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 Role of Estrogen Signaling and Exercise in Drug Abuse: A Review.

BACKGROUND: Discovering how sex differences impact the efficacy of exercise regimens used for treating drug addiction is becoming increasingly important. Estrogen is a hormone believed to explain a large portion of sex differences observed during drug addiction, and why certain exercise regimens are not equally effective between sexes in treatment. Addiction is currently a global hindrance to millions, many of whom are suffering under the influence of their brain's intrinsic reward system coupled with external environmental factors. Substance abuse disorders in the U.S. alone cost billions of dollars annually. REVIEW SUMMARY: Studies involving the manipulation of estrogen levels in female rodents, primarily via ovariectomy, highlight its impact regarding drug addiction. More specifically, female rodents with higher estrogen levels during the estrus phase increase cocaine consumption, whereas those in the non-estrus phase (low estrogen levels) decrease cocaine consumption. If estrogen is reintroduced, self-administration increases once again. Exercise has been proven to decrease relapse tendency, but its effect on estrogen levels is not fully understood. CONCLUSIONS: Such findings and results discussed in this review suggest that estrogen influences the susceptibility of females to relapse. Therefore, to improve drug-abuse-related treatment, exercise regimens for females should be generated based on key sex differences with respect to males.

Potential Link Between Exercise and N-Methyl-D-Aspartate Glutamate Receptors in Alcohol Use Disorder: Implications for Therapeutic Strategies.

Alcohol use disorder (AUD) is a significant risk factor, accounting for approximately 13% of all deaths in the US. AUD not only destroys families but also causes economic losses due to reduced productivity, absenteeism, and healthcare expenses. Statistics revealing the sustained number of individuals affected by AUD over the years underscore the need for further understanding of the underlying pathophysiology to advance novel therapeutic strategies. Previous research has implicated the limbic brain regions N-methyl-D-aspartate glutamate receptors (NMDAR) in the emotional and behavioral effects of AUD. Given that aerobic exercise can modulate NMDAR activity and sensitivity to alcohol, this review presents a summary of clinical and basic science studies on NMDAR levels induced by alcohol consumption, as well as acute and protracted withdrawal, highlighting the potential role of aerobic exercise as an adjunctive therapy for AUD. Based on our findings, the utility of exercise in the modulation of reward-linked receptors and AUD may be mediated by its effects on NMDA signaling. These data support further consideration of the potential of aerobic exercise as a promising adjunctive therapy for AUD.

Effects of Exercise on Testosterone and Implications of Drug Abuse: A Review.

OBJECTIVE: Research points to exercise having a positive effect in fighting relapse and use of drugs of abuse. Through conducting this research, differences have been observed in the effects of exercise on drug abuse between sexes. Many of the studies found that exercise tends to cause a more profound effect in blocking drug relapse or reinstatement in males when compared with females. METHODS: Our hypothesis is that these differences in response to drugs of abuse after an exercise regimen could in part be attributed to variations in testosterone levels between males and females. RESULTS: Testosterone has been shown to have a modulatory impact on the dopaminergic activity in the brain, causing an effect on the brain's response to drugs of abuse. Exercise has demonstrated a causal effect on increasing testosterone levels in males, whereas drugs of abuse decrease testosterone levels in males. CONCLUSIONS: Thus, exercise raising testosterone levels in males helps to decrease the dopaminergic response in the brain to drugs of abuse causing attenuation to drugs. To find sex-specific exercise treatments for drugs of abuse, it is important to continue researching exercise's efficacy against drugs of abuse.

Combined Chronic Oral Methylphenidate and Fluoxetine Treatment During Adolescence: Effects on Behavior.

BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) can be comorbid with depression, often leading to the prescription of both methylphenidate (MP) and selective serotonin reuptake inhibitor (SSRI) antidepressants, such as fluoxetine (FLX). Moreover, these drugs are often misused as cognitive enhancers. This study examined the effects of chronic oral co-administration of MP and FLX on depressive- and anxiety-like behaviors. METHODS: Adolescent rats received daily either water (control), MP, FLX, or the combination of MP plus FLX in their drinking water over the course of 4 weeks. RESULTS: Data analysis shows a decrease in food consumption and body weight for rats exposed to FLX or the combination of MP and FLX. Sucrose consumption was significantly greater in FLX or MP+FLX groups compared to controls. FLX-treated rats showed no effect in the elevated plus maze (EPM; open arm time) and forced swim test (FST; latency to immobility). However, rats treated with the combination (MP+FLX) showed significant anxiolytic-like and anti-depressive-like behaviors (as measured by EPM and FST), as well as significant increases in overall activity (distance traveled in open field test). Finally, the combined MP+FLX treatment induced a decrease in anxiety and depressive- like behaviors significantly greater than the response from either of these drugs alone. CONCLUSION: These behavioral results characterize the long-term effects of these drugs (orally administered) that are widely co-administered and co-misused and provide important insight into the potential neurobiological and neurochemical effects. Future research will determine the potential risks of the long-term use of MP and FLX together.

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.

High intensity interval training exercise increases dopamine D2 levels and modulates brain dopamine signaling.

Background: Previous research has outlined the health benefits of exercise including its therapeutic potential for substance use disorders (SUD). These data have already been utilized and it is now common to find exercise as part of SUD treatment and relapse prevention programs. However, we need to better understand different exercise regimens and determine which would be the most beneficial for SUDs. Recently, high intensity interval training (HIIT) has gained attention in comparison with aerobic and resistance exercise. Little is known regarding the neurobiological mechanisms of HIIT, including its effects on dopamine signaling and receptor levels in the brain. The present study examined the effects of chronic HIIT exercise on dopamine signaling as measured by dopamine type 1-like receptor (D1R)-like, dopamine type 2-like receptor (D2R)-like, and tyrosine hydroxylase (TH) quantification in the brains of male and female rats as measured by [3H] SCH 23390 and [3H] spiperone autoradiography, and TH-immunoreactive optical density values. Methods: Rats were separated in two groups: sedentary and HIIT exercise. Exercise was on a treadmill for 30 min daily (10 3 min cycles) for six weeks with progressive speed increased up to 0.8 mph (21.5 m/min). Results: Results showed for D2R-like binding, a significant effect across the ventral caudate putamen (V CPU) between sexes, such that mean D2R-like binding was 14% greater for males than females. In the nucleus accumbens shell (Nac Shell), the HIIT Exercise rats showed 16% greater D2R-like binding as compared to the sedentary rats. No significant effects of HIIT exercise were found across groups for brain D1R-like binding levels or TH expression. Conclusion: These results suggest that HIIT exercise can modulate dopamine signaling by way of increased D2R. These findings support the premise that HIIT exercise plays an important role in dopamine signaling and, may provide a potential mechanism for how HIIT exercise can impact the brain and behavior.

Unpredictable chronic mild stress differentially impacts resting brain glucose metabolism in fatty acid-binding protein 7 deficient mice.

Fatty acid-binding proteins (FABPs) are intracellular chaperone proteins involved in the trafficking of n-3 polyunsaturated fatty acids and endocannabinoids. Inhibiting two of the main FABP subtypes found in the brain (FABP5 and FABP7) hinders endocannabinoid uptake and hydrolysis. Prior data indicates that cannabinoid receptor stimulation can ameliorate the consequences associated with chronic stress. To this end, FABP expression may play a similar role in response to stressful conditions. Male C57BL/6 J (WT) and FABP7 knockout (KO) mice were assigned to either a non-stress cohort or an unpredictable chronic mild stress (UCMS) cohort for a period of 4 weeks. Immediately after 4 weeks, mice were injected with [18F]2-fluoro-2-deoxy-d-glucose (FDG) and scanned using micro positron emission tomography (mPET) to examine brain glucose metabolism (BGluM). WT mice exposed to UCMS showed reduced BGluM in striatal, cortical, and hypothalamic regions and showed increased BGluM in the hippocampus, thalamus, periaqueductal gray, superior colliculi, inferior colliculi, and cerebellum. In contrast, there were limited effects of UCMS on BGluM in FABP7 KO mice, with a reduction in the thalamus, periaqueductal gray, and superior colliculi. These findings provide novel insight into FABP7 expression and indicate this gene to play an important role in response to aversive stimuli.