Dopamine modulates excitatory transmission to orexin neurons in a receptor subtype-specific manner.

Dopamine (DA) can promote or inhibit consummatory and reward-related behaviors by activating different receptor subtypes in the lateral hypothalamus and perifornical area (LH/PF). Because orexin neurons are involved in reward and localized in the LH/PF, DA may modulate these neurons to influence reward-related behaviors. To determine the cellular mechanism underlying dopaminergic modulation of orexin neurons, the effect of DA on excitatory transmission to these neurons was investigated using in vitro electrophysiology on rat brain slices. We found that low concentrations (0.1-1 µM) of DA increased evoked excitatory postsynaptic current amplitude while decreasing paired-pulse ratio. In contrast, high concentrations (10-100 µM) of DA did the opposite. The excitatory effect of low DA was blocked by the D1 receptor antagonist SCH-23390, whereas the inhibitory effect of high DA was blocked by the D2 receptor antagonist sulpiride. These results indicate distinct roles of D1 and D2 receptors in bidirectional presynaptic modulation of excitatory transmission. DA had stronger effects on isolated synaptic activity than repetitive ones, suggesting that sensitivity to dopaminergic modulation depends on the level of network activity. In orexin neurons from high-fat diet-fed rats, a high concentration of DA was less effective in suppressing repetitive synaptic activity compared with chow controls. Therefore, in diet-induced obesity, intense synaptic inputs may preferentially reach orexin neurons while intermittent signals are inhibited by high DA levels. In summary, our study provides a cellular mechanism by which DA may exert opposite behavioral effects in the LH/PF through bidirectional modulation of orexin neurons via different DA receptors.