathological conditions such as Tourette's' syndrome and attention deficit hyperactivity disorder, and a review of the key molecular systems involved in this plasticity and how some commonly abused substances alter brain development. The role of stimulants used in the treatment of attention deficit hyperactivity disorder (ADHD) in the plasticity of the reward circuit is then described. Lastly, clinical data promoting an understanding of peer-influences on risky behavior in adolescents provides evidence for the complexity of the roles that peers play in decision making, a phenomenon different from that in the adult. Imaging studies have revealed that activation of the social network by the presence of peers at times of decision making is unique in the adolescent. Since normal brain development relies on experiences which alter the functional and structural connections between cells within circuits and networks to ultimately alter behavior, readers can be made aware of the myriad of ways normal developmental processes can be hijacked. The vulnerability of developing adolescent brain places the adolescent at risk for the development of a life time of abnormal behaviors and mental disorders.

Endocannabinoids in brain plasticity: Cortical maturation, HPA axis function and behavior.

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.

Sexually-dimorphic alterations in cannabinoid receptor density depend upon prenatal/early postnatal history.

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 5days of handling as controls for a behavior study and all rats were sacrificed at approximately PND48-50 within 2hours of the last behavioral test. All brains were processed together for CB1 receptor binding using 3H 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.

Effects of gaboxadol on the expression of cocaine sensitization in rats.

Behavioral sensitization to psychostimulants is associated with changes in dopamine (DA), glutamate, and GABA within the mesocorticolimbic and nigrostriatal DA systems. Because GABAA receptors are highly expressed within these systems, we examined the role of these receptors containing a δ subunit in cocaine behavioral sensitization. Experiment 1 examined the effects of Gaboxadol (GBX, also known as THIP [4,5,6,7-tetrahydro-isoxazolo[5,4-c]pyridin-3-ol]), a selective δ-GABAA receptor agonist, on the locomotor responses to acute cocaine. GBX at 1.25 mg/kg produced locomotor depression in female rats alone. We then examined the effects of GBX on the expression of cocaine-induced locomotion and stereotypy in female and male rats treated with 5 days of cocaine (15 mg/kg) followed by cocaine challenge 7 days later. We administered systemic (Experiment 2) or intranucleus accumbens (intra-NAC; Experiment 3) injections of GBX (0, 1.25, 2.5, 5, or 10 mg/kg subcutaneously, or 1 µmol/L or 1 mM intra-NAC, respectively) prior to cocaine challenge (10 mg/kg). In our experiments females were robustly sensitized to cocaine at low dose whereas males did not show such sensitization-limiting comparisons between the 2 sexes. Sensitized females showed a biphasic response to low (1.25 mg/kg and 1 µmol/L) and high (10 mg/kg and 1 mM) dose GBX whereas nonsensitized males showed this pattern only following intra-NAC injection. Immunohistochemical analysis of the NAC revealed that females have more δ-containing GABAA receptors than do males and that following chronic cocaine injections this difference persisted (Experiment 4). Together, our results support the notion of the key role of extrasynaptic GABAA δ-subunit containing receptors in cocaine sensitization.

Sex and age specific effects of delta-9-tetrahydrocannabinol during the periadolescent period in the rat: The unique susceptibility of the prepubescent animal.

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 3mg/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 [35S]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.

Sex-specific alterations in hippocampal cannabinoid 1 receptor expression following adolescent delta-9-tetrahydrocannabinol treatment in the rat.

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 24h and 2 weeks post chronic THC treatment. Consistent with other reported findings, we found downregulation of the CB1 receptor in the hippocampal formation at 24h 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.

Single trial nicotine conditioned place preference in pre-adolescent male and female rats.

The mean age of first voluntary tobacco inhalation is 12.3 years (DiFranza et al., 2004). 60% of smokers start smoking before the age of 14 and 90% are dependent before reaching the age of 19. Females are typically more sensitive to nicotine than males yet few studies examine the effects of nicotine on the reward systems in pre-adolescent female subjects. This study utilized the single trial conditioned place preference (CPP) test in very young (postnatal day 25-27) rats of both sexes. Latent effects on anxiety and amphetamine response were determined 5 and 7 days following a second nicotine exposure. Results show that 0.05 mg/kg nicotine induced CPP in females following a single trial while both sexes showed CPP following the 0.5 mg/kg dose. Five days later, rats dosed with 0.05 mg/kg show increased time on the open arm of the elevated plus maze, an anxiolytic response. While baseline activity was increased in nicotine-exposed males 7 days following dosing, amphetamine response was not affected by the treatments in either sex. Therefore, our data suggest that young females are more sensitive to nicotine reward than males supporting a heightened sensitivity of the mesolimbic dopamine system in very young females. However, alterations in baseline activity were only seen in males suggesting that different components of the system are affected by nicotine in each sex. An anxiolytic response to nicotine 5 days after dosing may suggest that this very young age group is uniquely affected by this very low nicotine dose. Clearly, nicotine has substantial acute and lasting effects during pre-adolescence at doses substantially lower than seen at older ages as reported by others. These effects, which could potentially result from cigarette or e-cigarette smoking by 11-12 year old children , focus attention on the vulnerability of this age group to nicotine.

The effects of prenatal cocaine, post-weaning housing and sex on conditioned place preference in adolescent rats.

RATIONALE: Gestational exposure to cocaine now affects several million people including adolescents and young adults. Whether prenatal drug exposures alter an individual's tendency to take and/or abuse drugs is still a matter of debate. OBJECTIVES: This study sought to answer the question "Does prenatal exposure to cocaine, in a dose-response fashion, alter the rewarding effects of cocaine using a conditioned place preference (CPP) procedure during adolescence in the rat?" Further, we wanted to assess the possible sex differences and the role of being raised in an enriched versus impoverished environment. METHODS: Virgin female Sprague-Dawley rats were dosed daily with cocaine at 30 mg/kg (C30), 60 mg/kg (C60), or vehicle intragastrically prior to mating and throughout gestation. Pups were culled, fostered and, on postnatal day (PND) 23, placed into isolation cages or enriched cages with three same-sex littermates and stimulus objects. On PND43-47, CPP was determined across a range of cocaine doses. RESULTS: C30 exposure increased sensitivity to the rewarding effects of cocaine in adolescent males, and being raised in an enriched environment further enhanced this effect. Rats exposed to C60 resembled the controls in cocaine CPP. Overall, females were modestly affected by prenatal cocaine and enrichment. CONCLUSIONS: These data support the unique sensitivity of males to the effects of gestational cocaine, that moderate prenatal cocaine doses produce greater effects on developing reward circuits than high doses and that housing condition interacts with prenatal treatment and sex such that enrichment increases cocaine CPP mostly in adolescent males prenatally exposed to moderate cocaine doses.

R6/2 Huntington's disease mice develop early and progressive abnormal brain metabolism and seizures.

A hallmark feature of Huntington's disease pathology is the atrophy of brain regions including, but not limited to, the striatum. Though MRI studies have identified structural CNS changes in several Huntington's disease (HD) mouse models, the functional consequences of HD pathology during the progression of the disease have yet to be investigated using in vivo functional MRI (fMRI). To address this issue, we first established the structural and functional MRI phenotype of juvenile HD mouse model R6/2 at early and advanced stages of disease. Significantly higher fMRI signals [relative cerebral blood volumes (rCBVs)] and atrophy were observed in both age groups in specific brain regions. Next, fMRI results were correlated with electrophysiological analysis, which showed abnormal increases in neuronal activity in affected brain regions, thus identifying a mechanism accounting for the abnormal fMRI findings. [(14)C] 2-deoxyglucose maps to investigate patterns of glucose utilization were also generated. An interesting mismatch between increases in rCBV and decreases in glucose uptake was observed. Finally, we evaluated the sensitivity of this mouse line to audiogenic seizures early in the disease course. We found that R6/2 mice had an increased susceptibility to develop seizures. Together, these findings identified seizure activity in R6/2 mice and show that neuroimaging measures sensitive to oxygen metabolism can be used as in vivo biomarkers, preceding the onset of an overt behavioral phenotype. Since fMRI-rCBV can also be obtained in patients, we propose that it may serve as a translational tool to evaluate therapeutic responses in humans and HD mouse models.

Withdrawal from THC during adolescence: sex differences in locomotor activity and anxiety.

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 15 mg/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.

Pretreatment with Δ9-tetrahydrocannabinol (THC) increases cocaine-stimulated activity in adolescent but not adult male rats.

Marijuana (Cannabis sativa) remains one of the most widely used illegal drugs, with adolescents being particularly vulnerable to its use and abuse. In spite of this, most studies are conducted in adult animals even though the effects might be quite different in adolescents. Additionally, the use of marijuana often precedes the use of other psychoactive drugs including cocaine, especially when marijuana exposure begins during early adolescence. The purpose of this study was to examine the effects of repeated Δ9-tetrahydrocannabinol (THC), the major active ingredient in marijuana, in adolescents compared to adults and to determine its subsequent effects on cocaine-stimulated activity. To this end, adolescent (postnatal day PND 34) and adult (PND 66) rats were administered 3 mg/kg/day THC for 8 days and locomotor activity was measured on days 1, 2, 7 and 8 after dosing. On day 12 (4 days after the last dose of THC), rats were injected with escalating doses of cocaine and behavior was recorded. Results show that THC depressed locomotor activity in adult rats but not in adolescents. However, following a cocaine challenge, adolescents exposed to THC showed increased locomotor responses to cocaine compared to chronic vehicle-injected controls. This was not seen in adults. These results show that the effects of cocaine are enhanced after THC in adolescents, but not adults, and that this might account for the greater transition to cocaine after early, as opposed to later, marijuana use.

Prenatal tetrahydrocannabinol (THC) alters cognitive function and amphetamine response from weaning to adulthood in the rat.

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 0.15 mg/kg Δ(9)-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.

Maternal cannabis use alters ventral striatal dopamine D2 gene regulation in the offspring.

BACKGROUND: Prenatal cannabis exposure has been linked to addiction vulnerability, but the neurobiology underlying this risk is unknown. METHODS: Striatal dopamine and opioid-related genes were studied in human fetal subjects exposed to cannabis (as well as cigarettes and alcohol). Cannabis-related gene disturbances observed in the human fetus were subsequently characterized with an animal model of prenatal Δ-9-tetrahydrocannabinol (THC) (.15 mg/kg) exposure. RESULTS: Prenatal cannabis exposure decreased dopamine receptor D2 (DRD2) messenger RNA expression in the human ventral striatum (nucleus accumbens [NAc]), a key brain reward region. No significant alterations were observed for the other genes in cannabis-exposed subjects. Maternal cigarette use was associated with reduced NAc prodynorphin messenger RNA expression, and alcohol exposure induced broad alterations primarily in the dorsal striatum of most genes. To explore the mechanisms underlying the cannabis-associated disturbances, we exposed pregnant rats to THC and examined the epigenetic regulation of the NAc Drd2 gene in their offspring at postnatal day 2, comparable to the human fetal period studied, and in adulthood. Chromatin immunoprecipitation of the adult NAc revealed increased 2meH3K9 repressive mark and decreased 3meH3K4 and RNA polymerase II at the Drd2 gene locus in the THC-exposed offspring. Decreased Drd2 expression was accompanied by reduced dopamine D2 receptor (D(2)R) binding sites and increased sensitivity to opiate reward in adulthood. CONCLUSIONS: These data suggest that maternal cannabis use alters developmental regulation of mesolimbic D(2)R in offspring through epigenetic mechanisms that regulate histone lysine methylation, and the ensuing reduction of D(2)R might contribute to addiction vulnerability later in life.

Translational issues for prenatal cocaine studies and the role of environment.

Prenatal cocaine exposure produces a wide variety of effects particularly within the nervous system. While not considered a structural teratogen, preclinical studies have documented the biological effects of cocaine exposure during development; effects which to a large extent resemble those described among exposed human populations. This review evaluates the translational value of preclinical studies in terms of three factors: dose of drug administered, timing of events in brain development in the animal compared to human and pharmacokinetics of the drug in animals and humans. Cocaine's effects on cortical development are compared across non-human primate, rabbit and rodent models. Examples of studies utilizing dose-response approaches and clinically relevant plasma drug curves are presented. And lastly, the role of environment in the manifestation of prenatal cocaine effects and published neurochemical effects of enrichment are discussed. The review concludes that there is ample evidence for the biological effects of cocaine on cortical and mesolimbic dopamine system development and that manipulation of the rearing environment can dramatically alter the manifestation of these effects including function of the mesolimbic dopamine reward system.

Sexually dimorphic alterations in locomotion and reversal learning after adolescent tetrahydrocannabinol exposure in the rat.

Research suggests that use and abuse of marijuana can be especially harmful if it occurs during adolescence, a period of vast developmental changes throughout the brain. We examined the effects of 2mg/kg (9)-tetrahydrocannabinol (THC) administered daily via intra-peritoneal injections during juvenile/early adolescence (postnatal day 22-40) or late adolescence (postnatal day 41-60) on locomotor activity, development of tolerance, and acquisition/retention of spatial avoidance in adulthood. THC caused locomotor depression in both male and female animals dosed during early adolescence but only in female animals dosed during late adolescence. Evidence of reverse tolerance to THC was seen in early adolescent animals only. In the active place avoidance test (APA), male and female animals administered THC during early adolescence made more errors on the reversal trial requiring flexibility in learning, but in animals dosed during late adolescence there were no significant sex or treatment differences. The results of the locomotor activity study indicate that females may be more sensitive to the effects of THC than males, while results of both locomotor activity and APA studies suggest that early adolescents appear to be more vulnerable to these effects than late adolescents/young adults.