Astrocytic Mechanisms Involving Kynurenic Acid Control Δ9 -Tetrahydrocannabinol-Induced Increases in Glutamate Release in Brain Reward-Processing Areas
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...Continue Reading
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Evidence that alpha7 nicotinic receptor modulates glutamate release from mouse neocortical gliosomes
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