Investigation of Lifelong Cognitive Impairments Following Perinatal and Perpubertal THC Exposure

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Marijuana is a widely-used psychoactive substance, but its potency as a developmental neurotoxicant is poorly understood and little data on developmental exposure to marijuana has been collected. This data gap is alarming since marijuana consumption will increase in the United States as a consequence of the legalization trend. It is well known that the developing brain can be more sensitive to neurotoxicants than the adult brain. The impact of neurotoxicants on fetal brain development following maternal consumption of marijuana has only begun to be understood. Emerging clinical evidence indicates that prenatal exposure to marijuana is associated with tremors and exaggerated startles in infants and attention deficits and other executive dysfunctions in older children. The long-term effects of cannabinoids on adolescents is also not well understood. Adolescents could affect their own brains directly if they smoke marijuana during this second critical period of brain development. Since there is little or no data indicating whether early cannabinoid exposure in utero or during adolescence can produce latent toxicity that emerges later in life, the goal of the proposed research is to identify age, sex, and dose-specific effects of marijuana on cognitive behaviors and the brain structures that mediate them. The proposed research will identify the most sensitive, lifelong sex- specific behavioral deficits and cognitive impairments produced by the lowest dose exposure to marijuana, specifically to one cannabinoid, delta-9-tetrahydrocannabinol (THC), the principle psychoactive agent in marijuana that is known to cross the placenta and enter the developing brain during the perinatal and juvenile periods. A rat model of developmental THC exposure will be used to examine attention, learning, memory, motor, and social functions. Attention behaviors will be examined with the Go/no-go operant procedure. Learning and memory will be examined with operant procedures such as delayed spatial alternation. Motor function will be assessed with functional observation battery, open field exploration, grip strength and Rotarod tests. Social behavior will be measured with procedures using the 3-chamber sociability apparatus. Two cohorts of exposed rats will be used to examine different critical periods of brain development. For the perinatal cohort, rats will be gavaged with a daily oral dose of 0, 2, 5, or 10 mg/kg THC from gestation day 1 until weaning. For the peripubertal cohort, exposure to 0, 2, 7.5, or 15 mg/kg will begin immediately after weaning and continue throughout puberty (postnatal day 22-40). In each age cohort, male-female pairs of littermates will be assigned to one of three test ages: young adult (2-months), middle adult (12-months), and senescent (18-months). After the behavioral tests are completed, the GABA neurotransmitter system in the hippocampus and glutamate system in the prefrontal cortex will be examined histochemically. A third, smaller perinatal exposure cohort will be generated to provide blood and brain samples to determine THC and metabolite disposition following oral administration. Collectively, this data will fill a gap in the literature and provide information about the relationship between applied dose, disposition in the offspring, and long-term behavioral deficits.