Astrocytic Mechanisms Involving Kynurenic Acid Control Δ9-Tetrahydrocannabinol-Induced Increases in Glutamate Release in Brain Reward-Processing Areas.
Maria E Secci, Paola Mascia, Claudia Sagheddu, Sarah Beggiato, Miriam Melis, Andrea C Borelli, Maria C Tomasini, Leigh V Panlilio, Charles W. Schindler, Gianluigi Tanda, Sergi Ferré, Charles W. Bradberry, Luca Ferraro, Marco Pistis, Steven R Goldberg, Robert Schwarcz, Zuzana Justinova
Molecular Neurobiology May 2019 DOI: 10.1007/s12035-018-1319-y (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Rats (in vivo microdialysis, electrophysiology, RNAscope in situ hybridization in brain slices) and primary cultures of rat cortical astrocytes |
| Interventions | THC Ro 61-8048 rimonabant KYNA |
| Topics | Cannabis |
| Keywords | Astrocytes Cannabinoids Glutamate Kynurenic acid Rat |
| Key findings | Acute THC increased extracellular glutamate in the nucleus accumbens shell, ventral tegmental area, and medial prefrontal cortex, and decreased KYNA in the accumbens shell; these effects were prevented by Ro 61-8048 or rimonabant. THC also increased firing of prefrontal pyramidal neurons projecting to the accumbens or ventral tegmental area, prevented by Ro 61-8048. In cultured astrocytes, THC elicited glutamate release blocked by KYNA and rimonabant. The authors suggest astrocytes link the endocannabinoid system, kynurenine pathway, and glutamatergic neurotransmission. |
Abstract
The reinforcing effects of Δ9-tetrahydrocannabinol (THC) in rats and monkeys, and the reinforcement-related dopamine-releasing effects of THC in rats, can be attenuated by increasing endogenous levels of kynurenic acid (KYNA) through systemic administration of the kynurenine 3-monooxygenase inhibitor, Ro 61-8048. KYNA is a negative allosteric modulator of α7 nicotinic acetylcholine receptors (α7nAChRs) and is synthesized and released by astroglia, which express functional α7nAChRs and cannabinoid CB1 receptors (CB1Rs). Here, we tested whether these presumed KYNA autoreceptors (α7nAChRs) and CB1Rs regulate glutamate release. We used in vivo microdialysis and electrophysiology in rats, RNAscope in situ hybridization in brain slices, and primary culture of rat cortical astrocytes. Acute systemic administration of THC increased extracellular levels of glutamate in the nucleus accumbens shell (NAcS), ventral tegmental area (VTA), and medial prefrontal cortex (mPFC). THC also reduced extracellular levels of KYNA in the NAcS. These THC effects were prevented by administration of Ro 61-8048 or the CB1R antagonist, rimonabant. THC increased the firing activity of glutamatergic pyramidal neurons projecting from the mPFC to the NAcS or to the VTA in vivo. These effects were averted by pretreatment with Ro 61-8048. In vitro, THC elicited glutamate release from cortical astrocytes (on which we demonstrated co-localization of the CB1Rs and α7nAChR mRNAs), and this effect was prevented by KYNA and rimonabant. These results suggest a key role of astrocytes in interactions between the endocannabinoid system, kynurenine pathway, and glutamatergic neurotransmission, with ramifications for the pathophysiology and treatment of psychiatric and neurodegenerative diseases.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
Citations in the library
Cited by 3
- Dopamine, γ-aminobutyric acid, and glutamate balance in the nucleus accumbens shell: Differential effects of cannabinoid 1 receptor agonists Δ9-Tetrahydrocannabinol, AM11101, and AM8936. Neuropharmacology June 1, 2026
- Effects of nicotinic receptor antagonism on nicotine and THC self-administration in a model of polysubstance use The International Journal of Neuropsychopharmacology April 1, 2026
- HIV Transgenic Rats Demonstrate Impaired Sensorimotor Gating But Are Insensitive to Cannabinoid (Δ9-Tetrahydrocannabinol)-Induced Deficits. The International Journal of Neuropsychopharmacology November 12, 2021
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