Pituitary Adenylate Cyclase Activating Polypeptide Inhibits A10 Dopamine Neurons and Suppresses the Binge-like Consumption of Palatable Food

by Selleckchem | Oct 19 2023

Pituitary adenylate cyclase-activating polypeptide (PACAP) binds to PACAP-specific (PAC1) receptors in multiple hypothalamic areas, especially those regulating energy balance. PACAP neurons in the ventromedial nucleus (VMN) exert anorexigenic effects within the homeostatic energy balance circuitry. Since PACAP can also reduce the consumption of palatable food, we tested the hypothesis that VMN PACAP neurons project to the ventral tegmental area (VTA) to inhibit A10 dopamine neurons via PAC1 receptors and KATP channels, and thereby suppress binge-like consumption. We performed electrophysiological recordings in mesencephalic slices from male PACAP-Cre and tyrosine hydroxylase (TH)-Cre mice. Initially, we injected PACAP (30 pmol) into the VTA, where it suppressed binge intake in wildtype male but not female mice. Subsequent tract tracing studies uncovered projections of VMN PACAP neurons to the VTA. Optogenetic stimulation of VMN PACAP neurons in voltage clamp induced an outward current and increase in conductance in VTA neurons, and a hyperpolarization and decrease in firing in current clamp. These effects were markedly attenuated by the KATP channel blocker tolbutamide (100 μM) and PAC1 receptor antagonist PACAP6-38 (200 nM). In recordings from A10 dopamine neurons in TH-Cre mice, we replicated the outward current by perfusing PACAP1-38 (100 nM). This response was again completely blocked by tolbutamide and PACAP6-38, and associated with a hyperpolarization and decrease in firing. These findings demonstrate that PACAP activates PAC1 receptors and KATP channels to inhibit A10 dopamine neurons and sex-dependently suppress binge-like consumption. Accordingly, they advance our understanding of how PACAP regulates energy homeostasis via the hedonic energy balance circuitry.

Comments:

The passage you provided describes a study that investigates the role of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) in regulating energy balance and binge-like consumption. Here's a breakdown of the key findings and their implications:

1. PACAP and its receptors: PACAP is a neuropeptide that binds to PACAP-specific (PAC1) receptors in various hypothalamic areas involved in energy balance regulation. In this study, the focus is on the ventromedial nucleus (VMN) of the hypothalamus.

2. Anorexigenic effects: The PACAP neurons in the VMN are shown to have anorexigenic effects, meaning they reduce food intake. This effect is observed within the homeostatic energy balance circuitry.

3. Projection to the ventral tegmental area (VTA): The study demonstrates that the VMN PACAP neurons project to the ventral tegmental area (VTA), a brain region associated with reward and motivation. This suggests a potential connection between energy balance regulation and the brain's reward system.

4. Suppression of binge-like consumption: By injecting PACAP into the VTA, the researchers observed a suppression of binge-like food intake in male mice. Notably, this effect was observed in male mice but not female mice, indicating a sex-dependent response.

5. Electrophysiological recordings: Electrophysiological experiments were conducted in brain slices to investigate the mechanisms underlying the observed effects. Stimulation of VMN PACAP neurons resulted in an outward current and increased conductance in VTA neurons. In current clamp mode, this stimulation led to hyperpolarization and decreased firing of VTA neurons.

6. Involvement of PAC1 receptors and KATP channels: The effects of PACAP stimulation on VTA neurons were significantly attenuated by blocking PAC1 receptors using PACAP6-38 and by inhibiting KATP channels using tolbutamide. This suggests that PACAP activates PAC1 receptors and KATP channels to modulate the activity of VTA neurons.

7. Replication in A10 dopamine neurons: Further experiments targeting A10 dopamine neurons, which are found in the VTA, replicated the outward current response when perfused with PACAP1-38. Again, this response was blocked by tolbutamide and PACAP6-38, and associated with hyperpolarization and decreased firing of the dopamine neurons.

8. Implications for energy homeostasis and hedonic circuitry: The study's findings contribute to our understanding of how PACAP regulates energy homeostasis through interactions with the brain's hedonic (reward-related) circuitry. By inhibiting A10 dopamine neurons, PACAP may suppress binge-like consumption, providing insights into potential therapeutic strategies for managing overeating and related disorders.

It's important to note that the passage represents a summary of the study's findings and their implications. If you have any specific questions or need further information, feel free to ask.