Desrochers, S. S. | bioRxiv Science

bioRxiv2026

Pavlovian conditioned approach with different reward magnitudes reveals opposing effects of acute and chronic semaglutide treatment

Rationale: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have attracted interest for their effects on motivational processes beyond satiation and weight loss, including motivation for drug rewards. Reward-predictive cues can acquire motivational value and promote food- and drug-seeking, raising the possibility that GLP-1RAs affect intake by altering cue-motivated behavior. Preclinical studies report reduced food intake and responding for drug rewards following GLP-1RA treatment. However, many preclinical studies have used acute treatment; whereas, clinically, GLP1-RAs are administered as chronic treatments with dose escalation to mitigate adverse effects. Objectives: Using a modified Pavlovian conditioned approach (PavCA) paradigm, we directly compared the effects of acute and chronic semaglutide treatment on conditioned approach behavior elicited by cues predicting different magnitudes of palatable food reward in male and female rats. Results: Although both treatment regimens reduced body weight relative to vehicle treatment, chronic semaglutide increased, whereas acute semaglutide decreased, sign-tracking toward reward-associated cues. Rats exhibited greater sign-tracking toward cues predicting large versus small rewards, but semaglutide did not differentially alter this reward-magnitude effect. Acutely treated rats consumed fewer reward pellets and exhibited less food-cup activity during non-cue periods. These findings suggest that nonspecific behavioral suppression or malaise may have contributed to reduced responding after acute treatment. Conclusions: The effects of semaglutide on cue-motivated behavior depend on the treatment regimen. Acute-treatment studies should be interpreted cautiously because adverse or nonspecific effects may contribute to apparent reductions in motivation.

neuroscience↗

bioRxiv2020

A role for reward sensitivity in the serotonergic modulation of impulsivity

Impulsive behavior is a deleterious component of a number of mental health disorders but has few targeted pharmacotherapies. One contributing factor to the difficulty in understanding the neural substrates of disordered impulsivity is the diverse presentations of impulsive behavior. Defining the behavioral and cognitive processes which contribute to different subtypes of impulsivity is integral to understanding and treating disorders with dysregulated impulsive behavior. Our approach was to first determine what behavioral and cognitive phenotypes are associated with increased impulsive behavior, and then probe if they could causally contribute to increasing impulsivity. We used a mouse model for disordered impulsivity - mice lacking the serotonin 1B receptor (5-HT1BR) which have deficits specific to impulsive action, and not other components of impulsive behavior. Here we report, that in addition to increased impulsive action, mice lacking expression of 5-HT1BR also have increased goal-directed responding and motivation, with no differences in extinction, development of habitual behavior, delay discounting, or effort-based discounting. Interestingly, mice lacking 5-HT1BR expression did show an overall increase in the choice of higher value rewards, increased hedonic responses to sweet rewards, and responded more to cues that predict reward, compared to controls. We developed a novel paradigm to demonstrate that increasing anticipated reward value could directly increase impulsive action. Furthermore, we found that 5-HT1BR KO-induced impulsivity could be ameliorated by decreasing the reward value relative to controls, suggesting that the increased 5-HT1BR-associated impulsive action is a result of increased reward valuation. Taken together, these data show that the effects of serotonin on impulsive action are mediated through the modulation of hedonic value, which may alter the reward representations that motivate action. Additionally this work supports a role for reward valuation as an important substrate in impulsive action which may drive clinically-relevant increases in impulsivity.

neuroscience↗