Mood, cognitive, and metabolic consequences of chronic vaporized cannabis exposure in mouse models of menopause

PROJECT SUMMARY The legalization of recreational and medicinal cannabis in several states across the US has increased the need to better understand its effects on the body, brain, and behaviors in diverse populations. Notably, people 50 and over are the fastest growing group of cannabis users in the US. Among this group are women who have undergone the transition to reproductive senescence, known as menopause, which occurs at the average age of 51. Menopause and the attending decrease in circulating estrogens is associated with a variety of symptoms including mood, anxiety, and cognitive impairments as well as metabolic changes that are linked to poor health outcomes. As an increasing number of post-menopausal women use cannabis, either recreationally or medicinally to treat menopause symptoms, it will be important to evaluate the health risks and benefits of cannabis use in this unique population. Here, preclinical mouse models are particularly valuable, as they provide precise control over cannabis treatment (composition, frequency etc.) and enable researchers to dissociate the contribution of age and endocrine status to various neural, behavioral, and metabolic outcomes. To produce readily translatable findings from mice to humans, preclinical models should closely resemble human patterns of cannabis consumption. To this end, along with co-I Dr. Ryan McLaughlin, the Delevich lab has recently validated a novel vapor inhalation model of whole plant cannabis extract for use in mice. Thus, the objective of this R21 proposal is to utilize this model of cannabis use to model the consequences of chronic cannabis use in the post-menopausal state. To this end, in Aim 1A we will first establish the pharmacokinetics of vaporized cannabis in young adult (postnatal day 90) and aged (18 month) female mice who differ by endocrine status (ovarian intact vs. ovariectomized). Next, in Aim 1B we will assess the effect of chronic cannabis vapor exposure on energy balance, including weight gain, body composition, food intake, and home cage locomotor activity, in these same groups. In Aim 2A we will examine how chronic cannabis vapor exposure influences mood-related endpoints and cognitive flexibility in young vs. aged OVX and ovarian intact female mice. Finally, given the co- expression of estrogen receptors and endocannabinoid system components within the medial prefrontal cortex (mPFC), and this region’s function in mood regulation and cognitive flexibility, in Aim 2B we will assess the effect of chronic cannabis vapor exposure on glutamatergic and GABAergic synaptic transmission onto layer II/III and V pyramidal neurons within the prelimbic subregion of the mPFC in young vs. aged OVX and ovarian intact mice. Together, these aims employ a conceptually and technically innovative approach to study the brain, body, and behavioral effects of chronic cannabis use in a vastly understudied population. Funding this R21 proposal will establish the vaporized cannabis exposure model within a mouse model of menopause and generate necessary pilot data to support future collaborative proposals to investigate the impact of cannabis use on women’s health during aging.