Obesity attenuates D2 autoreceptor-mediated inhibition of putative ventral tegmental area dopaminergic neurons

The ventral tegmental area (VTA) in the midbrain is important for food reward. High-fat containing palatable foods have reinforcing effects and accelerate obesity. We have previously reported that diet-induced obesity selectively decreased the spontaneous activity of VTA GABA neurons, but not dopamine neurons. The spontaneous activity of VTA dopamine neurons is regulated by D-2 autoreceptors. In this study, we hypothesized that obesity would affect the excitability of VTA dopamine neurons via D-2 autoreceptors. To examine this hypothesis, we compared D-2 receptor-mediated responses of VTA dopamine neurons between lean and obese mice. Mice fed on a high-fat (45%) diet and mice fed on a standard diet were used as obese and lean models, respectively. Brain slice preparations were made from these two groups. Spontaneous activity of VTA neurons was recorded by extracellular recording. Putative VTA dopamine neurons were identified by firing inhibition with a D-2 receptor agonist quinpirole, and electrophysiological criteria (firing frequency < 5 Hz and action potential current duration > 1.2 msec). Single-dose application of quinpirole (3 - 100 nmol/L) exhibited similar firing inhibition of putative VTA dopamine neurons between lean and obese mice. In stepwise application by increasing quinpirole concentrations of 3, 10, 30, and 100 nmol/L subsequently, quinpirole-induced inhibition of firing decreased in putative VTA dopamine neurons of obese mice compared with those of lean mice. In conclusion, high-fat diet-induced obesity attenuated D-2 receptor-mediated inhibition of putative VTA dopamine neurons due to the acceleration of D-2 receptor desensitization.