Abstract
Marijuana is the most commonly used drug of abuse among adolescents. Considerable clinical evidence supports the hypothesis that adolescent neurodevelopmental exposure to high levels of the principal psychoactive component in marijuana, -delta-9-tetrahydrocanabinol (THC), is associated with a high risk of developing psychiatric diseases, such as schizophrenia later in life. This marijuana-associated risk is believed to be related to increasing levels of THC found within commonly used marijuana strains. Adolescence is a highly vulnerable period for the development of the brain, where the inhibitory GABAergic system plays a pivotal role in the maturation of regulatory control mechanisms in the central nervous system (CNS). Specifically, adolescent neurodevelopment represents a critical period wherein regulatory connectivity between higher-order cortical regions and sub-cortical emotional processing circuits such as the mesolimbic dopamine (DA) system is established. Emerging preclinical evidence demonstrates that adolescent exposure to THC selectively targets schizophrenia-related molecular and neuropharmacological signaling pathways in both cortical and sub-cortical regions, including the prefrontal cortex (PFC) and mesolimbic DA pathway, comprising the ventral tegmental area (VTA) and nucleus accumbens (NAc). Prefrontal cortical GABAergic hypofunction is a key feature of schizophrenia-like neuropsychopathology. This GABAergic hypofunction may lead to the loss of control of the PFC to regulate proper sub-cortical DA neurotransmission, thereby leading to schizophrenia-like symptoms. This review summarizes preclinical evidence demonstrating that reduced prefrontal cortical GABAergic neurotransmission has a critical role in the sub-cortical DAergic dysregulation and schizophrenia-like behaviors observed following adolescent THC exposure.
Highlights
Marijuana is the most widely used illicit drug in the world [1]
We have demonstrated previously that the behavioral deficits induced by THC are associated with a profound hyperDAergic neuronal state in the ventral tegmental area (VTA), characterized by hyperactive frequency and bursting levels in A10 DA neurons, consistent with mesolimbic dysregulation found in schizophrenia
Adolescence represents a critical period of neurodevelopment during which external stimuli can persistently change brain function
Summary
Marijuana is the most widely used illicit drug in the world [1]. With more jurisdictions looking to legalize cannabis, there is potential for increasing rates of regular use and dependence within the general population. Chronic marijuana use before the age of 17 and elevated THC concentration in current popular street strains are factors that can increase this risk of developing schizophrenia. The action of THC on CB1Rs during neurodevelopment can impair PFC-CB1R signaling and associated GABAergic functionality leading to dysregulation of the normal prefrontal maturation process These observable deficits in PFC functionality can induce long-term impairments of prefrontal inhibition and synchronized cortical activity states leading to psychopathological disease [16, 21]. This attenuated GABAergic function in the PFC may cause abnormalities in the synchronization of gamma-band, prefrontal neuronal activity, and sub-cortical dopaminergic (DAergic) transmission, which may in turn lead to schizophrenia-like symptoms such as hallucinations as well as pathological affective and cognitive deficits [31, 32]
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