Hot Off the Press – August 28, 2023
In this research paper, Briana Hempel et al. investigated the role of peroxisome proliferator-activated receptors (PPARs) in the CNS effects of cannabinoids. The study focuses on two specific PPAR subtypes, PPARα and PPARγ. The study found that both PPARα and PPARγ were present in approximately 70% of midbrain dopamine (DA) neurons. Furthermore, PPARα was found to be expressed in around 60% of amygdala glutamatergic neurons, whereas PPARγ was detected in roughly 60% of amygdala GABA neurons. Notably, these receptors were not detected in nucleus accumbens GABA neurons. Behavioral experiments using optical intracranial self-stimulation (oICSS) indicated that optogenetic stimulation of midbrain DA neurons was rewarding in DAT-cre mice. Interestingly, Δ9-tetrahydrocannabinol (Δ9-THC) and pioglitazone (a selective PPARγ agonist) dose-dependently inhibited oICSS, suggesting that both Δ9-THC and PPARγ agonists negatively impact reward function. Pre-treatment of animals with PPARα or PPARγ antagonists effectively counteract the aversive and anxiogenic effects induced by Δ9-THC in oICSS and elevated plus maze tests, suggesting that blocking PPARα or PPARγ receptors could mitigate the negative effects associated with cannabinoids. These findings provide groundbreaking anatomical and functional evidence suggesting the notion that, in addition to CB1 and CB2 receptors, PPARα/γ also play an important role in dopamine-dependent behaviors and the effects of cannabinoids.