The loss of NMDAR-dependent LTD following cannabinoid self-administration is restored by positive allosteric modulation of CB1 receptors.
Daniela Neuhofer, Sade M Spencer, Vivian C Chioma, Lauren N Beloate, Danielle J Schwartz, Peter W Kalivas
Addiction Biology November 2020 DOI: 10.1111/adb.12843 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical rodent study Peer reviewed |
|---|---|
| Population | Rats self-administering cannabinoids or sucrose |
| Interventions | Δ9-tetrahydrocannabinol (THC) cannabidiol (CBD) GAT211 |
| Topics | Addiction Neuroplasticity |
| Keywords | Cannabinoids |
| Key points | Cannabinoid self-administration abolished NMDAR-dependent LTD in the nucleus accumbens core, unlike sucrose self-administration, and this loss was accompanied by CB1R desensitization. LTD was restored during cue-induced cannabinoid seeking and by the CB1 positive allosteric modulator GAT211, implicating NAcore CB1R in metaplasticity related to cannabis use and relapse. |
Abstract
Glutamatergic plasticity in the nucleus accumbens core (NAcore) is a key neuronal process in appetitive learning and contributes to pathologies such as drug addiction. Understanding how this plasticity factors into cannabis addiction and relapse has been hampered by the lack of a rodent model of cannabis self-administration. We used intravenous self-administration of two constituents of cannabis, Δ9 -tetrahydrocannabinol (THC) and cannabidiol (CBD) to examine how contingent cannabis use and cue-induced cannabinoid-seeking alters glutamatergic neurotransmission and synaptic plasticity in NAcore. NMDA receptor (NMDAR)-dependent long-term depression (LTD) in the NAcore was lost after cannabinoid, but not sucrose self-administration. Surprisingly, when rats underwent cue-induced cannabinoid seeking, LTD was restored. Loss of LTD was accompanied by desensitization of cannabinoid receptor 1 (CB1R). CB1R are positioned to regulate synaptic plasticity by being expressed on glutamatergic terminals and negatively regulating presynaptic excitability and glutamate release. Supporting this possibility, LTD was restored by promoting CB1R signaling with the CB1 positive allosteric modulator GAT211. These data implicate NAcore CB1R as critical regulators of metaplasticity induced by cannabis self-administration and the cues predicting cannabis availability.
Comparable studies
Other preclinical and animal studies on neuroplasticity, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| Psychedelics promote plasticity by directly binding to BDNF receptor TrkB Mice | 2023 | Experimental study | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study | |
| The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro Progenitor cells from subventricular and subgranular zones of adult mice brains | 2017 | In vitro experimental study | |
| N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo Mice | 2020 | In vitro and in vivo experimental study |
Citations in the library
Cited by 4
- Experimenter administered Δ9-THC decreases nicotine self-administration in a rat model. Pharmacology, Biochemistry, and Behavior October 2023
- Δ9 -Tetrahydrocannabinol self-administration induces cell type-specific adaptations in the nucleus accumbens core. Addiction Biology August 2023
- Cannabinoid use is enhanced by stress and changes conditioned stress responses. Neuropsychopharmacology April 2022
- Impairment of Synaptic Plasticity by Cannabis, Δ9-THC, and Synthetic Cannabinoids. Cold Spring Harbor perspectives in medicine May 3, 2021
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