Effects of Adolescent THC Exposure on the Prefrontal GABAergic System: Implications for Schizophrenia-Related Psychopathology

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.

In utero Δ9-tetrahydrocannabinol exposure confers vulnerability towards cognitive impairments and alcohol drinking in the adolescent offspring: Is there a role for neuropeptide Y?

“…Adolescent neurodevelopment represents a critical period wherein regulatory connectivity between higher-order cortical regions and subcortical emotional processing circuits is established (Gogtay et al, 2004). THC-induced perturbation of neurodevelopmental trajectories poses a risk for mood disorders, vulnerability to alcohol and drug consumption during adolescence (Renard et al, 2017, 2018). Significant evidence shows that the neuropeptide Y (NPY) system is crucial for emotional control and resilience to stress in accordance with its wide expression in key regions for neuro-excitability and plasticity (Plescia et al, 2014a; Reichmann and Holzer, 2016; Robinson and Thiele, 2017).…”

Disrupted-in-Schizophrenia 1 (DISC1) Overexpression and Juvenile Immune Activation Cause Sex-Specific Schizophrenia-Related Psychopathology in Rats

“…Schizophrenia, as well as many other psychiatric disorders, arise from genetic confounders, but are also strongly influenced by the environmental factors. Such factors include prenatal and postnatal immune activation (10), several forms of stress (11), adolescent cannabis use (12), and late paternal age (13). Monozygotic twin studies also support the involvement of non-genetic contributors.…”

Cannabis use and suicide attempts among 86,254 adolescents aged 12–15 years from 21 low- and middle-income countries

“…Furthermore, a large body of evidence has suggested that cannabis use during adolescence may be particularly detrimental to brain development and to the emergence of psychopathology across the lifespan [6][7][8]. It has also been suggested that cannabis use during adolescence may increase the risk of suicidality during both adolescence [2,9,10] and adulthood [11,12].…”