These findings support the hypothesis that aerobic exercise results in changes in the mesolimbic pathway that could mediate exercise-induced attenuation of drug-seeking behavior.

BackgroundFatty acid binding proteins (FABPs) serve as intracellular carriers that deliver endocannabinoids and N-acylethanolamines to their catabolic enzymes. Inhibition of FABPs reduces endocannabinoid transport and catabolism in cells and FABP inhibitors produce antinociceptive and anti-inflammatory effects in mice. Potential analgesic effects in mice lacking FABPs, however, have not been tested.FindingsMice lacking FABP5 and FABP7, which exhibit highest affinities for endocannabinoids, possessed elevated levels of the endocannabinoid anandamide and the related N-acylethanolamines palmitoylethanolamide and oleoylethanolamide. There were no compensatory changes in the expression of other FABPs or in endocannabinoid-related proteins in the brains of FABP5/7 knockout mice. These mice exhibited reduced nociception in the carrageenan, formalin, and acetic acid tests of inflammatory and visceral pain. The antinociceptive effects in FABP5/7 knockout mice were reversed by pretreatment with cannabinoid receptor 1, peroxisome proliferator-activated receptor alpha, and transient receptor potential vanilloid 1 receptor antagonists in a modality specific manner. Lastly, the knockout mice did not possess motor impairments.ConclusionsThis study demonstrates that mice lacking FABPs possess elevated levels of N-acylethanolamines, consistent with the idea that FABPs regulate the endocannabinoid and N-acylethanolamine tone in vivo. The antinociceptive effects observed in the knockout mice support a role for FABPs in regulating nociception and suggest that these proteins should serve as targets for the development of future analgesics.

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Aging produces cellular, molecular, and behavioral changes affecting many areas of the brain. The dopamine (DA) system is known to be vulnerable to the effects of aging, which regulate behavioral functions such as locomotor activity, body weight, and reward and cognition. In particular, age-related DA D2 receptor (D2R) changes have been of particular interest given its relationship with addiction and other rewarding behavioral properties. Male and female wild-type (Drd2 +/+), heterozygous (Drd2 +/−) and knockout (Drd2 −/−) mice were reared post-weaning in either an enriched environment (EE) or a deprived environment (DE). Over the course of their lifespan, body weight and locomotor activity was assessed. While an EE was generally found to be correlated with longer lifespan, these increases were only found in mice with normal or decreased expression of the D2 gene. Drd2 +/+ EE mice lived nearly 16% longer than their DE counterparts. Drd2 +/+ and Drd2 +/− EE mice lived 22% and 21% longer than Drd2 −/− EE mice, respectively. Moreover, both body weight and locomotor activity were moderated by environmental factors. In addition, EE mice show greater behavioral variability between genotypes compared to DE mice with respect to body weight and locomotor activity.

Roux-en-Y gastric bypass surgery (RYGB) is one of the most effective treatments for morbid obesity. However, increased substance abuse following RYGB has been observed clinically. This study examined the effects of RYGB on the dopamine system to elucidate these observed changes in reward-related behavior. Rats were assigned to four groups: normal diet with sham surgery, ad libitum high fat (HF) diet with sham surgery, restricted HF diet with sham surgery, and HF diet with RYGB surgery. Following surgeries, rats were kept on their respective diets for 9 weeks before they were sacrificed. [ H]SCH 23390, [ H]Spiperone, and [ H]WIN35 428 autoradiography was performed to quantify the effects of diet and RYGB surgery on dopamine type 1-like receptor (D1R)-like, dopamine type 2-like receptor (D2R)-like, and dopamine transporter (DAT) binding. Rats on a chronic HF diet became obese with reduced D1R-like binding within the ventrolateral striatum and the nucleus accumbens core, reduced D2R-like binding in all areas of the striatum and nucleus accumbens core and shell, and reduced DAT binding in the dorsomedial striatum. Restricted HF diet rats showed similar reductions in D1R-like and D2-R-like binding as the obese rats, and reduced DAT binding within all areas of the striatum. Both RYGB and restricted HF diet rats showed similar weight reductions, with RYGB rats showing no difference in binding compared to controls. The observed changes in binding between non-treated obese rats and RYGB rats demonstrates that HF dietary effects on the dopamine system were reversed by RYGB.

Exercise is a key component to health and wellness and is thought to play an important role in brain activity. Changes in brain activity after exercise have been observed through various neuroimaging techniques, such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET). The precise impact of exercise on brain glucose metabolism (BGluM) is still unclear; however, results from PET studies seem to indicate an increase in regional metabolism in areas related to cognition and memory, direction, drive, motor functions, perception, and somatosensory areas in humans. Using PET and the glucose analog [18F]-Fluorodeoxyglucose (18F-FDG), we assessed the changes in BGluM between sedentary and chronic exercise in rats. Chronic treadmill exercise treatment demonstrated a significant increase in BGluM activity in the following brain regions: the caudate putamen (striatum), external capsule, internal capsule, deep cerebellar white matter, primary auditory cortex, forceps major of the corpus callosum, postsubiculum, subiculum transition area, and the central nucleus of the inferior colliculus. These brain regions are functionally associated with auditory processing, memory, motor function, and motivated behavior. Therefore, chronic daily treadmill running in rats stimulates BGluM in distinct brain regions. This identified functional circuit provides a map of brain regions for future molecular assessment which will help us understand the biomarkers involved in specific brain regions following exercise training, as this is critical in exploring the therapeutic potential of exercise in the treatment of neurodegenerative disease, traumatic brain injury, and addiction.

The therapeutic properties of cannabinoids have been well demonstrated but are overshadowed by such adverse effects as cognitive and motor dysfunction, as well as their potential for addiction. Recent research on the natural lipid ligands of cannabinoid receptors, also known as endocannabinoids, has shed light on the mechanisms of intracellular transport of the endocannabinoid anandamide by fatty acid-binding proteins (FABPs) and subsequent catabolism by fatty acid amide hydrolase. These findings facilitated the recent development of SBFI26, a pharmacological inhibitor of epidermal- and brain-specific FABP5 and FABP7, which effectively increases anandamide signaling. The goal of this study was to examine this compound for any possible rewarding and addictive properties as well as effects on locomotor activity, working/recognition memory, and propensity for sociability and preference for social novelty (SN) given its recently reported anti-inflammatory and analgesic properties. Male C57BL mice were split into four treatment groups and conditioned with 5.0, 20.0, 40.0 mg/kg SBFI26, or vehicle during a conditioned place preference (CPP) paradigm. Following CPP, mice underwent a battery of behavioral tests [open field, novel object recognition (NOR), social interaction (SI), and SN] paired with acute SBFI26 administration. Results showed that SBFI26 did not produce CPP or conditioned place aversion regardless of dose and did not induce any differences in locomotor and exploratory activity during CPP- or SBFI26-paired open field activity. We also observed no differences between treatment groups in NOR, SI, and SN. In conclusion, as SBFI26 was shown previously by our group to have significant analgesic and anti-inflammatory properties, here we show that it does not pose a risk of dependence or motor and cognitive impairment under the conditions tested.

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