Sex Differences in the Neural and Behavioral Effects of Acute High-Dose Edible Cannabis Consumption in Rats.

The consumption of Δ9-tetrahydrocannabinol (THC)- or cannabis-containing edibles has increased in recent years; however, the behavioral and neural circuit effects of such consumption remain unknown, especially in the context of ingestion of higher doses resulting in cannabis intoxication. We examined the neural and behavioral effects of acute high-dose edible cannabis consumption (AHDECC). Sprague-Dawley rats (six males, seven females) were implanted with electrodes in the prefrontal cortex (PFC), dorsal hippocampus (dHipp), cingulate cortex (Cg), and nucleus accumbens (NAc). Rats were provided access to a mixture of Nutella (6 g/kg) and THC-containing cannabis oil (20 mg/kg) for 10 minutes, during which they voluntarily consumed all of the provided Nutella and THC mixture. Cannabis tetrad and neural oscillations were examined 2, 4, 8, and 24 hours after exposure. In another cohort (16 males, 15 females), we examined the effects of AHDECC on learning and prepulse inhibition and serum and brain THC and 11-hydroxy-THC concentrations. AHDECC resulted in higher brain and serum THC and 11-hydroxy-THC levels in female rats over 24 hours. AHDECC also produced: 1) Cg, dHipp, and NAc gamma power suppression, with the suppression being greater in female rats, in a time-dependent manner; 2) hypolocomotion, hypothermia, and antinociception in a time-dependent manner; and 3) learning and prepulse inhibition impairments. Additionally, most neural activity and behavior changes appear 2 hours after ingestion, suggesting that interventions around this time might be effective in reversing/reducing the effects of AHDECC. SIGNIFICANCE STATEMENT: The effects of high-dose edible cannabis on behavior and neural circuitry are poorly understood. We found that the effects of acute high-dose edible cannabis consumption (AHDECC), which include decreased gamma power, hypothermia, hypolocomotion, analgesia, and learning and information processing impairments, are time and sex dependent. Moreover, these effects begin 2 hours after AHDECC and last for at least 24 hours, suggesting that treatments should target this time window in order to be effective.

Behavioral and pharmacokinetic assessment of nicotine e-cigarette inhalation in female rats.

INTRODUCTION: Nicotine and tobacco use remain high both globally and in the USA, contributing to large healthcare expenditures. With a rise in e-cigarette use, it is important to have clinically relevant models of inhaled nicotine exposure. This study aims to extend prior preclinical nicotine inhalation animal data to females and provide both behavior and serum pharmacokinetics. METHODS: We tested two inhalation doses of nicotine (24 mg/ml and 59 mg/ml) and compared these to injected doses (0.4 mg/kg and 1 mg/kg). In addition, we assessed locomotor behavior after the same doses. Blood was collected at 10- and 120-minutes post-administration. We assessed nicotine and cotinine serum concentrations by LC-MS/MS. RESULTS: showed that while nicotine serum concentrations for the respective high and low-dose administrations were similar between both routes of administration, the route had differential effects on locomotor behavior. Inhaled nicotine showed a dose-dependent decrease in locomotor activity while injected doses showed the opposite trend. CONCLUSIONS: Our results indicate that the route of administration is an important factor when establishing preclinical models of nicotine exposures. Given that the overall use of e-cigarettes in vulnerable populations is on the rise, our study provides important behavioral and pharmacokinetic information to advance our currently limited understanding of the effects of nicotine vapor exposure. IMPLICATIONS: This study highlights behavioral differences between different routes of administration of similar doses of nicotine. Using a low and high dose of nicotine, we found that nicotine serum concentrations were similar between the different routes of administration. Our results indicate that different routes of administration have opposing effects on locomotor activity. These findings provide important implications for future behavioral models.

Intermittent cold exposure improves glucose homeostasis despite exacerbating diet-induced obesity in mice housed at thermoneutrality.

KEY POINTS: Ambient cold exposure is often regarded as a promising anti-obesity treatment in mice. However, most preclinical studies aimed at treating obesity via cold-induced thermogenesis have been confounded by subthermoneutral housing temperatures. Therefore, the ability of ambient cold to combat diet-induced obesity in mice housed under humanized thermoneutral conditions is currently unknown. Moreover, mammals such as mice are rarely exposed to chronic ambient cold without reprieve, yet mice are often subjected to experimental conditions of chronic rather than intermittent cold exposure (ICE), despite ICE being more physiologically relevant. In the present study, we provide novel evidence that thermoneutral housing uncouples the effects of ICE on glucose and energy homeostasis suggesting that ICE, despite improving glucose tolerance, is not an effective obesity treatment when mice are housed under humanized thermoneutral conditions. ABSTRACT: The present study examines whether a physiologically relevant model of ambient cold exposure, intermittent cold exposure (ICE), could ameliorate the metabolic impairments of diet-induced obesity in male and female mice housed under humanized thermoneutral conditions. Male and female C57BL/6J mice housed at thermoneutrality (29°C) were fed a low-fat diet or high-fat diet for 6 weeks before being weight matched into groups that remained unperturbed or underwent ICE for 4 weeks (4°C for 60 min day-1 ; 5 days week-1 ) when being maintained on their respective diets. ICE induced rapid and persistent hyperphagia exacerbating rather than attenuating high-fat diet-induced obesity over time. These ICE-induced increases in adiposity were found to be energy intake-dependent via pair-feeding. Despite exacerbating high-fat diet-induced obesity, ICE improved glucose tolerance, independent of diet, in a sex-specific manner. The effects of ICE on glucose tolerance were not attributed to improvements in whole-body insulin tolerance, tissue specific insulin action, nor differences in markers of hepatic insulin clearance or pancreatic beta cell proliferation. Instead, ICE increased serum concentrations of insulin and C-peptide in response to glucose, suggesting that ICE may improve glucose tolerance by potentiating pancreatic glucose-stimulated insulin secretion. These data suggest that ICE, despite improving glucose tolerance, is not an effective obesity treatment in mice housed under humanized conditions.

Addiction-Related Outcomes of Nicotine and Alcohol Co-use: New Insights Following the Rise in Vaping.

PURPOSE: Nicotine and alcohol-containing products are some of the most commonly used substances of abuse and are both leading causes of preventable death. These substances also have significant interactions that have additive and, in some cases, multiplicative effects on the health consequences of their use. Thus, to reduce these negative consequences, it is important to understand the abuse liability of nicotine and alcohol in combination, especially in the most relevant use cases among those who are most vulnerable. Specifically, as tobacco cigarette use is continually decreasing, vaping is quickly replacing cigarettes as the primary mode of nicotine use. This pattern is especially true in adolescent populations in which vaping has grown considerably. Particularly concerning is that adolescents are more vulnerable than adults to the negative consequences of substance use. It is therefore imperative to revisit the literature as it relates to the rising state of co-use of vaping products with alcohol. Here, we review the clinical outcomes of nicotine and alcohol co-use as they relate to the abuse liability of each individually. Special attention is paid to adolescent findings, where available, as well as investigations that use nontobacco nicotine products as these may more accurately reflect the more recent trends of co-use. IMPLICATIONS: Though nicotine alone has previously been considered a proxy for tobacco and tobacco cigarette use, combustible routes of administration have been decreasing. They are, instead, being replaced by e-cigarettes that do not involve other tobacco constituents and contain additional nonnicotine constituents of their own. Unfortunately, the literature remains limited with regard to e-cigarettes and their interactions with other substances, especially their prevalent co-use with alcohol. This review attempts to discuss the current literature on nicotine and alcohol co-use in the context of the vaping epidemic, predominantly focusing on addiction-related outcomes and why e-cigarette use may be unique.

Alcohol and Vaporized Nicotine Co-exposure During Adolescence Contribute Differentially to Sex-Specific Behavioral Effects in Adulthood.

INTRODUCTION: Co-occurrence of e-cigarette use and alcohol consumption during adolescence is frequent. Here, we examined whether adolescent co-exposure to alcohol drinking and vaporized nicotine would impact reward- and cognition-related behaviors in adult male and female rats during adulthood. AIMS AND METHODS: Four groups of male and female Sprague Dawley rats (n = 8-11/group/sex) received either nicotine (JUUL 5% nicotine pods) or vehicle vapor for 10 minutes daily between postnatal days 30-46, while having continuous voluntary access to ethanol and water during this time in a two-bottle preference design. Upon reaching adulthood, all rats underwent behavioral testing (ie, Pavlovian conditioned approach testing, fear conditioning and a two-bottle alcohol preference). RESULTS: A sex-dependent effect, not related to adolescent nicotine or alcohol exposure, on alcohol drinking in adulthood was found, such that females had a higher intake and preference for alcohol compared to males; both male and female adult rats also had greater alcohol preference compared to their alcohol preference as adolescents. Male rats exposed to vaporized nicotine with or without alcohol drinking during adolescence exhibited altered reward-related learning in adulthood, evidenced by enhanced levels of sign-tracking behavior. Male rats that drank alcohol with or without nicotine vapor in adolescence showed deficits in associative fear learning and memory as adults. In contrast, these effects were not seen in female rats exposed to alcohol and nicotine vapor during adolescence. CONCLUSIONS: The present study provides evidence that co-exposure to alcohol and vaporized nicotine during adolescence in male, but not female, rats produces long-term changes in reward- and cognition-related behaviors. IMPLICATIONS: These findings enhance our understanding of the effects of alcohol drinking and nicotine vapor exposure in adolescence. Moreover, they highlight potential sex differences that exist in the response to alcohol and nicotine vapor, underscoring the need for follow-up studies elucidating the neurobiological mechanisms that drive these sex differences, as well as the long-term effects of alcohol and nicotine vapor use.

Clozapine Increases Nestin Concentration in the Adult Male Rat Hippocampus: A Preliminary Study.

Patients with schizophrenia, and rodent models of the disease, both exhibit suppressed neurogenesis, with antipsychotics possibly enhancing neurogenesis in pre-clinical models. Nestin, a cytoskeletal protein, is implicated in neuronal differentiation and adult neurogenesis. We hypothesized that schizophrenia pathogenesis involves nestin downregulation; however, few studies have related nestin to schizophrenia. We assessed nestin protein concentration, prepulse inhibition (PPI), and social interaction in the MK-801 model of schizophrenia, with or without antipsychotic (clozapine) treatment. Adult male Sprague-Dawley rats were intraperitoneally administered saline or MK-801 (0.1 mg/kg) to produce a schizophrenia-like phenotype, with concomitant subcutaneous injections of vehicle or clozapine (5 mg/kg). PPI was assessed on days 1, 8, and 15, and social interaction was assessed on day 4. Hippocampus tissue samples were dissected for Western blotting of nestin concentration. MK-801 alone did not alter nestin concentration, while clozapine alone enhanced hippocampal nestin concentration; this effect was not apparent in animals with MK-801 and clozapine co-administration. MK-801 also produced schizophrenia-like PPI disruptions, some of which were reversed by clozapine. Social interaction deficits were not detected in this model. This is the first report of clozapine-induced enhancements of hippocampal nestin concentration that might be mediated by NMDA receptors. Future studies will explore the impact of neurodevelopmental nestin concentration on symptom onset and antipsychotic treatment.

Sex-Specific Cannabidiol- and Iloperidone-Induced Neuronal Activity Changes in an In Vitro MAM Model System of Schizophrenia.

Cortical circuit dysfunction is thought to be an underlying mechanism of schizophrenia (SZ) pathophysiology with normalization of aberrant circuit activity proposed as a biomarker for antipsychotic efficacy. Cannabidiol (CBD) shows potential as an adjunctive antipsychotic therapy; however, potential sex effects in these drug interactions remain unknown. In the present study, we sought to elucidate sex effects of CBD coadministration with the atypical antipsychotic iloperidone (ILO) on the activity of primary cortical neuron cultures derived from the rat methylazoxymethanol acetate (MAM) model used for the study of SZ. Spontaneous network activity measurements were obtained using a multielectrode array at baseline and following administration of CBD or ILO alone, or combined. At baseline, MAM male neurons displayed increased bursting activity whereas MAM female neurons exhibited no difference in bursting activity compared to sex-matched controls. CBD administered alone showed a rapid but transient increase in neuronal activity in the MAM networks, an effect more pronounced in females. Furthermore, ILO had an additive effect on CBD-induced elevations in activity in the MAM male neurons. In the MAM female neurons, CBD or ILO administration resulted in time-dependent elevations in neuronal activity, but the short-term CBD-induced increases in activity were lost when CBD and ILO were combined. Our findings indicate that CBD induces rapid increases in cortical neuronal activity, with sex-specific drug interactions upon ILO coadministration. This suggests that sex should be a consideration when implementing adjunct therapy for treatment of SZ.

Finding the balance between model complexity and performance: Using ventral striatal oscillations to classify feeding behavior in rats.

The ventral striatum (VS) is a central node within a distributed network that controls appetitive behavior, and neuromodulation of the VS has demonstrated therapeutic potential for appetitive disorders. Local field potential (LFP) oscillations recorded from deep brain stimulation (DBS) electrodes within the VS are a pragmatic source of neural systems-level information about appetitive behavior that could be used in responsive neuromodulation systems. Here, we recorded LFPs from the bilateral nucleus accumbens core and shell (subregions of the VS) during limited access to palatable food across varying conditions of hunger and food palatability in male rats. We used standard statistical methods (logistic regression) as well as the machine learning algorithm lasso to predict aspects of feeding behavior using VS LFPs. We were able to predict the amount of food eaten, the increase in consumption following food deprivation, and the type of food eaten. Further, we were able to predict whether the initiation of feeding was imminent up to 42.5 seconds before feeding began and classify current behavior as either feeding or not-feeding. In classifying feeding behavior, we found an optimal balance between model complexity and performance with models using 3 LFP features primarily from the alpha and high gamma frequencies. As shown here, unbiased methods can identify systems-level neural activity linked to domains of mental illness with potential application to the development and personalization of novel treatments.

Plasma essential amino acid levels in first episode psychosis at baseline and after antipsychotic treatment.

This study assessed plasma levels of essential amino acids (EAA) in drug-naïve first episode psychosis (FEP) patients at diagnosis and after 10 weeks of antipsychotic treatment. Forty FEP patients were enrolled at baseline, with blood samples collected before and after a 10-week antipsychotic treatment period. Plasma EAA levels were measured using an LC/MS/MS method. Psychotic symptoms were evaluated using standardized inventories before and after treatment. A decrease in BPRS score of more than 40% was used to indicate treatment response. Thirty-five healthy volunteers served as the control group. Baseline plasma levels of Thr, Met, Leu, Lys, His, and Tyr were higher in FEP patients than in healthy controls. After 10 weeks of treatment, Leu, His, and Tyr increased further, primarily in treatment-responsive patients. Conversely, Val level was lower than controls in patients at baseline and remained unchanged after treatment. Increased EAA levels were correlated with lower (less severe) scores in positive symptom scales. Treatment non-responders had persistently low Tyr/large neutral amino acid (LNAA) ratio. Tyr/LNAA ratio increased after treatment, specifically in treatment-responders. Phe/Tyr ratio decreased post-treatment in both responder and non-responder groups. Elevated EAA levels in FEP patients may signify compensatory responses to increased physiological demand for neurotransmitters or energy. Combining specific EAA supplementation with antipsychotic treatment may enhance treatment response in these patients.

DNA methylation, but not microRNA expression, is affected by in vitro THC exposure in bovine granulosa cells.

BACKGROUND: A global increase in cannabis use has led to questions about its effects on fertility. The rise in consumption amongst women of reproductive age is a growing concern, as this group is vulnerable in terms of reproductive health. Ample evidence suggests that the psychoactive component of cannabis, Δ9-Tetrahydrocannabinol (THC), interacts with the endocannabinoid system (ECS), that helps regulate mammalian reproduction. This study aimed to research the epigenetic effects of THC in bovine granulosa cells (GCs) by (1) investigating global DNA methylation via measuring 5-mC and 5-hmC levels; (2) measuring key methylation regulators, including the methylating enzymes DNMT1, DNMT3a, DNMT3b and the demethylases TDG and TET1/2/3; and (3) assessing fertility-associated miRNAs key in developmental competency, including miR-21, -155, -33b, -324 and -346. METHODS: Bovine GCs were used as a translational model for reproductive toxicity in humans. To determine THC effects, GCs were isolated from Cumulus-Oocyte-Complexes (COCs) from bovine ovaries, cultured in vitro for 7 days, or until confluent, and cryopreserved at passage 1 (P1). For experimentation, cells were thawed, cultured until passage 2 (P2), serum restricted for 24-h and treated for 24-h in one of five groups: control, vehicle (1:1:18 ethanol: tween: saline) and three clinically relevant THC doses (0.032, 0.32 and 3.2 µM). Global methylation was assessed by measuring 5-mC and 5-hmC levels with flow cytometry. To assess mRNA and protein expression of methylation regulators and miRNA profiles, qPCR and Western Blotting were utilized. Shapiro-Wilk test was used to determine normality within datasets. One-way ANOVA was applied to determine statistical significance using GraphPad Prism 6.0.0. RESULTS: Results indicate a significant decrease (p = 0.0435) in 5-mC levels following low THC exposure, while no changes were observed in 5-hmC levels. A significant increase in DNMT1 following high THC exposure at the RNA level (p < 0.05) and a significant increase following low THC exposure at the protein level (p = 0.0048) were also observed. No significant differences were observed in DNMT3a/3b, TDG, TET1/2/3 mRNAs or in any of the miRNAs analyzed. CONCLUSIONS: This research suggests that THC mainly affects DNA methylation, but not miRNA profiles, ultimately altering gene expression and likely impairing oocyte competence, maturation, and fertilization potential.

Factors influencing JUUL e-cigarette nicotine vapour-induced reward, withdrawal, pharmacokinetics and brain connectivity in rats: sex matters.

Though vaping likely represents a safer alternative to smoking, it is not without risks, many of which are not well understood, especially for vulnerable populations. Here we evaluate the sex- and age-dependent effects of JUUL nicotine vapour in rats. Following passive nicotine vapour exposures (from 59 mg/ml JUUL nicotine pods), rats were evaluated for reward-like behaviour, locomotion, and precipitated withdrawal. Pharmacokinetics of nicotine and its metabolites in brain and plasma and the long-term impact of nicotine vapour exposure on functional magnetic resonance imaging-based brain connectivity were assessed. Adult female rats acquired conditioned place preference (CPP) at a high dose (600 s of exposure) of nicotine vapour while female adolescents, as well as male adults and adolescents did not. Adult and adolescent male rats displayed nicotine vapour-induced precipitated withdrawal and hyperlocomotion, while both adult and adolescent female rats did not. Adult females showed higher venous and arterial plasma and brain nicotine and nicotine metabolite concentrations compared to adult males and adolescent females. Adolescent females showed higher brain nicotine concentration compared to adolescent males. Both network-based statistics and between-component group connectivity analyses uncovered reduced connectivity in nicotine-exposed rats, with a significant group by sex interaction observed in both analyses. The short- and long-term effects of nicotine vapour are affected by sex and age, with distinct behavioural, pharmacokinetic, and altered network connectivity outcomes dependent on these variables.

THC and sperm: Impact on fertilization capability, pre-implantation in vitro development and epigenetic modifications.

Global cannabis use has risen 23% since 2010, with 209 million reported users, most of whom are males of reproductive age. Delta-9-tetrahydrocannabinol (THC), the main psychoactive phytocannabinoid in cannabis, disrupts pro-homeostatic functions of the endocannabinoid system (ECS) within the male reproductive system. The ECS is highly involved in regulating morpho-functional and intrinsic sperm features that are required for fertilization and pre-implantation embryo development. Previous work by our group demonstrated that THC altered sperm capacitation and the transcriptome, including several fertility-associated microRNAs (miRs). Despite the prevalent use of cannabis among males of reproductive age, clinical and pre-clinical research investigating the impact of paternal cannabis on sperm function and the outcomes of artificial reproductive technologies (ARTs) remains inconclusive. Therefore, the present study investigates the impact of in vitro THC exposure on morpho-functional and intrinsic sperm functions, including contributions to embryo development following IVF. Bovine sperm were used as a translational model for human and treated with concentrations of THC that reflect plasma levels after therapeutic (0.032µM), and low (0.32µM)-high (4.8µM) recreational cannabis use. After 6-hours of treatment, THC did not alter the acrosomal reaction, but 4.8µM significantly reduced mitochondrial membrane potential (MMP) (p<0.05), primarily through agonistic interactions with CB-receptors. Fertilization of bovine oocytes with THC-treated sperm did not alter developmental rates, but blastocysts generated from sperm treated with 0.32-4.8µM THC had fewer trophoblasts (p<0.05), while blastocysts generated from sperm exposed to any concentration of THC had fewer cells in the inner cell mass (ICM), particularly within the 0.032µM group (p<0.001). Fertility associated miRs, including miR-346, miR-324, miR-33b, and miR-34c were analyzed in THC-exposed sperm and associated blastocysts generated by IVF, with lower levels of miRs-346, -324, and -33b found in sperm treated with 0.32µM THC, while miR-34c levels were higher in sperm treated with 0.032µM THC (p<0.05). Levels of miR-346 were also lower in sperm treated with 0.032µM THC, but higher in blastocysts generated from sperm exposed to 0.32µM THC (p<0.05). Our findings suggest that THC may alter key morpho-functional and epigenetic sperm factors involved in fertilization and embryo development. This is the first study to demonstrate that sperm exposed to THC in vitro negatively affects embryo quality following IVF.

Randomized Laboratory Study of Single-Dose Cannabis, Dronabinol, and Placebo in Patients With Schizophrenia and Cannabis Use Disorder.

BACKGROUND AND HYPOTHESIS: Up to 43% of people with schizophrenia have a lifetime cannabis use disorder (CUD). Tetrahydrocannabinol (THC) has been shown to exacerbate psychosis in a dose-dependent manner, but little research has assessed its effects on schizophrenia and co-occurring CUD (SCZ-CUD). In this double-dummy, placebo-controlled trial (total n = 130), we hypothesized that a modest dose of THC would worsen cognitive function but not psychosis. STUDY DESIGN: Effects of single-dose oral THC (15 mg dronabinol) or smoked 3.5% THC cigarettes vs placebo in SCZ-CUD or CUD-only on positive and negative symptoms of schizophrenia (only for SCZ-CUD), cognition, and drug experiences assessed several hours after drug administration. SCZ-only and healthy control participants were also assessed. STUDY RESULTS: Drug liking was higher in THC groups vs placebo. Neither smoked THC nor oral dronabinol predicted positive or negative symptom subscale scores 2 and 5 h, respectively, after drug exposure in SCZ-CUD participants. The oral dronabinol SCZ-CUD group, but not smoked THC SCZ-CUD group, performed worse than placebo on verbal learning (B = -9.89; 95% CI: -16.06, -3.18; P = .004) and attention (B = -0.61; 95% CI: -1.00, -0.23; P = .002). Every 10-point increment in serum THC + THCC ng/ml was associated with increased negative symptoms (0.40 points; 95% CI: 0.15, 0.65; P = .001; subscale ranges 7-49) and trends were observed for worse positive symptoms and performance in verbal learning, delayed recall, and working memory. CONCLUSIONS: In people with SCZ-CUD, a modest single dose of oral THC was associated with worse cognitive functioning without symptom exacerbation several hours after administration, and a THC dose-response effect was seen for negative symptoms.

Genome-wide association studies of lifetime and frequency cannabis use in 131,895 individuals.

Cannabis is one of the most widely used drugs globally. Decriminalization of cannabis is further increasing cannabis consumption. We performed genome-wide association studies (GWASs) of lifetime (N=131,895) and frequency (N=73,374) of cannabis use. Lifetime cannabis use GWAS identified two loci, one near CADM2 (rs11922956, p=2.40E-11) and another near GRM3 (rs12673181, p=6.90E-09). Frequency of use GWAS identified one locus near CADM2 (rs4856591, p=8.10E-09; r2 =0.76 with rs11922956). Both traits were heritable and genetically correlated with previous GWASs of lifetime use and cannabis use disorder (CUD), as well as other substance use and cognitive traits. Polygenic scores (PGSs) for lifetime and frequency of cannabis use associated cannabis use phenotypes in AllofUs participants. Phenome-wide association study of lifetime cannabis use PGS in a hospital cohort replicated associations with substance use and mood disorders, and uncovered associations with celiac and infectious diseases. This work demonstrates the value of GWASs of CUD transition risk factors.

Cross-ancestry genetic investigation of schizophrenia, cannabis use disorder, and tobacco smoking.

Individuals with schizophrenia frequently experience co-occurring substance use, including tobacco smoking and heavy cannabis use, and substance use disorders. There is interest in understanding the extent to which these relationships are causal, and to what extent shared genetic factors play a role. We explored the relationships between schizophrenia (Scz), cannabis use disorder (CanUD), and ever-regular tobacco smoking (Smk) using the largest available genome-wide studies of these phenotypes in individuals of African and European ancestries. All three phenotypes were positively genetically correlated (rgs = 0.17 - 0.62). Causal inference analyses suggested the presence of horizontal pleiotropy, but evidence for bidirectional causal relationships was also found between all three phenotypes even after correcting for horizontal pleiotropy. We identified 439 pleiotropic loci in the European ancestry data, 150 of which were novel (i.e., not genome-wide significant in the original studies). Of these pleiotropic loci, 202 had lead variants which showed convergent effects (i.e., same direction of effect) on Scz, CanUD, and Smk. Genetic variants convergent across all three phenotypes showed strong genetic correlations with risk-taking, executive function, and several mental health conditions. Our results suggest that both horizontal pleiotropy and causal mechanisms may play a role in the relationship between CanUD, Smk, and Scz, but longitudinal, prospective studies are needed to confirm a causal relationship.

Acute nicotine vapor normalizes sensorimotor gating and reduces locomotor activity deficits in HIV-1 transgenic rats.

Rationale: Despite improved life expectancy of people with HIV (PWH), HIV-associated neurocognitive impairment (NCI) persists, alongside deficits in sensorimotor gating and neuroinflammation. PWH exhibit high smoking rates, possibly due to neuroprotective, anti-inflammatory, and cognitive-enhancing effects of nicotine, suggesting potential self-medication. Objectives: Here, we tested the effects of acute nicotine vapor exposure on translatable measures of sensorimotor gating and exploratory behavior in the HIV-1 transgenic (HIV-1Tg) rat model of HIV. Methods: Male and female HIV-1Tg and F344 control rats (n=57) were exposed to acute nicotine or vehicle vapor. Sensorimotor gating was assessed using prepulse inhibition (PPI) of the acoustic startle response, and exploratory behavior was evaluated using the behavioral pattern monitor (BPM). Results: Vehicle-treated HIV-1Tg rats exhibited PPI deficits at low prepulse intensities compared to F344 controls, as seen previously. No PPI deficits were observed in nicotine-treated HIV1-Tg rats, however. HIV-1Tg rats were hypoactive in the BPM relative to controls, whilst nicotine vapor increased activity and exploratory behavior across genotypes. Cotinine analyses confirmed comparable levels of the primary metabolite of nicotine across genotypes. Conclusions: Previous findings of PPI deficits in HIV-1Tg rats were replicated and, importantly, attenuated by acute nicotine vapor. Evidence for similar cotinine levels suggest a nicotine-specific effect in HIV-1Tg rats. HIV-1Tg rats had reduced exploratory behavior compared to controls, attenuated by acute nicotine vapor. Therefore, acute nicotine may be beneficial for remediating sensorimotor and locomotor activity deficits in PWH. Future studies should determine the long-term effects of nicotine vapor on similar HIV/NCI-relevant behaviors.

Cross-ancestry genetic investigation of schizophrenia, cannabis use disorder, and tobacco smoking.

Individuals with schizophrenia frequently experience co-occurring substance use, including tobacco smoking and heavy cannabis use, and substance use disorders. There is interest in understanding the extent to which these relationships are causal, and to what extent shared genetic factors play a role. We explored the relationships between schizophrenia (Scz; European ancestry N = 161,405; African ancestry N = 15,846), cannabis use disorder (CanUD; European ancestry N = 886,025; African ancestry N = 120,208), and ever-regular tobacco smoking (Smk; European ancestry N = 805,431; African ancestry N = 24,278) using the largest available genome-wide studies of these phenotypes in individuals of African and European ancestries. All three phenotypes were positively genetically correlated (rgs = 0.17-0.62). Genetic instrumental variable analyses suggested the presence of shared heritable factors, but evidence for bidirectional causal relationships was also found between all three phenotypes even after correcting for these shared genetic factors. We identified 327 pleiotropic loci with 439 lead SNPs in the European ancestry data, 150 of which were novel (i.e., not genome-wide significant in the original studies). Of these pleiotropic loci, 202 had lead variants which showed convergent effects (i.e., same direction of effect) on Scz, CanUD, and Smk. Genetic variants convergent across all three phenotypes showed strong genetic correlations with risk-taking, executive function, and several mental health conditions. Our results suggest that both shared genetic factors and causal mechanisms may play a role in the relationship between CanUD, Smk, and Scz, but longitudinal, prospective studies are needed to confirm a causal relationship.

Genome-wide association studies of coffee intake in UK/US participants of European ancestry uncover cohort-specific genetic associations.

Coffee is one of the most widely consumed beverages. We performed a genome-wide association study (GWAS) of coffee intake in US-based 23andMe participants (N = 130,153) and identified 7 significant loci, with many replicating in three multi-ancestral cohorts. We examined genetic correlations and performed a phenome-wide association study across hundreds of biomarkers, health, and lifestyle traits, then compared our results to the largest available GWAS of coffee intake from the UK Biobank (UKB; N = 334,659). We observed consistent positive genetic correlations with substance use and obesity in both cohorts. Other genetic correlations were discrepant, including positive genetic correlations between coffee intake and psychiatric illnesses, pain, and gastrointestinal traits in 23andMe that were absent or negative in the UKB, and genetic correlations with cognition that were negative in 23andMe but positive in the UKB. Phenome-wide association study using polygenic scores of coffee intake derived from 23andMe or UKB summary statistics also revealed consistent associations with increased odds of obesity- and red blood cell-related traits, but all other associations were cohort-specific. Our study shows that the genetics of coffee intake associate with substance use and obesity across cohorts, but also that GWAS performed in different populations could capture cultural differences in the relationship between behavior and genetics.

Pharmacogenetics of drug dependence: role of gene variations in susceptibility and treatment.

Drug dependency is a highly prevalent mental health disorder that imposes a significant burden on those directly affected, health care systems, and society in general. There is substantial heritability in the susceptibility to drug addiction, which indicates that there are genetic risk factors. Variation in the human genome is abundant and can directly affect drug dependency phenotypes, for example, by altering the function of a gene product or by altering gene expression. Pharmacogenetic studies can assess the effects of genetic variation on the risk for a particular phenotype (e.g., being an alcoholic). In addition, pharmacogenetic variability in treatment efficacy and adverse reactions can be investigated to identify particular genetic variants associated with altered responses. This review highlights examples of genetic variations that are important in the development and maintenance of specific drug dependencies as well as those that affect the response to treatment.