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.

The Effects of Nicotine and Cannabinoids on Cytokines.

BACKGROUND: The usage of nicotine and cannabinoids has rapidly grown in popularity, leading to increased research into how they can affect people's health, both positively and negatively. Nicotine, Cannabidiol (CBD), and Tetrahydrocannabidiol (THC) have been shown to have significant effects on cytokine function and inflammatory response. OBJECTIVE: This study aimed to review and summarize the current literature on the effects of nicotine and cannabinoids on cytokines, including interleukins, TNF, IFN, and TGF-ß. METHODS: Literature search was conducted on Medline/PubMed electronic databases utilizing the search terms "nicotine" OR "cannabis" OR "cannabinoids" AND "cytokine" AND "inflammation" AND "stress" AND "immune" from 11/1973 to 02/2024. RESULTS: THC and CBD usage have been associated with conflicting impacts on immune response, and observed to both exacerbate and inhibit inflammation. Nicotine has been shown to be generally proinflammatory with regards to cytokines. These responses have been reported to have significant effects on bodily response to inflammation-related diseases. Nicotine usage is associated with worsened outcomes for some conditions, like chronic pain, but improved outcomes for others, like arthritis. The impacts of cannabinoid usage tend to be more positive, exerting anti-inflammatory effects across a wide range of diseases. Given the widespread usage of these substances, it is important to understand the nature of their consequences on immune functions and the underlying mechanisms by which they act. CONCLUSION: This review has covered how cannabinoids and nicotine affect inflammation directly and how these effects can be attributed to the treatment of inflammatory diseases. In summary, the existing research studying the effects of cannabinoids and nicotine supports the major relationship between nicotine and cannabis use and inflammatory diseases.

Selenoprotein P in a Rodent Model of Exercise; Theorizing Its Interaction with Brain Reward Dysregulation, Addictive Behavior, and Aging.

Exercise promotes health and wellness, including its operation as a protective factor against a variety of psychological, neurological, and chronic diseases. Selenium and its biomarker, selenoprotein P (SEPP1), have been implicated in health, including cancer prevention, neurological function, and dopamine signaling. SEPP1 blood serum levels were compared with a one-way ANOVA between sedentary (SED), moderately exercised (MOD) [10 m/min starting at 10 min, increasing to 60 min], and high-intensity interval training (HIIT) exercised rats [30 min in intervals of 2-min followed by a 1-min break, speed progressively increased from 10 to 21 m/min]. HIIT rats showed significantly higher serum SEPP1 concentrations compared to MOD and SED. More specifically, HIIT exercise showed an 84% increase in SEPP1 levels compared to sedentary controls. MOD rats had greater serum SEPP1 concentrations compared to SED, a 33% increase. The results indicated that increased exercise intensity increases SEPP1 levels. Exercise-induced increases in SEPP1 may indicate an adaptive response to the heightened oxidative stress. Previous studies found a significant increase in dopamine D2 receptor (D2R) binding in these same rats, suggesting a potential association between SEPP1 and dopamine signaling during exercise. Modulating antioxidants like SEPP1 through personalized therapies, including exercise, has broad implications for health, disease, and addiction.

Vaporized Δ9-tetrahydrocannabinol exposure in utero has negative effects on attention in a dose- and sex-dependent manner.

There has been an increasing use of cannabis during pregnancy in recent years. Studies have indicated that THC exposure in utero may increase the risk of attention deficits and memory impairments in adolescence. The goal of the present study is to investigate the effects of vaporized THC exposure during pregnancy on offspring memory and attention performance in early and late adolescence. Pregnant dams were exposed to vaporized THC (10 mg or 40 mg) daily from gestational day 2 until labor. Pups were given either a standard or a high-fat diet at weaning and tested in early and late adolescence in two memory tests, the Novel Object Recognition (NOR) test and the Morris Water Maze (MWM) test, and a test of attention, the Object-Based Attention (OBA) test. Rats exposed to low-dose THC showed significantly decreased object exploration in both the NOR and OBA tests, indicating decreased attention. Object exploration time in OBA was significantly lower in females than males. Additionally, post hoc analysis of MWM tests showed some differences in learning patterns for HD THC offspring in early adolescence, possibly due to diet interaction, but ultimate performance was not impacted. While there are existing studies examining prenatal exposure to THC in rodents, this is the first to our knowledge examining memory and attention in adolescence following vaporized THC exposure in utero, and we find indications that prenatal THC exposure may lead to attention deficits and altered memory performance.

Vaporized nicotine in utero results in reduced birthweight, increased locomotion, and decreased voluntary exercise, dependent on sex and diet in offspring.

Rationale Clinical research has shown that prenatal exposure to nicotine may result in increased obesity risk later in life. Preclinical research has corroborated this finding, but few studies have investigated inhaled nicotine or the interaction with diet on obesity risk. Objective The aim of this study was to investigate the effects of prenatal nicotine exposure on both direct and indirect obesity measures, with both sex and diet as factors. Methods Pregnant rats were exposed to either vehicle or nicotine vapor (24 mg/mL or 59 mg/mL) throughout the entire gestational period. Offspring from each treatment group were given either a normal diet or a high fat diet starting at postnatal day 22. Caloric intake, body weight, spontaneous locomotion, sleep/wake activity, and voluntary exercise were measured throughout adolescence. Pregnancy weight gain and pup birthweights were collected to further measure developmental effects of prenatal nicotine exposure. Results Both maternal weight gain during pregnancy and pup weight at birth were decreased with prenatal nicotine exposure. Early adolescent males showed increased spontaneous activity in the open field following prenatal nicotine exposure compared to vehicle counterparts, particularly those given high-fat diet. Additionally, high dose nicotine prenatal treated males ran significantly less distance on the running wheel in late adolescence compared to vehicle counterparts, in the normal diet group only. Conclusion The results presented here show decreased birthweight, hyperactivity, and decreased voluntary exercise in adolescence following prenatal nicotine exposure in dose, sex, and diet dependent manners, which could lead to increased obesity risk in adulthood.

Vaporized Δ9-THC in utero results in reduced birthweight, increased locomotion, and altered wake-cycle activity dependent on dose, sex, and diet in the offspring.

AIMS: Preclinical studies have found that chronic ∆9-tetrahydrocannabinol (THC) treatment is directly associated with weight gain when introduced during adolescence and adulthood, but the effect of prenatal THC is unclear. Clinical studies have demonstrated prenatal exposure to THC is a prospective predictor of increased health risks associated with obesity. Our study aims to examine prenatal THC impact on obesity risks in males and females throughout adolescence using a clinically relevant inhalation model. METHODS: Pregnant rats were exposed to one of the following from gestational day 2 through birth: 10 mg THC, 40 mg THC, or air. Daily 10-min inhalations were conducted in each animal from 0900 to 1200. Offspring from each treatment group were given either a high-fat diet (HFD) or a normal diet (ND). Food and bodyweights were collected daily, while circadian activity, locomotion, and exercise were measured periodically (PND 21-60). Pregnancy weight gain and birth weight were collected to determine early-life developmental effects. RESULTS: Rats prenatally treated with low-dose THC (LDTHC) generally had lower dark-cycle activity compared with control counterparts, but this altered activity was not observed at the higher dose of THC (HDTHC). In terms of open-field activity, THC doses displayed a general increase in locomotion. In addition, the LDTHC male rats in the ND showed significantly greater exploratory behavior. Prenatal THC had dose-dependent effects on maternal weight gain and birth weight. CONCLUSIONS: Overall, our findings indicate there are some activity-related and developmental effects of prenatal THC, which may be related to obesity risks later in life.

Fatty Acid-Binding Protein 5 Gene Deletion Enhances Nicotine-Conditioned Place Preference: Illuminating the Putative Gateway Mechanisms.

Emerging evidence indicates that the endogenous cannabinoid system modulates the behavioral and physiological effects of nicotine. Fatty acid-binding proteins (FABPs) are among the primary intracellular trafficking mechanisms of endogenous cannabinoids, such as anandamide. To this end, changes in FABP expression may similarly impact the behavioral manifestations associated with nicotine, particularly its addictive properties. FABP5 +/+ and FABP5 -/- mice were tested for nicotine-conditioned place preference (CPP) at two different doses (0.1 or 0.5 mg/kg). The nicotine-paired chamber was assigned as their least preferred chamber during preconditioning. Following 8 days of conditioning, the mice were injected with either nicotine or saline. The mice were allowed to access to all the chambers on the test day, and their times spent in the drug chamber on the preconditioning versus the test days were used to examine the drug preference score. The CPP results showed that the FABP5 -/- mice displayed a higher place preference for 0.1 mg/kg nicotine than the FABP5 +/+ mice, while no CPP difference was observed for 0.5 mg/kg nicotine between the genotypes. In conclusion, FABP5 plays an important role in regulating nicotine place preference. Further research is warranted to identify the precise mechanisms. The results suggest that dysregulated cannabinoid signaling may impact nicotine-seeking behavior.

Vaporized Delta-9-tetrahydrocannabinol Inhalation in Female Sprague Dawley Rats: A Pharmacokinetic and Behavioral Assessment.

BACKGROUND: Delta-9-tetrahydrocannabinol (THC) is the main psychoactive component of cannabis. Historically, rodent studies examining the effects of THC have used intraperitoneal injection as the route of administration, heavily focusing on male subjects. However, human cannabis use is often through inhalation rather than injection. OBJECTIVE: We sought to characterize the pharmacokinetic and phenotypic profile of acutely inhaled THC in female rats, compared to intraperitoneal injection, to identify any differences in exposure of THC between routes of administration. METHODS: Adult female rats were administered THC via inhalation or intraperitoneal injection. Serum samples from multiple time points were analyzed for THC and metabolites 11-hydroxy-delta-9-tetrahydrocannabinol and 11-nor-9-carboxy-delta-9-tetrahydrocannabinol using ultra-performance liquid chromatography-tandem mass spectrometry. Rats were similarly treated for locomotor activity analysis. RESULTS: Rats treated with 2 mg/kg THC intraperitoneally reached a maximum serum THC concentration of 107.7 ± 21.9 ng/mL. Multiple THC inhalation doses were also examined (0.25 mL of 40 or 160 mg/mL THC), achieving maximum concentrations of 43.3 ± 7.2 and 71.6 ± 22.5 ng/mL THC in serum, respectively. Significantly reduced vertical locomotor activity was observed in the lower inhaled dose of THC and the intraperitoneal injected THC dose compared to vehicle treatment. CONCLUSION: This study established a simple rodent model of inhaled THC, demonstrating the pharmacokinetic and locomotor profile of acute THC inhalation, compared to an i.p. injected THC dose in female subjects. These results will help support future inhalation THC rat research which is especially important when researching behavior and neurochemical effects of inhaled THC as a model of human cannabis use.

FABP5 is important for cognitive function and is an important regulator of the physiological effects and pharmacokinetics of acute Δ9 tetrahydrocannabinol inhalation in mice.

Fatty acid binding protein 5 (FABP5) interacts with the endocannabinoid system in the brain via intracellular transport of anandamide, as well as Δ9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis. Previous work has established the behavioral effects of genetic deletion of FABP5, but not in the presence of THC. The present study sought to further elucidate the role of FABP5 on the pharmacokinetic and behavioral response to THC through global deletion. Adult FABP5+/+ and FABP5-/- mice were tested for behavioral response to THC using Open Field (OF), Novel Object Recognition (NOR), T-Maze, Morris Water Maze (MWM), and Elevated Plus Maze (EPM). An additional cohort of mice was used to harvest blood, brains, and liver samples to measure THC and metabolites after acute administration of THC. Behavioral tests showed that some cognitive deficits from FABP5 deletion, particularly in MWM, were blocked by THC administration, while this was not observed in other measures of memory and anxiety (such as T-Maze and EPM). Measurement of THC and metabolites in blood serum and brain tissue through UPLC-MS/MS analysis showed that the pharmacokinetics of THC was altered by FABP5. The present study shows further evidence of the importance of FABP5 in cognitive function. Additionally, results showed that FABP5 is an important regulator of the physiological effects and pharmacokinetics of THC.

Effects of Δ9-Tetrahydrocannibinol (THC) on Obesity at Different Stages of Life: A Literature Review.

The Cannabis sativa plant has historically been used for both recreational and medical purposes. With the recent surge in recreational use of cannabis among adolescents and adults in particular, there is an increased obligation to determine the short- and long-term effects that consuming this plant may have on several aspects of the human psyche and body. The goal of this article was to examine the negative effects of obesity, and how the use of Δ9-tetrahydrocannibinol (THC) or cannabidiol (CBD) can impact rates of this global pandemic at different timepoints of life. Conflicting studies have been reported between adult and adolescents, as there are reports of THC use leading to increased weight due to elevated appetite and consumption of food, while others observed a decrease in overall body weight due to the regulation of omega-6/omega-3 endocannabinoid precursors and a decrease in energy expenditure. Studies supported a positive correlation between prenatal cannabis use and obesity rates in the children as they matured. The data did not indicate a direct connection between prenatal THC levels in cannabis and obesity rates, but that this development may occur due to prenatal THC consumption leading to low birthweight, and subsequent obesity. There are few studies using animal models that directly measure the effects that prenatal THC administration on obesity risks among offspring. Thus, this is a critical area for future studies using a developmental framework to examine potential changes in risk across development.

Examining the role of cannabinoids on osteoporosis: a review.

PURPOSE: Prior research studies have shown that the endocannabinoid system, influenced by CBD and THC, plays a role in bone remodeling. As both the research on cannabis and use of cannabis continue to grow, novel medicinal uses of both its constituents as well as the whole plant are being discovered. This review examines the role of cannabinoids on osteoporosis, more specifically, the endocannabinoid system and its role in bone remodeling and the involvement of the cannabinoid receptors 1 and 2 in bone health, as well as the effects of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and synthetic cannabinoids on bone. METHODS: A comprehensive literature search of online databases including PUBMED was utilized. RESULTS: A total of 29 studies investigating the effects of cannabis and/or its constituents as well as the activation or inactivation of cannabinoid receptors 1 and 2 were included and discussed. CONCLUSION: While many of the mechanisms are still not yet fully understood, both preclinical and clinical studies show that the effects of cannabis mediated through the endocannabinoid system may prove to be an effective treatment option for individuals with osteoporosis.

Environmental enrichment sex-dependently rescues memory impairment in FABP5 KO mice not mediated by brain-derived neurotrophic factor.

Fatty acid-binding proteins (FABPs) are intracellular carriers of bioactive lipids and play a role in the trafficking of endocannabinoids as well as polyunsaturated fatty acids. Mice lacking the FABP5 gene have memory impairments. Environmental enrichment is a potent manipulation known to rescue or improve memory performance. The extent to which the memory impairments in FABP5 knockout (KO) mice can be rescued or improved through environmental conditions remains to be understood. To address this, we raised wild type (WT) and FABP5 KO mice in either socially isolated or environmental enrichment conditions during adolescence. Once in adulthood, mice were tested for Novel Object Recognition (NOR), T-maze, and Morris Water Maze (MWM) to evaluate memory performance. Mice were then euthanized to assess hippocampal brain-derived neurotrophic factor (BDNF) concentrations. MWM results showed that male FABP5 KO mice performed worse compared to WT counterparts. Male and female mice raised in an enriched environment improved performance regardless of genotype. Results on the NOR test showed that male FABP5 KO mice displayed lower object recognition compared to WT counterparts across both environments. No differences of genotype or environment were seen in female mice. T-maze findings revealed impaired performance in socially isolated FABP5 KO mice. Adolescent environmental enrichment rescued this deficit in male, but not female, FABP5 KO mice. Lastly, environmental enrichment increased hippocampal BDNF levels in male WT mice only. Our results corroborate the previously observed role of the FABP5 gene on memory performance and identify an important interaction with the environment during adolescence.