Effects of buprenorphine, methadone, and cariprazine on economic choice between remifentanil and food in squirrel monkeys.

We recently reported an economic choice task in which squirrel monkeys chose between differing amounts of remifentanil, a fast-acting opioid, or a food reward to develop a preclinical screen for evaluating potential pharmacotherapies for opioid dependence. Herein, two known opioid addiction treatments are evaluated using this task, as well as a potential new agent, cariprazine, a dopamine D2/D3 receptor partial agonist currently used to treat bipolar disorder and schizophrenia. Preclinical rodent studies suggest this class of compounds may reduce opiate self-administration. Squirrel monkeys were pretreated daily with clinically relevant doses of each compound during the five days of treatment evaluation using the economic choice task. Shifts in drug preference were measured as changes in subjects' indifference values, where the probability of drug and milk choice are equivalent. Buprenorphine produced a significant shift in indifference value between baseline and treatment weeks, indicating a decrease in drug preference. Subjects treated with methadone and cariprazine did not show any significant shift in drug preference. Differences between the buprenorphine and methadone results likely reflect a lack of opioid dependence in the subjects. The cariprazine results suggest that it does not alter opioid reward in non-dependent primates over a five day period.

Structural and functional neuroimaging of the effects of the gut microbiome.

Interactions between intestinal microbiota and the central nervous system profoundly influence brain structure and function. Over the past 15 years, intense research efforts have uncovered the significant association between gut microbial dysbiosis and neurologic, neurodegenerative, and psychiatric disorders; however, our understanding of the effect of gut microbiota on quantitative neuroimaging measures of brain microstructure and function remains limited. Many current gut microbiome studies specifically focus on discovering correlations between specific microbes and neurologic disease states that, while important, leave critical mechanistic questions unanswered. To address this significant gap in knowledge, quantitative structural and functional brain imaging has emerged as a vital bridge and as the next step in understanding how the gut microbiome influences the brain. In this review, we examine the current state-of-the-art, raise awareness of this important topic, and aim to highlight immense new opportunities-in both research and clinical imaging-for the imaging community in this emerging field of study. Our review also highlights the potential for preclinical imaging of germ-free and gnotobiotic models to significantly advance our understanding of the causal mechanisms by which the gut microbiome alters neural microstructure and function. KEY POINTS: • Alterations to the gut microbiome can significantly influence brain structure and function in health and disease. • Quantitative neuroimaging can help elucidate the effect of gut microbiota on the brain and with future translational advances, neuroimaging will be critical for both diagnostic assessment and therapeutic monitoring.

Economic choice between remifentanil and food in squirrel monkeys.

Traditional approaches for evaluating if compounds are reinforcing, and thus a risk for abuse, include preclinical self-administration procedures conducted in the absence of alternative reinforcers. While the track record of this approach for determining abuse potential is good, that for predicting efficacy of addiction treatments is not. An alternate approach would be economic choice between drug and nondrug rewards, with parametrically varied options from trial to trial. This would promote goal-directed decisions between reward modalities and should provide metrics that reflect changes in internal state that influence desirability of a given option. We report herein a high throughput economic choice procedure in which squirrel monkeys choose between a short-lived opiate, remifentanil, and a palatable food reward. Stimuli on touchscreens indicate the amount of each reward type offered by varying the number of reward-specific elements. The rapid clearance of remifentanil avoids accumulation of confounding levels of drug, and permits a large number of trials with a wide range of offers of each reward modality. The use of a single metric encompassing multiple values of each reward type within a session enables estimation of indifference values using logistic regression. This indifference value is sensitive to reward devaluation within each reward domain, and is therefore a useful metric for determining shifts in reward preference, as shown with satiation and pharmacological treatment approaches.

Muscle cannabinoid 1 receptor regulates Il-6 and myostatin expression, governing physical performance and whole-body metabolism.

Sarcopenic obesity, the combination of skeletal muscle mass and function loss with an increase in body fat, is associated with physical limitations, cardiovascular diseases, metabolic stress, and increased risk of mortality. Cannabinoid receptor type 1 (CB1R) plays a critical role in the regulation of whole-body energy metabolism because of its involvement in controlling appetite, fuel distribution, and utilization. Inhibition of CB1R improves insulin secretion and insulin sensitivity in pancreatic ß-cells and hepatocytes. We have now developed a skeletal muscle-specific CB1R-knockout (Skm-CB1R-/-) mouse to study the specific role of CB1R in muscle. Muscle-CB1R ablation prevented diet-induced and age-induced insulin resistance by increasing IR signaling. Moreover, muscle-CB1R ablation enhanced AKT signaling, reducing myostatin expression and increasing IL-6 secretion. Subsequently, muscle-CB1R ablation increased myogenesis through its action on MAPK-mediated myogenic gene expression. Consequently, Skm-CB1R-/- mice had increased muscle mass and whole-body lean/fat ratio in obesity and aging. Muscle-CB1R ablation improved mitochondrial performance, leading to increased whole-body muscle energy expenditure and improved physical endurance, with no change in body weight. These results collectively show that CB1R in muscle is sufficient to regulate whole-body metabolism and physical performance and is a novel target for the treatment of sarcopenic obesity. -González-Mariscal, I., Montoro, R. A., O'Connell, J. F., Kim, Y., Gonzalez-Freire, M., Liu, Q.-R., Alfaras, I., Carlson, O. D., Lehrmann, E., Zhang, Y., Becker, K. G., Hardivillé, S., Ghosh, P., Egan, J. M. Muscle cannabinoid 1 receptor regulates Il-6 and myostatin expression, governing physical performance and whole-body metabolism.

Absence of cannabinoid 1 receptor in beta cells protects against high-fat/high-sugar diet-induced beta cell dysfunction and inflammation in murine islets.

AIMS/HYPOTHESIS: The cannabinoid 1 receptor (CB1R) regulates insulin sensitivity and glucose metabolism in peripheral tissues. CB1R is expressed on pancreatic beta cells and is coupled to the G protein Gαi, suggesting a negative regulation of endogenous signalling in the beta cell. Deciphering the exact function of CB1R in beta cells has been confounded by the expression of this receptor on multiple tissues involved in regulating metabolism. Thus, in models of global genetic or pharmacological CB1R blockade, it is difficult to distinguish the indirect effects of improved insulin sensitivity in peripheral tissues from the direct effects of inhibiting CB1R in beta cells per se. To assess the direct contribution of beta cell CB1R to metabolism, we designed a mouse model that allows us to determine the role of CB1R specifically in beta cells in the context of whole-body metabolism. METHODS: We generated a beta cell specific Cnr1 (CB1R) knockout mouse (ß-CB1R-/-) to study the long-term consequences of CB1R ablation on beta cell function in adult mice. We measured beta cell function, proliferation and viability in these mice in response to a high-fat/high-sugar diet and induction of acute insulin resistance with the insulin receptor antagonist S961. RESULTS: ß-CB1R-/- mice had increased fasting (153 ± 23% increase at 10 weeks of age) and stimulated insulin secretion and increased intra-islet cAMP levels (217 ± 33% increase at 10 weeks of age), resulting in primary hyperinsulinaemia, as well as increased beta cell viability, proliferation and islet area (1.9-fold increase at 10 weeks of age). Hyperinsulinaemia led to insulin resistance, which was aggravated by a high-fat/high-sugar diet and weight gain, although beta cells maintained their insulin secretory capacity in response to glucose. Strikingly, islets from ß-CB1R-/- mice were protected from diet-induced inflammation. Mechanistically, we show that this is a consequence of curtailment of oxidative stress and reduced activation of the NLRP3 inflammasome in beta cells. CONCLUSIONS/INTERPRETATION: Our data demonstrate CB1R to be a negative regulator of beta cell function and a mediator of islet inflammation under conditions of metabolic stress. Our findings point to beta cell CB1R as a therapeutic target, and broaden its potential to include anti-inflammatory effects in both major forms of diabetes. DATA AVAILABILITY: Microarray data have been deposited at GEO (GSE102027).