Anxiety and cognitive-related effects of Δ 9-tetrahydrocannabinol (THC) are differentially mediated through distinct GSK-3 vs. Akt-mTOR pathways in the nucleus accumbens of male rats

• Published in: Psychopharmacology Vol. 239; no. 2; pp. 509 - 524
• Main Authors: Hudson, Roger, Norris, Christopher, Szkudlarek, Hanna J., Khan, Dinat, Schmid, Susanne, Rushlow, Walter J., Laviolette, Steven R.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-02-2022; Springer Nature B.V
• Subjects: AKT protein; Anatomy; Animals; Anxiety; Anxiety - chemically induced; Biomedical and Life Sciences; Biomedicine; Brain architecture; Cannabis; Cognition; Cognitive ability; Dronabinol - pharmacology; Emotions; Glycogen; Glycogen Synthase Kinase 3; Information processing; Kinases; Male; Memory; Mental disorders; Molecular modelling; Neurosciences; Nucleus Accumbens; Original Investigation; Pharmacology/Toxicology; Phosphorylation; Proto-Oncogene Proteins c-akt; Psychiatry; Rats; Rats, Sprague-Dawley; Schizophrenia; Sensorimotor gating; Sensory integration; Side effects; Signal transduction; Tetrahydrocannabinol; THC; TOR protein; TOR Serine-Threonine Kinases; β-Catenin; Nucleus accumbens; Cannabinoids; GSK-3; Anxiety; Cognition; Akt; THC
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-021-06029-w

Rationale
Δ
9
-tetrahydrocannabinol (THC) is the primary psychoactive compound in cannabis and is responsible for cannabis-related neuropsychiatric side effects, including abnormal affective processing, cognitive and sensory filtering deficits and memory impairments. A critical neural region linked to the psychotropic effects of THC is the nucleus accumbens shell (NASh), an integrative mesocorticolimbic structure that sends and receives inputs from multiple brain areas known to be dysregulated in various disorders, including schizophrenia and anxiety-related disorders. Considerable evidence demonstrates functional differences between posterior vs. anterior NASh sub-regions in the processing of affective and cognitive behaviours influenced by THC. Nevertheless, the neuroanatomical regions and local molecular pathways responsible for these psychotropic effects are not currently understood.
Objectives
The objectives of this study were to characterize the effects of intra-accumbens THC in the anterior vs. posterior regions of the NASh during emotional memory formation, sensorimotor gating and anxiety-related behaviours.
Methods
We performed an integrative series of translational behavioural pharmacological studies examining anxiety, sensorimotor gating and fear-related associative memory formation combined with regionally specific molecular signalling analyses in male Sprague Dawley rats.
Results
We report that THC in the posterior NASh causes distortions in emotional salience attribution, impaired sensory filtering and memory retention and heightened anxiety, through a glycogen-synthase-kinase-3 (GSK-3)-β-catenin dependent signalling pathway. In contrast, THC in the anterior NASh produces anxiolytic effects via modulation of protein kinase B (Akt) phosphorylation states.
Conclusions
These findings reveal critical new insights into the neuroanatomical and molecular mechanisms associated with the differential neuropsychiatric side effects of THC in dissociable nucleus accumbens sub-regions.