Altered network function in hippocampus after sub-chronic activation of Cannabis receptors in peri-adolescence

The Cannabinoid 1-receptor (CB1R) is found in particularly high levels in the hippocampus (HPC), increased CB1R density and binding observed in patients with schizophrenia, and epidemiological studies suggest that regular cannabis use during adolescence is a risk factor for the disease. Historically, concerns around adolescent marijuana use focused on the development of psychosis later in life, however recent findings indicate that cognitive domains may also be at risk. CB1R was shown to interfere with neuronal network oscillations and to impair sensory gating and memory function. Neuronal oscillations are essential in multiple cognitive functions and their impairment was documented in neurological and psychiatric diseases. The aim of this study was to investigate how adolescent pre-treatment with the CB1R selective agonist CP-55940 may lead to abnormalities in theta synchronization in adulthood. Rats were pre-treated with CP-55940 (n=11, 6 males, 5 females) or vehicle (n=8, 4 males, 4 females) during adolescence (daily i/p injections between PND 32-36 or PND 42-46, n=10 and 9, respectively). They were then tested in adulthood (PND 70-88, n=17 or PND 111-115, n=2) under urethane anesthesia. Hippocampal theta rhythm was elicited by brainstem stimulation at 5 intensity levels one hour before and up to 5 hours after injection. We found a lasting significant decrease in theta power after CP-55940 in adult rats which was aggravated further in rats pre-treated in adolescence with the CB1R agonist. The effect was significantly larger (p=0.0462) in rats pre-treated during early adolescence (PND 32-36) compared to the group pre-treated during late adolescence (PND 42-46). We conclude that 1. Exposure to cannabis during adolescence leads to increased sensitivity to CB1R agonist in adulthood; 2. Early adolescence, a critical period for development of HPC networks generating theta rhythm, is particularly prone to this sensitivity.