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

Abstract

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 M₄ 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.

Keywords: addiction; biological rhythm; dopamine receptors; locomotor activity; muscarinic receptors; striatum.

Figure 1

Schematic representation of interconnections between neurons in the striatum. The direct pathway projects preferentially to the globus pallidus internal segment (not shown)/substantia nigra pars reticulata, while the indirect pathway projects to the globus pallidus external segment. Efferentation to the entopeduncular nucleus is not shown. The substantia nigra (dotted blue line) is divided into the pars compacta and pars reticulata. The connections are simplified. Specific receptors are shown by symbols. Alpha4, alpha6, beta2-cont. nicotinic receptors: nicotinic receptors containing the α₄, α₆, β₂ subunits, respectively. The neurons are schematized (see legend for explanation), and receptor localization is not specified (i.e., receptors are not shown to be expressed in nerve terminals or bodies). Please note that cholinergic neurons are also able to release glutamate. Both cholinergic and dopaminergic neurons can transmit the signal using volume transmission (see text); thus, the neurotransmitter can affect relatively remote receptors. Based on the data from [3,20,28,29,30,31,32,33,34].

Figure 2

Hierarchical model of striatal interactions between the dopamine and acetylcholine neurotransmitter systems.