Merging the Pathophysiology and Pharmacotherapy of Tics

Abstract

Background: Anatomically, cortical-basal ganglia-thalamo-cortical (CBGTC) circuits have an essential role in the expression of tics. At the biochemical level, the proper conveyance of messages through these circuits requires several functionally integrated neurotransmitter systems. In this manuscript, evidence supporting proposed pathophysiological abnormalities, both anatomical and chemical is reviewed. In addition, the results of standard and emerging tic-suppressing therapies affecting nine separate neurotransmitter systems are discussed. The goal of this review is to integrate our current understanding of the pathophysiology of Tourette syndrome (TS) with present and proposed pharmacotherapies for tic suppression.

Methods: For this manuscript, literature searches were conducted for both current basic science and clinical information in PubMed, Google-Scholar, and other scholarly journals to September 2018.

Results: The precise primary site of abnormality for tics remains undetermined. Although many pathophysiologic hypotheses favor a specific abnormality of the cortex, striatum, or globus pallidus, others recognize essential influences from regions such as the thalamus, cerebellum, brainstem, and ventral striatum. Some prefer an alteration within direct and indirect pathways, whereas others believe this fails to recognize the multiple interactions within and between CBGTC circuits. Although research and clinical evidence supports involvement of the dopaminergic system, additional data emphasizes the potential roles for several other neurotransmitter systems.

Discussion: A greater understanding of the primary neurochemical defect in TS would be extremely valuable for the development of new tic-suppressing therapies. Nevertheless, recognizing the varied and complex interactions that exist in a multi-neurotransmitter system, successful therapy may not require direct targeting of the primary abnormality.

Keywords: Tourette syndrome; neurotransmitters; pathophysiology; tics; treatment.

Figure 1. Cortical-Basal Ganglia-Thalamo-Cortical Circuit and their Interconnected Pathways. Abbreviations: CM-PF, Centromedial-parafascicular Nucleus; GPe, Globus Pallidus Externa; GPi, Globus Pallidus Interna; Hypo, Hypothalamus; Mthal, Motor Thalamus; NAc, Nucleus Accumbences; SMA, Supplemental Motor Area; SNT, Subthalamic Nucleus; SNpc, Sustantia nigra paras compacta; SNpr, Sustantia nigra paras reticulate; PN, Pontine Nucleus; PPTg, Peduculopontine Tegmental Nucleus; VTA, Ventral Tegmental Area.

Figure 2. Neurotransmitters within Cortical-Basal Ganglia-Thalamo-Cortical and Interconnecting Pathways. Abbreviations: ACh, Acetylcholine; CM-PF, Centromedial-parafascicular nucleus; Glu, Glutamate; GABA, Gamma (γ)-aminobutyric acid; GPe, Globus Pallidus Externa; GPi, Globus Pallidus Interna; Hypo, Hypothalamus; Mthal, Motor Thalamus; NAc, Nucleus Accumbences; SMA, Supplemental Motor Area; SNT, Subthalamic Nucleus; SNpc, Sustantia nigra paras compacta; SNpr, Sustantia nigra paras reticulate; PN, Pontine Nucleus; PPTg, Peduculopontine Tegmental Nucleus; VTA, Ventral Tegmental Area.

Figure 3. Diagram Showing the Interactions of Pharmacological Agents Used for Tic Suppression, and their Proposed Pre and Post-Synaptic Effects. α2-Agonists exert their effects on the pre and post synaptic α2-receptors while allosterically enhancing the affinity of GABA for the GABA-receptor complex (GABA-R). Post-synaptically, α2-Agonists enhance the synaptic impulses in recipient neurons by closing the hyperpolarization-activated cyclic nucleotide gated (HCN) channels and decreasing the cation ion efflux. Pre-synaptically, α2-Agonists inhibit excitatory glutamatergic transmission of the pyramidal cells in the prefrontal cortex. The effects of D1 and D2 receptor agonist/antagonist interactions have been recently reviewed. The mechanistic effects of D1-H3 and D2-H3 receptor heterodimers are inhibitory at the post-synaptic terminals. Dopamine has been shown to exert an inhibitory control over medium-sized spiny neurons (MSNs) when acting through D1-H3 heterodimers. This is in contrast to D1 receptor functionality in the direct pathway, where dopamine has an excitatory effect on D1 expressing MSNs. Cannabinoid receptor type 1 (CB1), on the glutamatergic and GABAergic corticostriatal projections is activated by 2-AG and AEA binding. These endocannabinoids are released by post synaptic membrane phospholipids. One intracellular effect of presynaptic CB1 activation on GABAergic interneurons is the increased production of mitochondrial H₂O₂. This H₂O₂ diffuses to adjacent axonal release sites, where it activates H₂O₂-sensitive K_ATP channels, leading to synaptic depression. Opioid receptors (mu, kappa, and delta) are activated by endogenous and exogenous opioid agonists. Although the exact mechanisms are unknown, however, the endogenous opioids are proposed to decrease the GABAergic tone within mesolimbic-mesocortical system by inhibiting voltage-sensitive Ca²⁺ channels, enhancing the outflow of K⁺ ions, and inhibiting the intracellular adenylate cyclase.