CB1-Dependent Long-Term Depression in Ventral Tegmental Area GABA Neurons: A Novel Target for Marijuana.
Lindsey Friend, Jared Weed, Philip Sandoval, Teresa Nufer, Isaac Ostlund, Jeffrey G Edwards
Journal of Neuroscience November 8, 2017 DOI: 10.1523/jneurosci.0190-17.2017 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Basic science electrophysiology study in mice Peer reviewed |
|---|---|
| Population | Juvenile-adolescent GAD67-GFP male mice |
| Topics | Cannabis Depression |
| Keywords | Trpv1 Anandamide Endocannabinoid Mglur5 Withdrawal |
| Key points | A novel CB1- and mGluR5-dependent long-term depression (LTD) was identified at excitatory synapses onto VTA GABA neurons. THC depressed GABA cell activity, which the authors argue would disinhibit downstream dopamine cells and potentially increase reward. Chronic THC injections occluded this LTD, while a single exposure did not, suggesting a possible mechanism for THC's addictive effects in juveniles. |
Abstract
The VTA is necessary for reward behavior with dopamine cells critically involved in reward signaling. Dopamine cells in turn are innervated and regulated by neighboring inhibitory GABA cells. Using whole-cell electrophysiology in juvenile-adolescent GAD67-GFP male mice, we examined excitatory plasticity in fluorescent VTA GABA cells. A novel CB1-dependent LTD was induced in GABA cells that was dependent on metabotropic glutamate receptor 5, and cannabinoid receptor 1 (CB1). LTD was absent in CB1 knock-out mice but preserved in heterozygous littermates. Bath applied Δ9-tetrahydrocannabinol depressed GABA cell activity, therefore downstream dopamine cells will be disinhibited; and thus, this could potentially result in increased reward. Chronic injections of Δ9-tetrahydrocannabinol occluded LTD compared with vehicle injections; however, a single exposure was insufficient to do so. As synaptic modifications by drugs of abuse are often tied to addiction, these data suggest a possible mechanism for the addictive effects of Δ9-tetrahydrocannabinol in juvenile-adolescents, by potentially altering reward behavioral outcomes.SIGNIFICANCE STATEMENT The present study identifies a novel form of glutamatergic synaptic plasticity in VTA GABA neurons, a currently understudied cell type that is critical for the brain's reward circuit, and how Δ9-tetrahydrocannabinol occludes this plasticity. This study specifically addresses a potential unifying mechanism whereby marijuana could exert rewarding and addictive/withdrawal effects. Marijuana use and legalization are a pressing issue for many states in the United States. Although marijuana is the most commonly abused illicit drug, the implications of legalized, widespread, or continued usage are speculative. This study in juvenile-adolescent aged mice identifies a novel form of synaptic plasticity in VTA GABA cells, and the synaptic remodeling that can occur after Δ9-tetrahydrocannabinol use.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
Citations in the library
Cited by 5
- LSD Restores Synaptic Plasticity in VTA of Morphine-Treated Mice and Disrupts Morphine-Conditioned Place Preference. bioRxiv : the preprint server for biology June 15, 2025
- Increased Mesostriatal Intrinsic Connectivity Associated With Cue Exposure in Adult Cannabis Users: Preliminary Findings. Addiction Biology August 1, 2025
- Three-day delta-9-tetrahydrocannabinol (THC) exposure eliminates long-term depression in ventral tegmental area of young, but not adult mice. Journal of Cannabis Research May 31, 2025
- Impairment of Synaptic Plasticity by Cannabis, Δ9-THC, and Synthetic Cannabinoids. Cold Spring Harbor perspectives in medicine May 3, 2021
- Adolescent Δ9-Tetrahydrocannabinol Exposure and Astrocyte-Specific Genetic Vulnerability Converge on Nuclear Factor-κB-Cyclooxygenase-2 Signaling to Impair Memory in Adulthood. Biological Psychiatry August 16, 2018