The monoamine-oxidase B inhibitor deprenyl increases selection of high-effort activity in rats tested on a progressive ratio/chow feeding choice procedure: Implications for treating motivational dysfunctions

Maintaining appropriate circadian rhythmicity is essential for coordinating the activity of biological functions in mammalian organisms. A variety of physiological and behavioral changes have been associated with disturbances of this complex clock mechanism.In the present study, we delve into the consequences of circadian arrhythmia using the Bmal1-knockout (KO) mouse line aiming to explore potential behavioral and motivational implications. We were able to identify the intricate activity patterns that define circadian disturbance in Bmal1-KO mice by utilizing a new analysis model based on entropy divergence.Alterations in locomotor activity were accompanied by disruptions of circadian expression patterns in various clock genes as revealed by gene expression analysis. Additionally, we found a dysregulated gene expression profile in Bmal1-KO mice regarding genes related to circadian control in various brain nuclei. Specifically, the ventral striatum exhibited a dysregulation in the expression levels of genes modulating reward and motivation.Further investigation revealed that BMAL1 deficient mice showed a sustained rise in motivation and seeking behavior for food and water reinforcers in the self-administration paradigm, independently of the caloric content of the reward. Together, our data reveal that disruptions in circadian rhythmicity, induced by alterations in the molecular clock, also impact the gene expression regulating the reward system. This, in turn, can lead to altered seeking behavior and motivation for natural rewards. In summary, the present study contributes to our understanding of how reward processing is under the regulation of circadian clock machinery.

The progressive ratio procedure is used across fields to assess motivation for different reinforcers, define the effects of experimental interventions on motivation, and determine experience‐dependent changes in motivation. However, less is known about how operant training schedules affect performance on this widely utilized task. Here we designed an experiment to examine the effect of variable ratio versus fixed ratio training schedules of reinforcement on progressive ratio performance while holding other performance variables constant between groups. We found a robust increase in maximum ratio completed between the pretest and posttraining test highlighting a robust training effect on progressive ratio performance. However, it did not matter if the training was under a fixed or variable ratio schedule. Additionally, we show that neither individual rates during training nor extinction responding correlated with maximum ratio achieved during the sessions. Finally, we show that rates during the training sessions do correlate with extinction performance, suggesting that these variables measure a different aspect of performance that does not predict motivation.

Background: Cigarette smoke (CS)-induced build-up of oxidative stress is the leading cause of chronic obstructive pulmonary disease (COPD). Monoamine oxidases (MAOs) are novel sources of reactive oxygen species (ROS) due to the production of hydrogen peroxide (H 2 O 2 ). However, it remains unclear whether MAO signaling is involved in CS-induced oxidative stress in vivo. This study aimed at investigating the impact of selegiline, a selective MAO-B inhibitor, on CS-induced lung oxidative stress and inflammation in vivo and its underlying mechanism.Methods: Sprague Dawley rats were randomly divided into four groups: saline plus sham air (Saline/air), saline plus cigarette smoke (Saline/CS), selegiline plus sham air (Slg/air) and selegiline plus cigarette smoke (Slg/CS). Rats from Saline/air and Saline/CS groups were intraperitoneally injected with saline (2 mL/kg body weight) while rats from Slg/air and Slg/CS groups were injected with selegiline (2 mg/kg body weight) about 30 min prior to exposure daily. The Saline/air and Slg/air groups were exposed to atmospheric air while the Saline/CS and Slg/CS groups were exposed to mainstream CS generated from the whole body inExpose smoking system (SCIREQ, Canada) for twice daily (each for 1 hour with 20 cigarettes). After 7 days, rats were sacrificed to collect bronchoalveolar lavage (BAL) and lung tissues for the measurement of oxidative/anti-oxidative and inflammatory/anti-inflammatory makers respectively.Results: CS caused significant elevation of MAO-B activity, reduction of total antioxidant capacity (T-AOC) and rGSH/GSSG ratio, and enhancement of superoxide dismutase (SOD) activity in rat lung. Selegiline significantly only reversed CS-induced elevation of MAO-B activity and reduction of rGSH/GSSG ratio.The CS-induced elevation of heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1) expression via nuclear factor erythroid 2-related factor 2 (Nrf2) was also reversed by selegiline. Despite of CSinduced increase in total cell counts, especially the number of macrophages, selegiline had no effect. Selegiline attenuated CS-induced elevation of pro-inflammatory mediators (CINC-1, MCP-1 and IL-6) and restored CSinduced reduction of anti-inflammatory mediator IL-10 in BAL, which was driven through MAPK and NF-κB.Conclusions: Inhibition of MAO-B may provide a promising therapeutic strategy for CS-mediated oxidative stress and inflammation in acute CS-exposed rat lungs.