Oral THC consumption during adolescence and its impact on adult mouse brain

PROJECT SUMMARY Edibles that contain Δ9-tetrahyrocannabinol (THC), the principal psychoactive ingredient produced by the Cannabis plant, are becoming increasingly popular among adolescents, making examination of this method of use on the adolescent developing brain urgently needed. An ongoing collaboration between the Stella, Land and Bruchas laboratories led to the development and validation of THC-gelatin voluntary consumption procedures for rodent and showed that adolescent exposure results in adulthood behavioral impairment due to select changes in molecular and cellular components in specific brain regions. Here we show that adolescent mice readily consume THC-gelatin, and that THC-gelatin consumption is increased when adding chocolate flavor (THC-E-gel) resulting in enhanced acute cannabimimetic effects. This approach can easily be combined with other drugs, here cannabidiol (CBD), to better understand its pharmacological interaction with THC. Adolescence represents a critical period where maturation of neural systems is still occurring, particularly in mesocorticolimbic brain regions, and disruption of this maturation process by drug use may lead to severe behavioral impairments in adulthood. Our recently published studies highlight one of the first successful voluntary consumption models of THC in rodents, thereby enabling the study of its long-term consequences on brain development and behavioral outcomes. Our new goals are to: 1) determine how long-term adolescent use of select regimens of THC-gelatin alone or in combination with CBD impact 2) cannabimimetic responses and natural aversive and reward behaviors in adulthood, which may provide insight as to the mechanism of 3) altered neurotransmission and receptor signaling within the mesocorticolimbic system. Neuronal activity and endocannabinoid signaling will be measured using innovative multi-site fiber photometry recoding of behaving animals, and IHC and electrophysiology will be used to identify structural and circuit changes related to adolescent THC use. Our aims will: Aim 1: Determine the impact of consumed THC- and THC:CBD-E-gel during adolescence on rewarding, avoidance, and exploratory behaviors in adult mice. Aim 2: Isolate how THC:CBD-E-gel consumption during adolescence modifies neural activity across mesocorticolimbic structures during adult motivated behaviors. Aim 3: Define specific molecular and circuit changes in adult mesocorticolimbic brain regions resulting from THC:CBD-E-gel consumption during adolescence. The completion of these studies, which utilize an innovative mouse model of voluntary oral consumption, will increase our pharmacological, molecular and cellular understanding of the impact of THC and THC/CBD use on adolescent brain development, and further determine how such perturbations influence behavior in adulthood.