This article explores the regulation of emotions through neuromodulators and the crosstalk of cell signaling. It discusses the roles of neurotransmitters and neuromodulators in maintaining the balance between excitatory and inhibitory signals in the brain, which is crucial for cognitive functions and emotional responses. Glutamate and GABA are the primary excitatory and inhibitory neurotransmitters, respectively. Disruptions in their balance are linked to various psychiatric disorders. Neuromodulators like dopamine and acetylcholine regulate this balance, influencing cognition and emotion. Dopamine is associated with reward-related behaviors, while acetylcholine is involved in aversive and attentional behaviors. The article reviews the molecular mechanisms of neuronal excitability by dopamine and its contribution to cognitive and emotional regulation. It highlights the role of dopamine in modulating the glutamatergic corticostriatal pathway and the distinct roles of D1-like and D2-like receptors in the dorsal striatum. The balance between these receptors is essential for the direct and indirect pathways that control motor behavior. The study also discusses the role of phosphoproteomics in evaluating dopamine signaling, identifying new PKA substrates and their involvement in reward behavior. The article further examines the interplay of dopamine and adenosine signaling in emotional behavior, highlighting their opposing effects on adenylate cyclase activity. It also explores the interaction between dopamine and acetylcholine, showing how they modulate neuronal excitation and the E/I balance. The study discusses the complex relationship between serotonin and dopamine in the dorsal striatum, where they can have opposing or synergistic effects on reward behavior. The article concludes by emphasizing the importance of data-driven studies using protein information databases to understand cell signaling and its role in emotional behavior. It highlights the need for specialized databases to accurately predict cell signaling and provide insights into the molecular mechanisms underlying neuromodulator regulation. The review underscores the significance of integrated phosphorylation studies in advancing our understanding of the complex interactions between neuromodulators and cell signaling in the regulation of emotions.This article explores the regulation of emotions through neuromodulators and the crosstalk of cell signaling. It discusses the roles of neurotransmitters and neuromodulators in maintaining the balance between excitatory and inhibitory signals in the brain, which is crucial for cognitive functions and emotional responses. Glutamate and GABA are the primary excitatory and inhibitory neurotransmitters, respectively. Disruptions in their balance are linked to various psychiatric disorders. Neuromodulators like dopamine and acetylcholine regulate this balance, influencing cognition and emotion. Dopamine is associated with reward-related behaviors, while acetylcholine is involved in aversive and attentional behaviors. The article reviews the molecular mechanisms of neuronal excitability by dopamine and its contribution to cognitive and emotional regulation. It highlights the role of dopamine in modulating the glutamatergic corticostriatal pathway and the distinct roles of D1-like and D2-like receptors in the dorsal striatum. The balance between these receptors is essential for the direct and indirect pathways that control motor behavior. The study also discusses the role of phosphoproteomics in evaluating dopamine signaling, identifying new PKA substrates and their involvement in reward behavior. The article further examines the interplay of dopamine and adenosine signaling in emotional behavior, highlighting their opposing effects on adenylate cyclase activity. It also explores the interaction between dopamine and acetylcholine, showing how they modulate neuronal excitation and the E/I balance. The study discusses the complex relationship between serotonin and dopamine in the dorsal striatum, where they can have opposing or synergistic effects on reward behavior. The article concludes by emphasizing the importance of data-driven studies using protein information databases to understand cell signaling and its role in emotional behavior. It highlights the need for specialized databases to accurately predict cell signaling and provide insights into the molecular mechanisms underlying neuromodulator regulation. The review underscores the significance of integrated phosphorylation studies in advancing our understanding of the complex interactions between neuromodulators and cell signaling in the regulation of emotions.