The influence of acetylcholine, dopamine, and GABA on the functioning of the corticostriatal neuronal network in Alzheimer’s and Parkinson’s diseases: A hypothetical mechanism

Abstract

A proposed model of the functioning of the basal ganglia complements the existing opinions about the complex interaction between cholinergic and dopaminergic systems. A hypothesis is proposed that one of the means of interaction between these systems is the operation of a negative feedback loop. In this loop, a conditioned stimulus evokes the excitation of dopaminergic neurons and GABAergic cells with long axons in the dopaminergic nuclei, which leads to an increase in the influence on dopamine D2 receptors on striatal cholinergic interneurons; an increase in their inhibition can lead to a pause in their responses. In turn, during this pause reduced action on presynaptic nicotinic receptors at axon terminals of dopaminergic neurons results in a decrease in dopamine release. In addition, dopaminergic neurons are under the inhibitory action of GABAergic striatonigral cells in the striosomes of the dorsal striatum and clusters in the ventral striatum. During the pause, stimulation of M2/M4 receptors located on these striatonigral cells weakens, which should promote potentiation of their excitation, subsequent enhancement of the inhibition of dopaminergic cells, and a decrease in the dopamine concentration in the striatum. In addition, a decrease in the stimulation of M1 receptors on striatopallidal cells and M2 receptors on striatonigral cells of the matrix during the pause should promote synergistic disinhibition through the direct and indirect pathways via the basal ganglia of certain groups of thalamic neurons and enhancement of the excitation of neocortical neurons connected with them. This interaction between cholinergic and dopaminergic systems contributes to the normal functioning of the various parallel cortico–basal ganglia–thalamocortical loops, which play a determining role in movement choice, sensory perception, learning, and intentional behavior. The proposed model implies that cholinergic and dopaminergic denervation of different structures, as well as changes in the density and affinity of receptors that are sensitive to acetylcholine, dopamine, and NMDA, which are typical for Alzheimer’s and Parkinson’s diseases, should lead to abnormal functioning of these loops. This may underlie various cognitive and motor disorders.