The pathophysiology of tic disorders involves an alteration in the transmission of messages through the cortico-basal ganglia-thalamo-cortical circuit. A major requirement for the passage of a message through this circuit is an intact chemically mediated synaptic neurotransmitter system (ie, neurotransmitters and second messengers). This article reviews the scientific evidence supporting the involvement of a variety of neurotransmitters (ie, dopamine, glutamate, gamma-aminobutyric acid, serotonin, acetylcholine, and the opioid system). Although there are favored neurotransmitter abnormalities, their complex interactions suggest the likelihood that several are involved in the production of tics.
Key points
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The steps of synaptic neurotransmission include the synthesis, storage, release, and binding of the neurotransmitter, and its termination of action.
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A variety of primary neurotransmitters are implicated in the pathophysiology of tics (ie, dopamine, glutamate, gamma-aminobutyric acid, serotonin, acetylcholine, histamine, endogenous cannabinoids, and the opioid system).
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Although the most widely scientifically supported neurotransmitter in tic disorders is dopamine, the complex interactions among a variety of agents suggest the likelihood that several neurotransmitters are involved in tic disorders.
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Second messengers, which operate downstream of the primary neurotransmitter, represent an understudied group of small molecules and ions that relay signals within the cell and could be involved in tic disorders.
Introduction
As discussed in Harvey S. Singer and Justin Pellicciotti’s article, “ The Pathophysiology of Tics: An Anatomical Review ,” in this issue, there is strong scientific evidence to support the hypothesis that tics can arise from an alteration in several brain regions within the cortico-basal ganglia-thalamo-cortical (CBGTC) circuit. Thus, recognizing that fully functional CBGTC circuitry requires intact synaptic neurotransmission throughout its complex pathways, this article reviews proposals implicating a variety of neurotransmitters (ie, dopamine, glutamate, gamma-aminobutyric acid (GABA), serotonin, acetylcholine, norepinephrine, adenosine, endogenous cannabinoids, and opioids) and other neuromodulators ( Fig. 1 ). In general, the supporting evidence for a proposed association between a specific neurotransmitter and tics is based on clinical responses to therapeutic trials, quantitative neurotransmitter measurements, various imaging protocols, genetic investigations, postmortem brain tissue analyses, and data from animal studies. Unfortunately, similar to anatomic correlations, although there are favored neurotransmitter abnormalities, none are universally accepted and a combination of irregularities is possible. For example, a recent study comparing children with chronic tic disorders to healthy controls identified several significant differences in measurements of various plasma and urine neurotransmitters (dopamine, glutamic acid, γ-aminobutyric acid, norepinephrine, and normetanephrine).
This article contains 3 major sections: (1) a brief overview of synaptic transmission; (2) a review of different synaptic neurotransmitters and evidence supporting their role in tic disorders; and (3) a discussion of second messengers and other neuromodulators that could disrupt signal transmission and cause tics.
Overview of synaptic neurotransmission
Chemically mediated transmission is the major means by which a signal is communicated from one nerve cell to another. The mechanism of chemical synaptic transmission consists of 5 steps—each being a potential site for an abnormality ( Fig. 2 ). (1) Synthesis of the neurotransmitter . This requires the availability of appropriate precursors and necessary enzymes in the presynaptic neuron. (2) Storage of neurotransmitters in presynaptic vesicles . As most neurotransmitters are synthesized in the cytosolic compartment, vesicular transport proteins are required for transmitter entry into the vesicle. (3) Release of neurotransmitters into the synaptic cleft . This requires fusion of the synaptic vesicle and exocytosis of the transmitter. (4) Binding and recognition of the neurotransmitter by postsynaptic receptors . (5) Inactivation and termination of the action of the released transmitter . This occurs via reuptake into specific presynaptic terminals (shown in Fig. 2 ), enzymatic conversion into an inactive substance, or a combination of both these processes. The ideal result of synaptic neurotransmission in the CBGTC circuit is the propagation of a signal with high fidelity until it reaches its target destination.
Specific neurotransmitters and evidence for their involvement in tic disorders
Dopamine
Dopamine remains the most widely implicated neurotransmitter in the pathophysiology of tic disorders. It has a well-established role in motor activity, movement disorders, temporal processing, reward processing, reinforced learning, cognitive functioning, and aversion. In addition, dopamine’s influence on sensorimotor integration and sensory motor processing suggests that its effect on tics could occur via either motor or sensory influences. The dopaminergic system is primarily divided into 3 sections: (1) the nigrostriatal system projects from the substantia nigra pars compacta (SNpc) to various locations within the basal ganglia; (2) the mesolimbic system arises in the ventral tegmental area (VTA) and projects to the nucleus accumbens (NAc, ventral striatum) and amygdala; and (3) the mesocortical system arises from the VTA and projects to the frontal cortex.
Over the past 4 plus decades, a variety of investigational studies have been performed with the goal of identifying the underlying dopaminergic abnormality in Tourrette Syndrome (TS). Historically, one of the earliest approaches was designed to detect a hyperdopaminergic condition via the measurement of cerebrospinal fluid (CSF) homovanillic acid (HVA), the major metabolite of dopamine. Despite the researchers’ initial expectations, basal and turnover levels of CSF HVA were statistically reduced in TS subjects, not elevated, and CSF HVA was restored to normal after the administration of haloperidol. Additionally, unconjugated plasma HVA did not correlate with tic severity scores.
Supporting evidence
Pharmacotherapeutic studies provide strong support for dopamine involvement in TS. Therapeutically, both typical and atypical antipsychotics have well-established roles as tic-suppressing agents. , Symptomatic improvement has also been reported following the treatment with medications that block dopamine synthesis (α-methyl-para-tyrosine), prevent dopamine (DA) accumulation into presynaptic vesicles (VMAT-2 inhibitors), and reduce DA release (pergolide). Conversely, tics may be exacerbated following treatment with agents that increase central dopaminergic activity (eg, l -dopa) and have appeared after withdrawal of neuroleptic drugs. , In TS plus attention-deficit/hyperactivity disorder (ADHD) subjects, metabolites of tetrahydroisoquinoline (modulates dopamine neurotransmission and metabolism) were elevated. Antibodies: Clinically, in a study of anti-dopamine D2 receptor antibodies in 137 children with chronic tic disorders, approximately 15% became anti-D2R positive either early or late within an exacerbation period. Genetic evidence: Genetic support for DA involvement in TS has been variable : (1) for D1, D3, and D5 dopamine receptors, no associations were identified in family and case-control studies of TS patients ; (2) for the D2 receptor, the D2Taq1A gene has been inconsistently linked with tic severity, whereas single-nucleotide polymorphisms (SNPs) of D2R were possibly associated with TS ; (3) for the D4 receptor, a greater number of 48 base pair variable number tandem repeats (VNTR) were possibly associated with TS ; (4) for tyrosine hydroxylase, no linkage has been identified , ; (5) for dopamine β-hydroxylase (DBH), a TaqB1 allele has been variably associated with TS , ; and (6) for the dopamine transporter (DAT1), unpredictable linkage to a 40 bp VNTR , and a significant association between TS and a dopamine transporter polymorphism (DAT1 Ddel) have been reported.
Animal models
In a rodent tic-like model induced by the focal disruption of GABAergic transmission in the dorsomedial striatum, deep brain stimulation of the thalamic centromedian parafascicular complex reduced the animals’ tics. This improvement in tics was, in turn, shown to be mediated by D2 receptor activation evoked by synaptic dopamine release and elevated tonic dopamine levels.
Four specific hypothesized abnormalities
Based on a variety of research approaches, 4 different dopamine abnormalities have been hypothesized including: (1) increased innervation (excess) of dopamine terminals; (2) presynaptic dysfunction; (3) an increased number or affinity of dopamine receptors; and (4) an increased amount of dopamine being released (high tonic levels or increased phasic release) (see Fig. 2 ). A comprehensive discussion of supporting data for each of these hypotheses has been previously published. ,
Glutamate
Glutamate is the brain’s primary excitatory neurotransmitter and is heavily involved in CBGTC pathways. It is the excitatory neurotransmitter of corticostriatal neurons, output neurons from the subthalamic nucleus, thalamostriatal and thalamocortical projections, and cerebellar-output neurons. Cortical glutamatergic pyramidal cells modulate mesocortical (VTA) and midbrain (SNpc) dopaminergic neurons and have extensive interactions with motor and cognitive controlling dopaminergic and GABAergic pathways.
Supporting evidence
Genetic studies have identified linkage to 5p13, an area which overlaps with the genomic region for the glial glutamate transporter1 ( SLC1A3 ). A missense variant involving a highly conserved residue, E219D, has been identified in a small number of individuals with TS, and a 3H-glutamate uptake assay showed that E219D conveys a significant increase in EAAT1-mediated glutamate uptake. Postmortem studies have reported reduced levels of glutamate from the GPi, GPe, and SNpr in TS samples. , Imaging studies: Magnetic resonance spectroscopy studies have quantified glutamate in TS patients. When determined at field strengths of 3T and lower, glutamate and glutamine are not well resolved. Glutamate measurements obtained in some studies at 3T have suggested that levels correlate with tic severity. In contrast, measurements at 7T showed glutamate was increased in the premotor cortex, but not striatum. This increase negatively correlated with motor overflow, but not tic severity. It is also important to recognize that measured glutamate and GABA are accumulations, more indicative of excitatory/inhibitory tone, rather than phasic or tonic release. Therapeutic trials: In a small study of TS patients, treatment with either a glutamate agonist ( d -serine) or a glutamate antagonist (riluzole) did not improve tics as compared with a placebo control group.
Animal model studies
Animal studies have suggested either a direct role for glutamatergic afferents or an altered balance with GABA or other neurotransmitters. For example, in a mouse model whose tics were induced by the striatal injection of a GABA receptor antagonist (picrotoxin), a reduction in movements followed the striatal injection of an N-methyl- d -aspartate (NMDA) receptor antagonist. Further, damaging NMDA receptors located on dopaminergic nigrostriatal neurons prevented habitual but not goal-directed learning (Figure 3 in Harvey S. Singer and Justin Pellicciotti’s article, “ The Pathophysiology of Tics: An Anatomical Review ,” in this issue). , In a conditional knock-out mouse, a deletion of NMDA receptors located on indirect pathway medium spiny neurons (MSNs) led to reduced habituation, delay in goal-directed learning, lack of associative behavior, and impaired skill learning. A hyperglutamatergic DICT-7 transgenic mouse exhibited TS-like head and body twitches and obbsessive-compulsive disorder (OCD)-like complex behaviors. , Tic-like movements in this latter model were alleviated by treatment using a variety of drugs that affected different sites within the CBGTC pathway.
Gamma-Aminobutyric Acid
GABA is the major inhibitory neurotransmitter within CBGTC circuits. In the cortex, GABAergic interneurons directly influence the output of cortical pyramidal cells. Within the striatum, GABA releasing MSNs are the primary projection neurons from the striatum for both direct and indirect pathways (Figure 4 in Harvey S. Singer and Justin Pellicciotti’s article, “ The Pathophysiology of Tics: An Anatomical Review ,” in this issue). GABA is also the neurotransmitter for striatal interneurons and GABAergic neurons located within the VTA. The latter modulates learning behaviors through the control of dopamine and cholinergic systems. Several GABAergic hypotheses have been proposed for tics including the impairment of cortical interneurons, reduced striatal interneurons, and alterations of GABAergic projections from the striatum.
Supporting evidence
Therapeutic trials with benzodiazepines, which enhance the inhibitory effect of GABA, have been suggested to have some tic-reducing effect. Open label studies, evaluating the therapeutic effect of baclofen, a GABA B receptor agonist, have been variable. , For example, a small double-blind placebo-controlled crossover study showed statistical improvement in an impairment score, but not in the reduction of tics. In a single trial, taurine, an agonist of GABA receptors, was felt to be safe and effective for tics. Gene studies have reported an altered splicing of GABRA4 and GABRG1 as well as some copy number variants. , In postmortem studies, the number of parvalbumin-positive GABAergic interneurons was increased in the GPi and decreased in the striatum. , As these interneurons project to both striatal MSNs as well as to other interneurons, these alterations could have a widespread effect on basal ganglia activity. Measurement of glutamate decarboxylase activity in postmortem TS cortex was normal. Brain imaging studies: MR spectroscopy evaluating GABA obtained at 3T and 7T has shown significant inconsistencies. , One study suggested that lower levels of GABA in the supplementary motor area were associated with more severe and frequent premonitory urges. A single PET imaging study of GABA A receptors using [( 11 C)] flumazenil showed decreased binding bilaterally in the ventral striatum, globus pallidus, thalamus, amygdala, and right insula. Transcranial magnetic stimulation using double-pulse stimulation of the cortex identified a reduction of short-interval intracortical inhibition, suggesting a deficiency of inhibitory interneurons. ,
Animal model studies
In animal studies, parvalbumin (PV+) interneurons in the NAc were shown to be essential for inhibition in the expression of amphetamine-induced locomotor sensitization. In primates and rodents, the striatal injection of a GABA A antagonist (bicuculine or picrotoxin) caused tic-like behaviors. , Subsequent studies in mice have showed that striatal picrotoxin-induced movements could be reduced or abolished by: (i) infusing a GABA A agonist (muscimol) into the striatum; (ii) infusing muscimol into the overlying cortex; or (iii) blocking striatal NMDA receptors with (RS)-4-(phosphonomethyl)-piperazine-2-carboxylic acid (PMPA). Hence, although precipitated by blocking striatal GABAergic activity, rebalancing the striatal GABA/glutamate system by, respectively, increasing striatal GABAergic activity or reducing glutamatergic striatal innervation (diminishing cortical input or blocking striatal receptors) effectively reduced tic activity. A positive allosteric modulator highly selective for GABA A receptors containing α6 subunits was effective in treating the D1CT-7 transgenic mouse model of tics.
Serotonin
Serotonin, 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter with biological involvement in reward and punishment processing, mood, higher cognitive function, consciousness, self-reflection, and hedonic experiences. Tics have been reported following the use of selective serotonin reuptake inhibitors. A hypothesized process by which serotonin might affect tics is primarily via its effect on other neurotransmitter systems. Serotonin alters the release of dopamine via several mechanisms including presynaptic 5-HT heteroceptors, inhibitory and stimulatory somatodendritic receptors, and 5-HT2 receptor action on the dopamine receptor site. Lastly, serotonin may suppress glutamatergic neurotransmission by reducing glutamate release via the activation of presynaptic 5-HT1B receptors.
Supporting evidence
Therapeutic trials : A preliminary treatment trial using pimavanserin, a serotonin 2A receptor inverse agonist and antagonist, was associated with improvement of motor and nonmotor TS symptoms. Genetics: Genetic polymorphic variants of tryptophan hydroxylase-2 and the serotonin transporter have been postulated to be associated with TS. Elevated expression of SLC6A4 which encodes the serotonin transporter (SERT) has been reported in TS. Biological measurements: Measurements of serotonin, its precursor tryptophan, and metabolite 5-hydroxyindoleacetic acid (5-HIAA) have been variable. For example, serotonin and tryptophan were reduced in serum, and 5-HIAA levels were normal in postmortem cortex, reduced in basal ganglia, and decreased in the CSF. Imaging studies : Binding studies to the serotonin transporter (SERT) using [ 123 I] β-CIT have suggested a negative correlation between binding in the midbrain and vocal tic severity. Another study using [ 123 I]ADAM showed that alterations in the serotonergic system in TS were related to the presence of comorbid OCD. PET imaging of 5-HT2A receptors using [ 18 F]-altanserin showed increased binding in most brain regions, not just those hypothesized to be involved in TS. PET studies of tryptophan metabolism in TS have demonstrated decreased uptake in the dorsolateral prefrontal cortical regions and increased uptake in the caudate nucleus and thalamus.
Animal Studies
In a rodent model, a repetitive head twitch response was induced following the injection of a 5-HT2A, 5-HT2B, and 5-HT2C receptor agonist (2, 5-dimethoxy-4-iodoamphetamine [DOI]). Overall, a precise role for serotonin in tic generation remains speculative.
Acetylcholine
In the striatum, large aspiny cholinergic interneurons influence MSNs and other interneurons. Cholinergic fibers also project from the basal forebrain to the cortex and from the lateral tegmental area to the locus coeruleus. In terms of their mechanism, striatal cholinergic interneurons may co-opt dopamine terminals and drive rapid GABA release.
Supporting evidence
Postmortem studies: The regional density of choline acetyltransferase (ChAT) containing interneurons was reduced in the caudate and putamen, but measurements of the neurotransmitter-synthesizing enzyme ChAT in postmortem frontal, temporal, and occipital brain regions from adult TS patients showed no significant differences. Postsynaptic receptor binding activity for muscarinic cholinergic ([ 3 H] quinuclidinyl benzilate) receptors identified no generalized impairment. Biological measurements using circulating lymphocytes as a peripheral means to measure changes in CNS muscarinic receptors showed [3H] QNB binding was reduced in untreated TS patients. In CSF, measurements of acetylcholinesterase and butyrylcholinesterase activities did not differ from controls. Therapeutic trials: The effects of cholinergic and anti-cholinergic agents in the treatment of tics are conflicting. The administration of cholinergic precursors, including choline, lecithin, and dimethylaminoethanol (deanol) had little effect on motor tics. , , In contrast, anticholinergic agents (physostigmine) reduced the frequency of motor tics but exacerbated vocal tics. Mecamylamine, a nicotinic acetylcholine antagonist, was reported to significantly improve motor and vocal tics whereas transdermal nicotine had unconvincing effects.
Opioid System
The endogenous cortico-striatal opioid system facilitates motor and nonmotor behaviors, including aspects of reward, motivation, executive function, and habit formation. Both exogenous and endogenous opioids act through complex interactions with different neurotransmitters including endocannabinoid, dopaminergic, glutamatergic, and GABAergic systems. The endogenous opioid system consists of 3 peptides (enkephalins, endorphins, and dynorphins) and 3 opioid receptors (mu, delta, and kappa). Cortical GABA interneurons predominantly produce enkephalin whereas non-GABAergic neurons produce dynorphin. In the striatum, D1 and D2 expressing MSNs are the source of dynorphin and enkephalin, respectively. Both enkephalin and dynorphin act presynaptically and postsynaptically to inhibit neurotransmission—enkephalin via mu/delta receptors and dynorphin via mu/kappa opioid receptors. Although much remains undetermined, opioid receptor activation is believed to inhibit the release of neurotransmitters from their presynaptic and postsynaptic terminals.
Supporting evidence
Genetic studies : Disrupting variants of OPRK1 , which encodes the opioid kappa receptor, have been identified in some TS patients. Postmortem studies quantifying dynorphin [1–17] showed decreased immunoreactivity in striatal fibers projecting to the GPe in a severely affected TS patient. CSF studies: One report showed dynorphin [1–8] was increased in the CSF but concentrations correlated with the severity of obsessive compulsive symptoms, not tic severity. A second study showed that both dynorphin A [1–8] and beta-endorphin levels were unaltered. Treatment: The use of the opiate antagonist naloxone in the treatment of tics has produced conflicting results. Some studies have identified a dramatic improvement in symptoms, , whereas others had only a rare responder or a significant dose-related effect.
Animal studies
Pharmacologic studies in animals have shown that apomorphine and morphine can induce stereotypic movements. , In Peromyscus maniculatas (deer mice), neurochemical analyses demonstrated a significant negative correlation between spontaneous repetitive behaviors and endogenous opioids (leu-enk and dyn-A) in the frontal cortex. Other investigators have also reported a significant positive correlation between repetitive behaviors and dynorphin/enkephalin content ratios.
Second messengers and other neuromodulators as potential causes of tics
In the preceding sections, a variety of individual neurotransmitters (first messengers) and their receptors were discussed as possible primary underlying mechanisms for tics. Unfortunately, the process of synaptic transmission is quite complex with the interaction between transmitter and its receptor producing action-related events via the regulation of ion channels and the generation of second messengers. Second messengers include a wide variety of small molecules and ions (eg, cyclic adenosine monophosphate (cAMP), phosphoinositide 3-kinase, phospholipase C, calcium, and receptor tyrosine kinases) that relay signals within membranes, the cytosol, and between the 2. One of the classic second messenger pathways, the activation of adenyl cyclase to generate cAMP, has been previously suggested as a possible link between tics and second messengers. More specifically, levels of cAMP were reduced in TS postmortem brain samples from frontal, temporal, and occipital cortices and the putamen. These early results, however, were not fully substantiated in subsequent postmortem studies.
In addition to second messengers, investigators have also suggested a potential role for other message signaling components identified in the causation of movement disorders. The list of candidates includes alterations of adenosine triphosphate (ATP), nitric oxide (NO), hydrogen sulfide (H 2 S), and other cellular factors. ATP neurotransmission plays an important role in the long-term potentiation. A strong positive association between NO and motor control has been emphasized in several reports and is supported by the presence of nitric oxide synthase in all basal ganglia nuclei. H 2 S is endogenously produced from l -cysteine and (a) facilitates a long-term potentiation via an NMDA-receptor mediated glutamatergic response in neurons and (b) induces Ca 2+ waves in astrocytes that propagate and modulate activity in surrounding neurons. In summary, there exists a variety of underinvestigated postreceptor alterations that could influence the presence of tics.
Summary
Proposed hypotheses for tic disorders have involved virtually all neurotransmitter systems present in CBGTC circuits. To date, the strongest evidence continues to favor a role for involvement of the dopaminergic system. Nevertheless, the existence of complex interactions among multiple neurotransmitter systems emphasizes the likelihood that several are involved in the production of tics. This possibility is fully supported in animal model studies which demonstrate that alterations and imbalances in various CBGTC neurotransmitters (DA, glutamate, GABA, serotonin, acetylcholine, opioids, etc.) can cause tic-like behaviors. A better understanding of the pathophysiology of tics should ultimately result in the development of improved pharmacologic therapies for the treatment of tic disorders.
Clinics care points
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Neurochemical hypotheses defining abnormal synaptic mechanisms underlying tic symptoms have implicated virtually all neurotransmitter systems in CBGTC circuits. The precise abnormality, however, remains speculative.
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The strongest evidence continues to favor a significant role for dopamine, although multiple neurotransmitters likely have a participating role.
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Identification of the major neurochemical alteration(s) underlying tic symptomatology should, in the future, result in improved therapeutic treatments.
Related posts:
Genetics of Tourette Syndrome
Evidence-Based Assessment of Tourette Syndrome
Evidence-Based Behavior Therapy for Tourette Syndrome
Pharmacotherapy for Tourette Syndrome
Mindfulness-Based Interventions for Tourette Syndrome
Systematic Literature Review on Public Health Impacts of Persistent Tic Disorders
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