| First Author | Hempel B | Year | 2023 |
| Journal | Mol Psychiatry | Volume | 28 |
| Issue | 10 | Pages | 4203-4214 |
| PubMed ID | 37479780 | Mgi Jnum | J:358390 |
| Mgi Id | MGI:7780266 | Doi | 10.1038/s41380-023-02182-0 |
| Citation | Hempel B, et al. (2023) PPARalpha and PPARgamma are expressed in midbrain dopamine neurons and modulate dopamine- and cannabinoid-mediated behavior in mice. Mol Psychiatry 28(10):4203-4214 |
| abstractText | Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that regulate gene expression. Delta(9)-tetrahydrocannabinol (Delta(9)-THC) is a PPARgamma agonist and some endocannabinoids are natural activators of PPARalpha and PPARgamma. 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 PPARalpha and PPARgamma expression in the mouse brain. We found that PPARalpha and PPARgamma are expressed in ~70% of midbrain dopamine (DA) neurons. In the amygdala, PPARalpha is expressed in ~60% of glutamatergic neurons, while PPARgamma is expressed in ~60% of GABA neurons. However, no PPARalpha/gamma signal was detected in GABA neurons in the nucleus accumbens. We then used a series of behavioral assays to determine the functional roles of PPARalpha/gamma in the CNS effects of Delta(9)-THC. We found that optogenetic stimulation of midbrain DA neurons was rewarding as assessed by optical intracranial self-stimulation (oICSS) in DAT-cre mice. Delta(9)-THC and a PPARgamma (but not PPARalpha) agonist dose-dependently inhibited oICSS. Pretreatment with PPARalpha or PPARgamma antagonists attenuated the Delta(9)-THC-induced reduction in oICSS and Delta(9)-THC-induced anxiogenic effects. In addition, a PPARgamma agonist increased, while PPARalpha or PPARgamma antagonists decreased open-field locomotion. Pretreatment with PPARalpha or PPARgamma antagonists potentiated Delta(9)-THC-induced hypoactivity and catalepsy but failed to alter Delta(9)-THC-induced analgesia, hypothermia and immobility. These findings provide the first anatomical and functional evidence supporting an important role of PPARalpha/gamma in DA-dependent behavior and cannabinoid action. |
