¹Harvard Medical School, Psychiatry/BIDMC, Boston, United States

Background: Historically, concern around adolescent marijuana use focused on the development of psychosis, 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 function. Neuronal oscillations are essential in multiple cognitive functions and their impairment was documented in neurological and psychiatric diseases. The Cannabinoid 1-receptor (CB1R), one of the most abundant G-protein coupled receptors in the nervous system, 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.

Aims & Objectives: The aim of this study was to investigate how adolescent pre-treatment with the CB1R selective agonist CP-55940 may lead to abnormal theta synchronization in adulthood. Two of our previous findings served as scientific premise of the project: 1. CP-55940 significantly reduced theta and gamma power in HPC in adult freely behaving and theta in anesthetized rats, the latter reversed by CB1R antagonist AM-251 [1] and 2. it was shown in urethane anaesthetized rats that early adolescence is critical for development of HPC networks generating theta rhythm as HPC theta power rapidly decreased through postnatal days PND32-39 with large interindividual variations but stabilized by late adolescence (PND41-49) and remained persistent until adulthood [2].

Method: Rats were pre-treated with subchronic administration of CP-55940 (n=11, 6 males, 5 females) or vehicle (n=8, 4 males, 4 females) during adolescence (daily i/p injections between PND32-36 or PND42-46, n=10 and 9, respectively). They were then tested in adulthood (PND70-88, 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.

Results: We found a lasting significant decrease in theta power after CP-55940 in adult rats which was aggravated further in rats pre-treated with the CB1R agonist. The effect was significantly larger (p=0.0462) in rats pre-treated during early adolescence (PND32-36) compared to the group pre-treated during late adolescence (PND42-46).

Discussion & Conclusions: We conclude that 1. CP55940 administration decreases HPC theta power in this model; 2. Pre-treatment with CP55940 in adolescence is associated with increased sensitivity to theta power reduction after its re-introduction in adulthood; 3. Early adolescence, a critical period for development of HPC networks generating theta rhythm, is particularly prone to this sensitivity.

1. Hajos M., Hoffman W.E., Kocsis B. Activation of cannabinoid-1 receptors disrupts sensory gating and neuronal oscillations: Relevance to schizophrenia. Biological Psychiatry, 63:1075-1083, 2008.
2. S. Sibilska, R. Mofleh, B. Kocsis. Development of network oscillations through adolescence in male and female rats. Frontiers in Cellular Neuroscience, 17:1135154, 2023. PMID: 37213214, PMCID: PMC10196069, DOI: 10.3389/fncel.2023.1135154