Δ9 -Tetrahydrocannabinol self-administration induces cell type-specific adaptations in the nucleus accumbens core.
Constanza Garcia-Keller, Madeline Hohmeister, Kailyn Seidling, Lauren N Beloate, Vivian C Chioma, Sade M Spencer, Peter W Kalivas, Daniela Neuhofer
Addiction Biology August 2023 DOI: 10.1111/adb.13286 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort Peer reviewed |
|---|---|
| Population | D1- and D2-Cre transgenic rats trained to self-administer THC + cannabidiol |
| Intervention | THC + cannabidiol |
| Topics | Addiction Neuroplasticity Cannabis |
| Keywords | Cannabinoid receptor 1 Medium spiny neurons Nucleus accumbens Δ9-tetrahydrocannabinol |
| Key findings | Extinction from THC + CBD self-administration reduced large spine heads and glutamate synaptic transmission and impaired presynaptic CB1 receptor function selectively in D1 medium spiny neurons, while D2 neurons showed unchanged CB1 receptor function and glutamate transmission but reduced cFOS after extinction that was restored during drug seeking. The authors propose that pathway-specific modulation of endocannabinoid signalling in D1 neurons could be a treatment avenue for cannabis use disorder. |
Abstract
Drugs of abuse induce cell type-specific adaptations in D1- and D2-medium spiny neurons (MSNs) in the nucleus accumbens core (NAcore) that can bias signalling towards D1-MSNs and enhance relapse vulnerability. Whether Δ9 -tetrahydrocannabinol (THC) use initiates similar neuroadaptations is unknown. D1- and D2-Cre transgenic rats were transfected with Cre-dependent reporters and trained to self-administer THC + cannabidiol (THC + CBD). After extinction training spine morphology, glutamate transmission, CB1R function and cFOS expression were quantified. We found that extinction from THC + CBD induced a loss of large spine heads in D1- but not D2-MSNs and commensurate reductions in glutamate synaptic transmission. Also, presynaptic CB1R function was impaired selectively at glutamatergic synapses on D1-MSNs, which augmented the capacity to potentiate glutamate transmission. Using cFOS expression as an activity marker, we found no change after extinction but increased cFOS expression in D1-MSNs after cue-induced drug seeking. Contrasting D1-MSNs, CB1R function and glutamate synaptic transmission on D2-MSN synapses were unaffected by THC + CBD use. However, cFOS expression was decreased in D2-MSNs of THC + CBD-extinguished rats and was restored after drug seeking. Thus, CB1R adaptations in D1-MSNs partially predicted neuronal activity changes, posing pathway specific modulation of eCB signalling in D1-MSNs as a potential treatment avenue for cannabis use disorder (CUD).
Comparable studies
Other preclinical and animal studies on cannabis for addiction, most cited first.