Two Players in the Field: Hierarchical Model of Interaction between the Dopamine and Acetylcholine Signaling Systems in the Striatum

Tight interactions exist between dopamine and acetylcholine signaling in the striatum. Dopaminergic neurons express muscarinic and nicotinic receptors, and cholinergic interneurons express dopamine receptors. All neurons in the striatum are pacemakers. An increase in dopamine release is activated by stopping acetylcholine release. The coordinated timing or synchrony of the direct and indirect pathways is critical for refined movements. Changes in neurotransmitter ratios are considered a prominent factor in Parkinson’s disease. In general, drugs increase striatal dopamine release, and others can potentiate both dopamine and acetylcholine release. Both neurotransmitters and their receptors show diurnal variations. Recently, it was observed that reward function is modulated by the circadian system, and behavioral changes (hyperactivity and hypoactivity during the light and dark phases, respectively) are present in an animal model of Parkinson’s disease. The striatum is one of the key structures responsible for increased locomotion in the active (dark) period in mice lacking M(4) muscarinic receptors. Thus, we propose here a hierarchical model of the interaction between dopamine and acetylcholine signaling systems in the striatum. The basis of this model is their functional morphology. The next highest mode of interaction between these two neurotransmitter systems is their interaction at the neurotransmitter/receptor/signaling level. Furthermore, these interactions contribute to locomotor activity regulation and reward behavior, and the topmost level of interaction represents their biological rhythmicity.