Impact of Cannabinoid Across the Lifespan (ICAL)

ICAL BEHAVIORAL PROJECT: PROJECT SUMMARY Early cannabis use is associated with long-term psychiatric risks including susceptibility to abuse of harder drugs like opioids. Yet in humans it is difficult to determine the impact of adolescent THC exposure (ado-THC) itself, versus underlying comorbidities or societal factors that also contribute to the association. Despite their shortcomings, rodent models are thus still crucial for establishing causal, biological influences of ado-THC on addiction susceptibility. Indeed, preclinical studies suggested that ado-THC conveys later susceptibility to opioids. In the first funding period, we confirmed and extended this finding, demonstrating that ado-THC causes a sex-dependent vulnerability in rats: males show a pre-sensitized locomotor response to heroin, while females show greater heroin place preference and economic demand for a fentanyl derivative. Regardless of founded criticisms of the THC “gateway effect,” such robust findings, seen across labs and behavioral models, cannot be ignored. How might adolescent THC promote opioid reward? Adolescence is a period of active brain maturation, especially in late-developing structures like the prefrontal cortex (PFC). Microglia, the resident immune cells of the brain parenchyma, play a key role in this process. Initially thought to respond solely to insults by attaining an “activated” phenotype with cytokine release and other pro-inflammatory processes, microglia do much more than counteract physical threats. Indeed, drugs of abuse like opioids recruit incompletely understood microglial processes which seem to be essential for the acutely reinforcing effects of opioids, as well as longer-term progression of use into addiction. Indeed, our preliminary data support the hypothesis that ado-THC impact microglia in short and long timeframes, and that these changes may be involved in the pro-opioid, sex-dependent phenotype. We test this novel hypothesis in three Aims: 1) determining how ado-THC and heroin impact microglial protein and RNA markers, and whether “resetting” microglia in adulthood selectively reverses ado-THC behavioral effects, 2) determining the precise developmental stages at which ado-THC has the most pronounced long-term pro-opioid effects, and 3) determining the mechanisms required for ado-THC to have its persistent effects on microglia and behavior, and whether these are the same or different from those underlying Molecular and Synaptic Project findings. These studies, especially in the context of our integrated Center-wide research program, will break new ground in understanding the roles played by microglia in opioid addiction, and in the neurodevelopmental consequences of adolescent use of drugs like cannabis.