The Impacts of Adolescent Cannabinoid Exposure on Striatal Anxiety- and Depressive-Like Pathophysiology Are Prevented by the Antioxidant N-Acetylcysteine

Marta De Felice; Hanna J Szkudlarek; Taygun C Uzuneser; Mar Rodríguez-Ruiz; Mohammed H Sarikahya; Mathusha Pusparajah; Juan Pablo Galindo Lazo; Shawn N Whitehead; Ken K-C Yeung; Walter J Rushlow; Steven R Laviolette

doi:10.1016/j.bpsgos.2024.100361

The Impacts of Adolescent Cannabinoid Exposure on Striatal Anxiety- and Depressive-Like Pathophysiology Are Prevented by the Antioxidant N-Acetylcysteine

Biol Psychiatry Glob Open Sci. 2024 Jul 20;4(6):100361. doi: 10.1016/j.bpsgos.2024.100361. eCollection 2024 Nov.

Authors

Marta De Felice^{1

2}, Hanna J Szkudlarek^{1

2}, Taygun C Uzuneser^{1

2}, Mar Rodríguez-Ruiz^{1

2}, Mohammed H Sarikahya^{1

2}, Mathusha Pusparajah³, Juan Pablo Galindo Lazo³, Shawn N Whitehead², Ken K-C Yeung^{3

4}, Walter J Rushlow^{1

2

5}, Steven R Laviolette^{1

2

5

6

7}

Affiliations

¹ Addiction Research Group, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
² Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
³ Department of Chemistry, Western University, London, Ontario, Canada.
⁴ Department of Biochemistry, Western University, London, Ontario, Canada.
⁵ Department of Psychiatry, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
⁶ Lawson Health Research Institute, London, Ontario, Canada.
⁷ Division of Maternal, Fetal and Newborn Health, Children's Health Research Institute (CHRI), London, Ontario, Canada.

Abstract

Background: Exposure to Δ⁹-tetrahydrocannabinol (THC) is an established risk factor for later-life neuropsychiatric vulnerability, including mood- and anxiety-related symptoms. The psychotropic effects of THC on affect and anxiogenic behavioral phenomena are known to target the striatal network, particularly the nucleus accumbens, a neural region linked to mood and anxiety disorder pathophysiology. THC may increase neuroinflammatory responses via the redox system and dysregulate inhibitory and excitatory neural balance in various brain circuits, including the striatum. Thus, interventions that can induce antioxidant effects may counteract the neurodevelopmental impacts of THC exposure.

Methods: In the current study, we used an established preclinical adolescent rat model to examine the impacts of adolescent THC exposure on various behavioral, molecular, and neuronal biomarkers associated with increased mood and anxiety disorder vulnerability. Moreover, we investigated the protective properties of the antioxidant N-acetylcysteine against THC-related pathology.

Results: We demonstrated that adolescent THC exposure induced long-lasting anxiety- and depressive-like phenotypes concomitant with differential neuronal and molecular abnormalities in the two subregions of the nucleus accumbens, the shell and the core. In addition, we report for the first time that N-acetylcysteine can prevent THC-induced accumbal pathophysiology and associated behavioral abnormalities.

Conclusions: The preventive effects of this antioxidant intervention highlight the critical role of redox mechanisms underlying cannabinoid-induced neurodevelopmental pathology and identify a potential intervention strategy for the prevention and/or reversal of these pathophysiological sequelae.

Keywords: Accumbens; Antioxidant; Anxiety; Cannabinoids; Depression; Neurodevelopment.

Plain language summary

Sustained cannabis use during adolescence increases vulnerability to neuropsychiatric disorders, including anxiety and depression. Pharmacotherapeutic interventions to normalize these pathological outcomes are still limited. We performed a comprehensive and integrative translational analysis of the effects of adolescent exposure to Δ⁹-tetrahydrocannabinol (THC), the main psychoactive component in cannabis. Moreover, we tested the protective properties of the antioxidant N-acetylcysteine (NAC). THC-treated rats exhibited anxiety and depressive-like phenotypes concomitant with neuronal and molecular dysregulations in the nucleus accumbens, a crucial area for mood disorders. NAC prevented the development of THC-related pathology. These findings identified a potential strategy to prevent the neurodevelopmental disorders induced by cannabis exposure.