A Tale of Two Neurotransmitters: Dopamine & Histamine

Your phone dings. You pick it up and see you have a text message from your partner. It says, “Hey. I love you tons. Thank you for being so great.” You set the phone down and can’t help but be giddy for a while because you’re so in love.

A few minutes later, your phone dings and you have an email. The email is from your boss saying your performance has not been great and you need to come in tomorrow for a meeting. You panic and you’re stressed for rest of the day.

Our phone is constantly giving us messages that impact the way we act. And just like humans, neurons (the cells of the brain) receive messages that impact their actions.

For a human it goes: Event→Message→Phone→Human→Altered Action

For neurons it goes: Event→Neurotransmitter→Receptor→Neuron→Altered Action

For neurons, an event occurs, and chemicals called neurotransmitters are sent to specific receptors. The neurons then receive the neurotransmitter’s message from these receptors and their action is altered. There are many types of neurotransmitters and receptors that determine the message and how it is received. Neurons can also receive messages from multiple neurotransmitter systems. Scientists are working to figure out how these messages impact neuronal actions.

Researchers wanted to better understand the interaction between two neurotransmitters: histamine and dopamine. Histamine is a molecule known for its role in inflammation and allergy symptoms in the body. However, it also acts as a neurotransmitter in the brain with roles in arousal and other cognitive processes. Histamine’s work as a neurotransmitter in the brain is greatly understudied and an area of growing attention. On the other hand, dopamine is a neurotransmitter well-characterized for its role in motivation, learning, and reward consumption.

The authors specifically looked at how two receptors – H3 for histamine and D2 for dopamine – interacted to influence mouse behavior and dopamine signaling. How histamine functions and especially how histamine influences dopamine is greatly understudied, making this paper an exciting advancement for science. Spiny projection neurons (SPNs) in the striatum of the brain are special because they contain both the H3 and D2 receptors, meaning they can receive messages from both of these neurotransmitters. Thus, the authors focused on these SPNs in mice to disentangle the relationship between histamine and dopamine signaling.

First, they activated the H3 and D2 receptors using special drugs and observed locomotor and stereotypic behaviors in mice. They found when they activated the D2 receptor, with a drug called Quin, it increased locomotor behavior. When they activated the H3 receptor at the same time as the D2 receptor, with a drug called RAMH, it reversed this effect and lowered locomotor activity. However, when they only activated the H3 receptor, through RAMH, they saw no effect on locomotor behavior indicating that it is the co-activation of D2 and H3 receptors that is necessary for this effect. demonstrated that there is some interaction between histamine and dopamine systems and that it impacts certain behaviors.

They next wanted to quantify what percentage of D2 receptor-containing SPNs in the striatum also contain H3 receptors. They found that about 50% of cells that had D2 also had H3. Because such a significant proportion of SPNs have the H3 receptor, SPNs are likely sites for biologically important histamine and dopamine receptor interactions.

Finally, they wanted to know how dopamine signaling pathways were affected by H3 and D2 activation. To do this, the authors looked at changes in phosphorylation of downstream molecules in the receiving neuron. This is a process whereby the neuron turns the signal from the neurotransmitter binding to its receptor into an action. It is the basic mechanism by which neurotransmitter signaling takes place. The authors specifically looked at the phosphorylation levels of important molecules in dopamine’s signaling pathway. They found that activating the D2 receptor with Quin decreased levels of phosphorylation of a molecule known as Akt. When the H3 receptor was activated at the same time with RAMH, this effect was reversed. However, solely activating the H3 receptor did not have any effect, similar to the previous experiments looking at locomotor behavior. They saw a similar effect with a molecule called GSK3B which is an important component of Akt signaling in the dopamine pathway, suggesting that coactivation of D2 and H3 receptors is important for regulating Akt-GSK3B signaling in D2 SPNs. And overall, this work demonstrates that H3 and D2 receptors work closely to influence dopamine signaling in SPNs of the striatum.

Just like us, neurons receive multiple messages from the environment around them. These messages, communicated through neurotransmitters and their receptors, are important for understanding how neurons respond and are affected by their environment. This paper was a great start to better understanding the histamine system and its interactions with the dopamine system.

Edited by Tamara Chan.

References

Xu, Jian, and Christopher Pittenger. "The histamine H3 receptor modulates dopamine D2 receptor–dependent signaling pathways and mouse behaviors." Journal of Biological Chemistry 299.4 (2023). https://www.jbc.org/article/S0021-9258(23)00225-9/fulltext