PPARα and PPARγ are expressed in midbrain dopamine neurons and modulate dopamine- and cannabinoid-mediated behavior in mice

Study Author Briana Hempel, Ph.D.

Hot Off the Press – August 28, 2023

Published in Molecular Psychiatry by Briana Hempel and Zheng-Xiong Xi, et al. of the NIDA IRP Addiction Biology Unit.

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.

Publication Information

Hempel, Briana; Crissman, Madeline; Pari, Sruti; Klein, Benjamin; Bi, Guo-Hua; Alton, Hannah; Xi, Zheng-Xiong

PPARα and PPARγ are expressed in midbrain dopamine neurons and modulate dopamine- and cannabinoid-mediated behavior in mice Journal Article

In: Mol Psychiatry, 2023, ISSN: 1476-5578.

Abstract | Links

@article{pmid37479780b,

title = {PPARα and PPARγ are expressed in midbrain dopamine neurons and modulate dopamine- and cannabinoid-mediated behavior in mice},

author = {Briana Hempel and Madeline Crissman and Sruti Pari and Benjamin Klein and Guo-Hua Bi and Hannah Alton and Zheng-Xiong Xi},

url = {https://pubmed.ncbi.nlm.nih.gov/37479780/},

doi = {10.1038/s41380-023-02182-0},

issn = {1476-5578},

year  = {2023},

date = {2023-07-01},

urldate = {2023-07-01},

journal = {Mol Psychiatry},

abstract = {Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that regulate gene expression. Δ-tetrahydrocannabinol (Δ-THC) is a PPARγ agonist and some endocannabinoids are natural activators of PPARα and PPARγ. However, little is known regarding their cellular distributions in the brain and functional roles in cannabinoid action. Here, we first used RNAscope in situ hybridization and immunohistochemistry assays to examine the cellular distributions of PPARα and PPARγ expression in the mouse brain. We found that PPARα and PPARγ are expressed in ~70% of midbrain dopamine (DA) neurons. In the amygdala, PPARα is expressed in ~60% of glutamatergic neurons, while PPARγ is expressed in ~60%  of GABA neurons. However, no PPARα/γ signal was detected in GABA neurons in the nucleus accumbens. We then used a series of behavioral assays to determine the functional roles of PPARα/γ in the CNS effects of Δ-THC. We found that optogenetic stimulation of midbrain DA neurons was rewarding as assessed by optical intracranial self-stimulation (oICSS) in DAT-cre mice. Δ-THC and a PPARγ (but not PPARα) agonist dose-dependently inhibited oICSS. Pretreatment with PPARα or PPARγ antagonists attenuated the Δ-THC-induced reduction in oICSS and Δ-THC-induced anxiogenic effects. In addition, a PPARγ agonist increased, while PPARα or PPARγ antagonists decreased open-field locomotion. Pretreatment with PPARα or PPARγ antagonists potentiated Δ-THC-induced hypoactivity and catalepsy but failed to alter Δ-THC-induced analgesia, hypothermia and immobility. These findings provide the first anatomical and functional evidence supporting an important role of PPARα/γ in DA-dependent behavior and cannabinoid action.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}