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

Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that regulate gene expression. Δ(9)-tetrahydrocannabinol (Δ(9)-THC) is a PPARg agonist and some endocannabinoids are natural activators of PPARa and PPARg. Therefore, both the receptors are putative cannabinoid receptors. 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 highly expressed in ~70% midbrain dopamine (DA) neurons and in ~50% GABAergic and ~50% glutamatergic neurons in the amygdala. However, no PPARα/γ signal was detected in GABAergic 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(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. Δ(9)-THC and a PPARγ (but not PPARα) agonist dose-dependently inhibited oICSS, suggesting that dopaminergic PPARγ modulates DA-dependent behavior. Surprisingly, pretreatment with PPARα or PPARγ antagonists dose-dependently attenuated the Δ(9)-THC-induced reduction in oICSS and anxiogenic effects. In addition, a PPARγ agonist increased, while PPARa or PPARγ antagonists decreased open-field locomotion. Pretreatment with PPARa or PPARγ antagonists potentiated Δ(9)-THC-induced hypoactivity and catalepsy but failed to alter Δ(9)-THC-induced analgesia, hypothermia and immobility. These findings provide the first anatomical and functional evidence supporting an important role of PPARa/g in DA-dependent behavior and cannabinoid action.