This review delves into the regulatory mechanisms of neuronal excitability and the role of neuromodulators in emotion regulation. Neurotransmitters like glutamate and GABA maintain the balance between excitatory and inhibitory signals, which is crucial for cognitive functions and emotional responses. Neuromodulators such as dopamine and acetylcholine influence this balance by modulating the activity of specific neurons, affecting cognitive processes and emotional behaviors. The review highlights the importance of cell signaling crosstalk in these processes and anticipates that integrated phosphorylation studies will provide deeper insights into the molecular mechanisms underlying neuronal excitability regulation by neuromodulators. Key findings include the role of dopamine in motor function, reward, and learning, and the involvement of acetylcholine in modulating excitatory signaling and affecting the E/I balance. The interplay between dopamine and adenosine, as well as dopamine and serotonin, is also discussed, emphasizing their complex interactions in regulating emotional behaviors. The review concludes by emphasizing the need for further research to understand the molecular mechanisms underlying these interactions and their implications for neurodevelopmental and neuropsychiatric disorders.This review delves into the regulatory mechanisms of neuronal excitability and the role of neuromodulators in emotion regulation. Neurotransmitters like glutamate and GABA maintain the balance between excitatory and inhibitory signals, which is crucial for cognitive functions and emotional responses. Neuromodulators such as dopamine and acetylcholine influence this balance by modulating the activity of specific neurons, affecting cognitive processes and emotional behaviors. The review highlights the importance of cell signaling crosstalk in these processes and anticipates that integrated phosphorylation studies will provide deeper insights into the molecular mechanisms underlying neuronal excitability regulation by neuromodulators. Key findings include the role of dopamine in motor function, reward, and learning, and the involvement of acetylcholine in modulating excitatory signaling and affecting the E/I balance. The interplay between dopamine and adenosine, as well as dopamine and serotonin, is also discussed, emphasizing their complex interactions in regulating emotional behaviors. The review concludes by emphasizing the need for further research to understand the molecular mechanisms underlying these interactions and their implications for neurodevelopmental and neuropsychiatric disorders.