ENDOCANNABINOID REINFORCEMENT OF PHYSICAL ACTIVITY

PROJECT SUMMARY/ABSTRACT----------------------------------------------------------------------------------- --- Greater than 80% of US adults do not meet physical activity recommendations leading to years of preventable disability, diminished well-being, early death, and annual healthcare costs estimated at upwards of $300 billion. Despite strong medical evidence that sedentary behavior is a health risk, current methods to increase physical activity rely on willpower and/or knowledge (e.g., doctors’ suggestions, public media) have been unsuccessful. Thus, there are currently no effective long-term methods to increase physical activity participation. Individuals who experience pain-relieving, destressing, antidepressant, and/or euphoric psychological affects during physical activity are more likely to participate. The source of these reinforcing affects has been linked to endogenously produced endocannabinoids. We hypothesize that enhancing the action of endocannabinoid receptors (CB1) during physical activity will increase these positive affective states leading to greater long-term participation. Under the mentorship of Drs. Jerrel Yakel and Guohong Cui at the National Institute of Environmental Health Sciences, along with the support of ten established scientists with expertise in the proposed studies, this Pathway to Independence Award offers an opportunity for postdoctoral fellow, Dr. Ayland Letsinger, to explore this hypothesis through three specific aims: SA1 (K99): To determine whether endocannabinoid release in the ventral tegmental area reinforces wheel running, SA2 (K99): To determine whether amplification of CB1 activity response to endocannabinoids by a CB1 positive allosteric modulator (PAM) will increase wheel running in mice that are innately low wheel runners, and SA3 (R00): To determine whether amplification of CB1 activity response to endocannabinoids via a CB1 PAM will increase wheel running in mice that have undergone an intervention to reduce wheel running. These findings will have a profound impact by identifying a target that can be acutely modulated to enhance long-term voluntary participation, thereby significantly improving human health. Moreover, this grant will support Dr. Letsinger’s transition to becoming an independent scientist in the field of addiction research. The award provides opportunities for training in photometry and pharmaceutical applications, comprehensive instruction in addiction-related study design and theory, mentorship from a diverse group of scientists in academia and government, and the production of high- quality data. This technical and professional foundation will support future research endeavors in addiction and related fields, enhancing Dr. Letsinger's potential to make significant contributions to science.