CHAPTER FOUR

Nondopaminergic Neurotransmission in the Pathophysiology of Tourette Syndrome Patrick T. Udvardi*,†, Ester Nespoli*,{, Francesca Rizzo*,†, Bastian Hengerer{, Andrea G. Ludolph*,1

*Department of Child and Adolescent Psychiatry, University of Ulm, Ulm, Germany † Institute of Anatomy and Cell Biology, University of Ulm, Ulm, Germany { Boehringer Ingelheim Pharma GmbH & Co. KG, CNS Research, Biberach an der Riss, Germany 1 Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 2. Role of the Monoamines Norepinephrine and Serotonin 2.1 Norepinephrine 2.2 Serotonin 3. Role of the Monoamine Histamine 3.1 Genetic, biomarker, and postmortem studies 3.2 Imaging studies 3.3 Pharmacological interventions 4. Role of Glutamate 4.1 Genetic, biomarker, and postmortem studies 4.2 Imaging studies 4.3 Pharmacological interventions 5. Role of GABA 5.1 Genetic, biomarker, and postmortem studies 5.2 Imaging studies 5.3 Pharmacological interventions 6. Role of ACh 6.1 Genetic, biomarker, and postmortem studies 6.2 Imaging studies 6.3 Pharmacological interventions 7. Role of Endocannabinoid 7.1 Genetic, biomarker, and postmortem studies 7.2 Imaging studies 7.3 Pharmacological interventions

International Review of Neurobiology, Volume 112 ISSN 0074-7742 http://dx.doi.org/10.1016/B978-0-12-411546-0.00004-4

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8. Role of Corticoid 8.1 Genetic, biomarker, and postmortem studies 8.2 Pharmacological interventions 9. Conclusion References

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Abstract A major pathophysiological role for the dopaminergic system in Tourette’s syndrome (TS) has been presumed ever since the discovery that dopamine-receptor antagonists can alleviate tics. Especially recent molecular genetic studies, functional imaging studies, and some rare postmortem studies have given more and more hints that other neurotransmitter systems are involved as well. Dysfunction in the dopamine metabolism—in particular during early development—might lead to counter-regulations in the other systems or vice versa. This chapter will give an overview of the studies that prove the involvement of other neurotransmitter systems such as the major monoaminergic neurotransmitters norepinephrine, serotonin, and histamine; the most important excitatory neurotransmitter, the amino acid glutamate; the major inhibitory neurotransmitter y-aminobutyric acid, as well as acetylcholine, endocannabinoid, corticoid; and others. These studies will hopefully lead to fundamental advances in the psychopharmacological treatment of TS. While tic disorders have been previously treated mainly with dopamine antagonists, some authors already favor alpha-agonists. Clinical trials with glutamate agonists and antagonists and compounds influencing the histaminergic system are currently being conducted. Since the different neurotransmitter systems consist of several receptor subtypes which might mediate different effects on locomotor activity, patients with TS may respond differentially to selective agonists or antagonists. Effects of agonistic or antagonistic compounds on tic symptoms might also be dose dependent. Further studies will lead to a broader spectrum of psychopharmacological treatment options in TS.

1. INTRODUCTION Although the precise underlying neurobiological basis is still speculative, a growing number of molecular genetic studies, functional imaging studies, and some rare postmortem studies have added to understanding the neural bases for Tourette syndrome (TS) and defining the neural systems that modulate TS phenomenology (Ludolph, Roessner, Mu¨nchau, & Mu¨ller-Vahl, 2012). There is expanding evidence that TS is an inherited developmental alteration of synaptic neurotransmission within the cortico-striatal-thalamic-cortical circuitry (CSTC) (Neuner & Ludolph, 2009, 2011). This circuitry might influence human behavior by loops for

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executive functions, attention, emotions, impulsivity/compulsivity, and motor activity (Stahl, 2009). Different neurotransmitter systems interact and overlap in the CSTC circuitry and connected brain areas. As the beneficial effects of haloperidol emerged in the early 1960s of the last century, a role of the dopaminergic system in the pathophysiology of TS seemed to be undisputable (Rickards, Hartley, & Robertson, 1997; Shapiro & Shapiro, 1968). More precise examination methods as applied in molecular genetics and functional neuroimaging made it possible to detect the involvement of other neurotransmitter systems. The complex interplay between these distinct systems as well as the interaction with environmental factors came into focus. Although many questions are still open, a tremendous progress has been made in the understanding of the pathophysiology of the disorder. The genetic background is undeniable and recent studies give hint to the involvement not only of other major neurotransmitter systems such as the monoamines norepinephrine, serotonin, and histamine or the excitatory neurotransmitter glutamate, the inhibitory transmitter g-aminobutyric acid (GABA) and acetylcholine (ACh), but also to the role of neurodevelopmental genes. This chapter will give an overview of the current study situation on nondopaminergic neurotransmission in TS. We will highlight the function of the distinct neurotransmitters and their interplay. For the distinct neurotransmitter systems, the latest state of genetic studies (see also for more details in this chapter and Chapter 6), functional imaging studies (see also Chapter 3), and also on current clinical trials (see also Chapters 10 and 11) will be given. Only positron emission tomography (PET), single photon emission computed tomography (SPECT), and the few magnetic resonance spectroscopy studies were considered in the functional imaging paragraphs, since only these techniques can give information about the involved neurotransmitter systems.

2. ROLE OF THE MONOAMINES NOREPINEPHRINE AND SEROTONIN Evidence supporting abnormalities in noradrenergic and serotonergic neurotransmission in TS is strong. The most common comorbidities in TS are attention deficit hyperactivity disorder (ADHD) and obsessive– compulsive disorder (OCD) (see also Chapters 13 and 14). About 50% of the pediatric patients with TS also suffer from ADHD (Ludolph et al., 2012). In the largest clinical study of 3500 TS patients from 64 international clinics, OCD was present in 27% (range 2–66%) (Freeman et al., 2000).

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For both disorders the exact pathophysiological background is similarly unclear as it is in TS. Neuroimaging studies in ADHD, which indicate that the dopaminergic system, especially variations in the density of presynaptic dopamine transporter, postsynaptic dopamine receptor, and also presynaptic dopamine metabolism play a role in the pathogenesis of ADHD (Ludolph et al., 2008), but also the noradrenergic system seems to be involved. Atomoxetine, the first nonstimulant agent licensed for the treatment of ADHD, is a selective norepinephrine reuptake inhibitor. Clonidine, a central alpha 2 adrenergic agonist, is licensed in the United States for ADHD treatment in an extended-release preparation. Clinical trials for approval of guanfacine, another alpha 2 agonist, are just completed in the European Union. Concerning research of the OCD pathophysiology, the serotonergic system is in the main focus. Selective serotonin reuptake inhibitors (SSRIs) are the first-line psychopharmacological treatment options (see also Chapter 13). If only a partial or no response is obtained (in combination with cognitive behavioral therapy), augmentation treatment with atypical antipsychotics is often attempted.

2.1. Norepinephrine 2.1.1 Genetic, biomarker, and postmortem studies An analysis of the dopamine beta hydroxylase gene in which 106 affected probands were genotyped for three polymorphisms did not find convincing evidence of the association of the DBH locus to TS pathophysiology (Ozbay et al., 2006). Liao, Corbett, Gilbert, Bunge, and Sharp (2010) measured blood gene expression in 20 medicated and 23 unmedicated subjects with TS by isolating RNA from peripheral blood. They found a positive correlation between phenylethanolamine N-methyltransferase, the enzyme that converts norepinephrine to epinephrine, and tic severity in the unmedicated TS patients. 2.1.2 Imaging studies No PET or SPECT study investigating the noradrenergic system in TS has been published so far. The evidence of the involvement of the noradrenergic system mainly comes from clinical and epidemiological studies and has never been verified via in vivo methods because brain imaging of the noradrenergic system in living systems has been hampered due to the lack of suitable radioligands (Ding, Lin, & Logan, 2006).

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2.1.3 Pharmacological interventions primarily influencing the noradrenergic system Clonidine and guanfacine, central alpha 2 adrenergic agonists, are commonly used in the treatment of TS (Scahill, 2009). Pringsheim et al. (2012) made a strong recommendation for the use of these two substances in TS treatment in their Canadian guidelines and prefer them to antipsychotic agents because of the better adverse effects (AEs) profile. The European guidelines came to a different conclusion since clonidine’s tic-suppressing effect seems to be rather weak in comparison to that of neuroleptics (Roessner et al., 2011). Cavanna, Selvini, Termine, Balottin, and Eddy (2012) investigated the prevalence and characteristics of AEs associated with clonidine through a retrospective chart review. Eleven out of 36 patients (30.5%, age range 10–62 years) withdrew clonidine because of the severity of AE (n ¼ 5) or absence (n ¼ 4)/reduction (n ¼ 2) in efficacy. The most commonly reported AEs were sedation and headache. Following treatment with clonidine hydrochloride (3–8 mg/kg/day for 12 weeks) abrupt clonidine withdrawal led to significant rebound phenomena in five out of seven patients aged 9–13 years (Leckman et al., 1986). Reapplication of clonidine again ameliorated the worsened tics.

2.2. Serotonin 2.2.1 Genetic, biomarker, and postmortem studies No significant relationship could be detected between the subunit genes of HTR3A and HTR3B and tic symptoms in 49 patients with TS (Niesler, Frank, Hebebrand, & Rappold, 2005), nor between the SLC6A4 or COMT in 52 patients (Cavallini, Di Bella, Catalano, & Bellodi, 2000). Dehning et al. (2010) observed a significant association between two polymorphisms in the serotonergic receptor HTR2C and tic symptoms in a comparison of 87 TS patients and 311 matched controls. Sallee, Richman, Beach, Sethuraman, and Nesbitt (1996) investigated the serotonin transporter (SERT) protein in platelets of child and adolescent 18 OCD patients, 10 patients with TS, and 19 normal controls. The platelet 5HTPR capacity was only reduced in OCD subjects, not in those with TS. 2.2.2 Imaging studies Wong et al. (2008) conducted a PET study investigating the serotonin system in 11 adult subjects with TS (6 M, 2 F, mean age 34,

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SD 9 years) compared to 10 normal controls (5 M, 5 F, mean age 32, SD 8 years). The radiotracer [11C]McN5652 (McN) was used to measure the presynaptic SERT, and in a second scan, the radiotracer [11C]MDL100,907 (MDL) was used for the 5-HT2A receptor. SERT binding potential (BP) was significantly reduced in the midbrain, caudate, and putamen of subjects with TS when compared with normal controls (see also Table 4.1). This was also true for both patient subgroups, TS þ OCD and TS  OCD. No significant differences were noted in 5-HT2A BP between the whole patient group and controls, but differences were observed between TS þ OCD (¼elevations in 5-HT2A BP) and TS  OCD. In another PET study [18F]altanserin was used as a radiotracer for 5_HT2A (Haugbøl et al., 2007). Twenty adults with TS were compared to 20 healthy controls. Here 5-HT2A binding was significantly increased for the whole TS group in the a priori selected regions anterior cingulate, orbitofrontal cortex, and putamen as well as in some post hoc analyzed cortical regions and hippocampus bilaterally. A SPECT study investigating the SERT binding capacity by the radioligand [I-123]2[beta]-carbomethoxy-3[beta]-(4iodeophenyl)tropane ([123I]beta-CIT) in 10 patients with TS and 10 age- and sex-matched normal volunteers found a significant negative correlation between a measure of overall tic severity and beta-CIT binding in the midbrain and the thalamus (Heinz et al., 1998). Another SPECT study using the identical radioligand also found a significantly reduced BP in 12 TS patients not receiving SSRIs compared to 16 age-matched controls (Muller-Vahl et al., 2005). Behen et al. (2007) used alpha-[(11) C]methyl-L-tryptophan (AMT) PET to assess brain abnormalities of tryptophan metabolism in 26 children with TS and nine controls. The study revealed decreased AMT uptake in bilateral dorsolateral prefrontal cortical and bilaterally increased uptake in the thalamus (P ¼ 0.001) in TS children. The ratio of AMT uptake in subcortical structures to dorsolateral prefrontal cortex was significantly increased bilaterally (P < 0.01) in TS patients also. Using the same tracer, Saporta et al. (2010) combined AMT PET and diffusion tensor imaging in 16 children (mean age 11 years). Their main finding was an increased tryptophan metabolism, suggesting increased serotonin synthesis, related to microstructural abnormalities in the caudate nucleus. The serotonergic system including pre- and postsynaptic membrane proteins and the tryptophan and serotonin metabolism seem to be dysregulated in TS. These functional imaging data provide evidence for a role of serotonergic mechanisms in the pathophysiology of TS.

Table 4.1 Nondopaminergic neurotransmission in TS investigated by PET, SPECT, and MR spectrocopy (see also Buse et al., 2013; Felling & Singer, 2011; Rickards, 2009) N of TS patients Nuclide (age) Treatment Result Author (year) Study Investigated NT

Wong et al. (2008) PET

Saporta et al. (2010)

PET

Serotonin

[11C] McN5652 and [11C] MDL100907

14 (age 29  8)

Significant increase in Seven treatment naı¨ve SERT BP in midbrain and patients, three not currently on medication, caudate/putamen and four voluntarily stopped their medication at least 6 months prior to the baseline PET scan

Alpha-[(11)C] 16 children Not mentioned methyl-Ltryptophan

Asymmetry values in the caudate nucleus

Heinz et al. (1998) SPECT

[123I]betaCIT

Significant negative correlation between tic severity and beta-CIT binding in the midbrain and the thalamus

Behen et al. (2007) PET

Alpha-[(11)C] 26 children Not mentioned methyl-Ltryptophan (AMT)

10

Not mentioned

Significant bilateral increase in AMT uptake in subcortical structures and dorsolateral prefrontal cortex of TS patients. Behaviorally defined subgroups showed differences in AMT uptake in the frontostriatal-thalamic circuit Continued

Table 4.1 Nondopaminergic neurotransmission in TS investigated by PET, SPECT, and MR spectrocopy (see also Buse et al., 2013; Felling & Singer, 2011; Rickards, 2009)—cont'd N of TS patients Author (year) Study Investigated NT Nuclide (age) Treatment Result

Haugbøl et al. (2007)

PET

[18F]altanserin 20 adults

Not mentioned

Increased 5-HT2A receptor binding in subcortical regions

Mu¨ller-Vahl

SPECT

[123I]betaCIT

12

Eight patients not receiving serotonin reuptake inhibitors (SSRI) Four patients received SSRI

Significantly reduced binding in SSRI free patients compared to controls SSRI treatment significantly reduced SERT availability

[11C] flumazenil

11

No medication for at least Decreased binding of 1 week prior to imaging GABA(A) receptors in the ventral striatum, globus pallidus, thalamus, amygdala, and right insula Increased GABA(A) receptor binding in the substantia nigra, left periaqueductal gray, right posterior cingulate cortex and bilateral cerebellum

Lerner et al. (2012) PET

GABA

Clinical trial NCT00034398 National Institute of Neurological Disorders and Stroke (unpublished)

PET

Tinaz et al. (2012) MRSa

Weeks, Lees, and Brooks (1994)

PET

Berding et al. (2004)

SPECT

a

MRS ¼ MR spectroscopy.

[11C] flumazenil

17 adults

Medications discontinued Results still not published before trial

8 (age 31  10)

medications discontinued Reduction in the 2 weeks prior to imaging GABA/Cre ratio in the SMC in a small cohort of TS patients

Endocannabinoid [11C] 6 diprenorphine

[123I]AM281 6

Drug naive at the time of Normal striatal/occipital scanning apart from one ratios in TS patients who was off neuroleptic medication for a month before scanning Analysis before and after Delta9-THC treatment

No significant differences with controls

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2.2.3 Pharmacological interventions primarily influencing the serotonergic system A very preliminary trial with fluoxetine in two young male TS patients (21 and 32 years old) led to a significant reduction of tic and OCD symptoms in both patients (Silvestri et al., 1994). In a double-blind placebo-controlled crossover trial of fluoxetine monotherapy with a fixed dose of 20 mg daily, crossover analysis showed that fluoxetine had no marked effect on tics in 14 subjects with TS (aged 8–33 years) after 8 weeks of treatment. Comorbid OCD symptoms significantly improved (Scahill et al., 1997). An open retrospective study found similar results. Seventy-six percentage of 30 TS patients with obsessive–compulsive behaviors (OCBs) showed an overall improvement in OCB (Eapen, Trimble, & Robertson, 1996). In another larger placebo-controlled study of adolescents with OCD, though, tic disorders seemed to adversely impact treatment with the SSRI sertraline (March et al., 2007). In 17 out of 112 patients who exhibited a comorbid tic disorder, sertraline did not differ from placebo treatment during a 12-week period. Hauser and Zesiewicz (1995) reported a sertralineinduced exacerbation of tics. Bruun and Budman (1998) treated 45 patients with TS and rage attacks which sometimes is a much more impairing symptom in children with TS than the tics themselves (Cath & Ludolph, 2013). After 8 weeks on paroxetine treatment, 29 out of the 45 patients reported a significant reduction of rages. Tic severity did not alter the efficacy of paroxetine and did not change. Ondansetron, a selective antagonist of 5-hydroytryptamine3 (5-HT3) receptor subtype, usually prescribed as an antinausea/antiemesis agent, was tested as an antitic drug in a 3-week, randomized, doubleblind, placebo-controlled study in 30 TS patients aged 12–46 years (Toren, Weizman, Ratner, Cohen, & Laor, 2005; Ye, Ponnudurai, & Schaefer, 2001). A significant effect was noted on tic severity measured by the Tourette’s Syndrome Global Scale, but not by the Yale Global Tic Severity Scale (YGTSS).

3. ROLE OF THE MONOAMINE HISTAMINE Biogenic amines such as dopamine, noradrenaline, serotonin, and histamine act as neuromodulators and fine tune the action of excitatory and inhibitory fast-acting neurotransmitters (Panula & Nuutinen, 2013). Whereas dopaminergic, noradrenergic, and serotonergic neurons send long projections throughout the brain and participate in most of the circuits

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involved in behavior control, the neuromodulatory effect of histamine was much less noted. In the past decades, the important role of histamine in the maintenance of wakefulness, cognition, and also motor control has been identified. Recent evidence suggests that dysfunctions in histamine signaling may be a key factor in TS. Histamine is synthesized from the amino acid L-histidine by the enzyme L-histidin decarboxylase (HDC) in mast cells and neurons. Whereas in adulthood only a small amount of total brain histamine is produced in mast cells, these cells generate a significant proportion of histamine during early postnatal development (Tuomisto & Panula, 1991). Ellender, HuertaOcampo, Deisseroth, Capogna, and Bolam (2011) identified the role of histamine in the striatal circuits that are implicated in TS. The striatum receives modulatory afferents from the histaminergic neurons in the hypothalamus. By whole-cell patch clamp recordings of striatal neurons, Ellender et al. (2011) could show histamine’s depolarizing effect on the striatal medium spiny neurons (MSNs) and a negative modulation of the excitatory, glutamatergic input to MSNs from cortical and thalamic afferents. Histamine’s action is terminated by two enzymes: histamine N-methyl-transferase and MAO-B. Different from the monoamines dopamine, noradrenaline, and serotonin, there is no presynaptic reuptake pump for histamine (Stahl, 2009). Four G protein-coupled histamine receptors are cloned, the best known is the postsynaptic histamine 1 receptor as the target of “antihistamines.” The H2 receptor is also postsynaptically located, whereas the histamine H3 receptor is presynaptic and functions as autoreceptor influencing the histamine release. Histamine H3 antagonists have been shown to improve memory performance in experimental animals (Van Ruitenbeek & Mehta, 2013). The histamine H4 receptor has not been found in the brain. Since there is no reuptake mechanism for histamine at the synapse, histamine can diffuse away to glutamatergic synapses and is able to alter glutamate action at NMDA receptors. If this mechanism might play a role in the pathophysiology of TS is still to be clarified.

3.1. Genetic, biomarker, and postmortem studies The first genetic study showing the involvement of the histaminergic system caused quite a stir (Ercan-Sencicek et al., 2010). In a family in which the father was affected by TS, the mother became pregnant 15 times. Seven of the pregnancies resulted in miscarriages. All of the eight surviving children (six boys, two girls) were also diagnosed with tic disorders. No tics or

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obsessive–compulsive disorder occurred in the mother’s family. Thus, an autosomal dominant inheritance could be postulated in this family. On chromosome 15, a nonsense mutation was found in exon 9 of the HDC gene encoding L-histidine decarboxylase, the rate-limiting enzyme in histamine biosynthesis. No other mutations could be detected in this family. Also strong support for the histaminergic hypothesis in TS etiology was given by another recent study investigating a sample of 520 nuclear families (Karagiannidis et al., 2013) from seven European countries and Canada. A strong overtransmission of alleles at two single nucleotide polymorphisms (SNPs) across the HDC region was found. Fernandez et al. (2012) conducted a case–control study of 460 individuals with TS and 1131 controls and analyzed rare copy number variations (CNVs). While they did not find significant differences in the number of CNVs, pathway analysis showed enrichment of genes within histamine receptor signaling pathways (H1R and H2R).

3.2. Imaging studies Neither PET nor SPECT studies have been performed to investigate the histamine metabolism in TS patients. Different ligands exist, especially to measure histamine H1 receptor occupancy by PET, namely, [11C]doxepin and [11C]pyrilamine (Tashiro et al., 2008). In a very recent PET study, the H3 receptor occupancy (H3RO) by a novel histamine H3 receptor antagonist, AZD5213, was investigated (Jucaite et al., 2013). The binding characteristics and the pharmacokinetic profile indicated a high daytime and low nighttime H3RO after one daily oral dose of AZD5213. A “Safety, Tolerability, Pharmacokinetic, and Efficacy Study of AZD5213 in Adolescents (12–17 years) With Tourette’s Disorder” is registered but not yet recruiting patients (ClinicalTrials.gov Identifier: NCT01904773). A study with another potent and selective histamine H3 receptor antagonist developed by Pfizer, PF-03654746, has been terminated “due to an internal reassessment of priorities by the sponsor” (ClinicalTrials.gov identifier: NCT01475383).

3.3. Pharmacological interventions Besides the already above-mentioned clinical trials with H3 antagonists, no controlled interventions with compounds influencing the histaminergic system are published for the treatment of TS. A small case series of three patients whose tics exacerbated after use of antihistaminergic agents was published in 1986 (Shafii, 1986). Hartmann, Worbe, and Arnulf (2012) reported about a

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patient with TS whose tic symptoms were refractory to several antipsychotics and who developed a severe narcolepsy. With the patient’s consent the authors tried an inverse H3 receptor agonist (BF2.649 or tiprolisant or pitolisant). The narcolepsy improved dramatically without worsening the tic symptoms (Hartmann et al., 2012). Controlled clinical trials of H3 receptor reverse agonists seem to be warranted.

4. ROLE OF GLUTAMATE Glutamate is the major excitatory neurotransmitter in the CNS— sometimes considered to be the “master switch of the brain” (Stahl, 2009). It has a predominant role in synaptic plasticity, learning, and memory. In the mammalian brain, nearly 60% of all synapses are glutamatergic. Upon depolarization of the presynaptic membrane, glutamate is released from presynaptic vesicles into the synaptic cleft, where it (a) is recycled to the presynaptic neuron via the glial excitatory amino-acid transporter (EAATs) and the glutamine/glutamate-shuttle and (b) binds to its postsynaptic receptors. These glutamate receptors include the G-protein coupled metabotropic glutamate receptors (mGluRs) and the ionotropic cation-permeable receptor channels, which are subdivided into three members, the kainate receptors, the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), and the N-methyl-D-aspartate receptors (NMDAR) (Fig. 4.1). Since its first characterization by Davies et al., 1979, various neuropsychiatric disorders have been linked to synaptic defects including dysfunctional NMDAR signaling and NMDAR-mediated excitotoxicity (Lau & Zukin, 2007). The NMDARs are organized into seven different subunits, NR1, NR2A-D and NR3A, B, which form NR1–NR2/NR1–NR3 heterodimers and finally assemble to the functional di- and/or triheterotetrameric receptors. Additionally, splicing variants of the genes Grin1 and Grin3A (coding for NR1 and NR3A, respectively) have been identified, thus further enhancing heterogeneity of the NMDAR (Paoletti, Bellone, & Zhou, 2013). The receptor subunits and their isoforms have unique biophysical properties and display defined regional and developmental expression pattern. The NR2 subunits are characterized by a large variation in their electrophysiological profile and play a crucial role during brain development (Cull-Candy, Brickley, & Farrant, 2001). Grin2B and Grin2D are predominantly expressed during early developmental stages, and their expression is downregulated around the third postnatal week (Monyer, Burnashev, Laurie, Sakmann, & Seeburg, 1994). The NMDARs are not limited to the

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Figure 4.1 Ionotropic and metabotropic glutamate receptors at pre- and postsynaptic sites. The vesicular glutamate transporters 1 and 2 (vGlut) load presynaptic vesicles with glutamate, which is released into the synaptic cleft upon stimulation of presynaptic boutons. Activation of the ionotropic glutamate receptors such as the a-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), kainate receptors, and N-methyl-D-aspartate receptors (NMDAR) mediates fast excitatory signal transmission, which is crucial for neuroplastic processes. The metabotropic glutamate receptors (mGluR) modulate excitatory signals from the ionotropic glutamate receptors and neurotransmitter release at presynaptic sites. An imbalance between glutamatergic excitation and GABAergic inhibition is hypothesized to contribute to the pathophysiological basis for the onset of various psychiatric disorders, such as ADHD or Tourette syndrome (TS) and the D1CT-7 mouse, an animal model for TS displays profound overexcitation, cyclic adenosine monophosphate (cAMP).

postsynaptic membrane, but were also identified at extra-/peri-/ and presynaptic sites where they display diverge physiological roles, for example, signaling through extrasynaptic NMDARs triggers a CREB shut-off pathway and loss of mitochondrial membrane potential, which leads to cell death (Hardingham, Fukunaga, & Bading, 2002) (Fig. 4.2).

4.1. Genetic, biomarker, and postmortem studies Recent linkage- and association-studies repeatedly found and studied the 5p13 locus. Within this genomic area the SLC1A3 gene is localized coding for the glial EAAT1. The linkage between TS and alterations in the EAAT1 gene are under controversial discussion (Adamczyk et al., 2011; Barr et al., 1999; TSAICG, 2007). Considering the high comorbidity of TS with OCD and/or ADHD, an overlap in genetic vulnerability can be postulated.

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Figure 4.2 The synaptic glutamate/glutamine shuttle. Once glutamate is released into the synaptic cleft, it is mainly cleared by the glial excitatory amino acid transporter 1 and 2 (EAAT1/2), a TS candidate gene. Linkage studies repeatedly revealed an association of Tourette syndrome with the 5p13 locus, a genomic region where the SLC61A3 gene, coding for the EAAT1, is localized. In the astrocytes glutamate is converted in an adenosine triphosphate (ATP)-dependent step into glutamine by the glutamine synthetase and released into the extracellular space, where it is taken up by the neuronal sodium-coupled amino acid transporter 7 (SNAT7). In consecutive steps glutamine is converted into glutamate, which is then loaded into vesicle by the vesicular glutamate transporter (vGlut). Adenosine diphosphate and an inorganic phosphate (ADP þ Pi), aspartate (asp), aspertate-aminotransferase (AST), glutamine (gln), glutamate (glu), tricarboxylic acid cycle (TCA cycle).

Cerebrospinal fluid (CSF) analysis of drug naive OCD patients revealed higher glutamate levels compared to healthy controls (Chakrabarty, Bhattacharyya, Christopher, & Khanna, 2005) and several studies reported SNPs in the SLC1A1 gene coding for the glial EAAT3 (Adamczyk et al., 2011; Arnold, Sicard, Burroughs, Richter, & Kennedy, 2006; Dickel et al., 2006). Furthermore, the NR2B subunit of the NMDA receptor has been linked to OCD (Arnold et al., 2004, 2009) and ADHD (Bredt & Nicoll, 2003). A postmortem study investigating glutamate in four individuals with TS revealed significantly lower levels of glutamate in the three major projection areas of the subthalamic nucleus: the medial globus pallidus, lateral globus pallidus, and substantia nigra reticulata (Anderson et al., 1992a,b). A TS animal model, the D1CT-7 transgenic mouse with specific developmental neural circuit deficits, displays amygdala, orbitofrontal, and

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cortico-striatal glutamatergic overexcitation (Swerdlow & Sutherland, 2005). This animal model of TS and the above-mentioned studies hint to an involvement of dysfunctional glutamatergic neurotransmission in the pathophysiology of TS.

4.2. Imaging studies There are no imaging studies investigating abnormalities in the glutamatergic system of TS patients so far. Glutamate receptors, potential binding sites for radiotracers, are widely distributed in the brain. Very recently, especially the mGluRs come into focus and putative radioligands have been developed.

4.3. Pharmacological interventions To date, no verified information exists whether TS is associated with a hypo- or hyperglutamatergic status or both depending on the brain area (Singer, Morris, & Grados, 2010). In consequence, both glutamate agonistic and antagonistic pharmacotherapeutical treatment strategies are investigated. Glutamatergic overexcitation within the CSTC loop might lead to a hyperglutamatergic state in the striatum, which in turn could contribute to hyperkinetic behavior, for example, tics. On the other hand, low glutamatergic signaling through the subthalamic nucleus might trigger reduced GABAergic activity within the pallidum and the substantia nigra, which in consequence might lower inhibitory signals in the CSTC and again could provoke a hyperkinesis (Anderson et al., 1992a). Previously indicated for the treatment of OCD patients (Coric et al., 2005), Riluzole, a compound with antiglutamatergic properties, has proven its efficacy also in other neuropsychiatric disorders associated with striatal dysfunctions. A trial with riluzole in TS is registered on ClinicalTrials.gov (NCT01018056). In the same trial, D-serine, a compound with agonistic effects in the glutamatergic system, will be evaluated. N-acetylcysteine (NAC) is a natural supplement that acts as an antioxidant and glutamate modulating agent. NAC has recently been demonstrated to be effective in a double-blind, placebo-controlled trial in adults with trichotillomania. A study for treatment of TS in children is also registered (NCT01172288).

5. ROLE OF GABA The GABA, synthesized from glutamate by the enzyme glutamate decarboxylase, is the most important inhibitory neurotransmitter in the

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brain. As in the glutamatergic system, ionotropic receptor channels (GABAA receptor) and metabotropic G-protein coupled (GABAB receptor) receptors have been identified. In the early developmental stages, due to nonfunctional AMPAR at the postsynapse—these synapses are silent at resting membrane potentials, excitation is managed by GABA signaling through the GABAA receptor by depolarizing membrane potential via Cl efflux (Connor, Tseng, & Hockberger, 1987). Nonetheless, both receptors mediate inhibitory effects by increasing membrane conductance also during brain development (Chen, Trombley, & van den Pol, 1996). GABAergic neurons are classified in two distinct groups: (a) the projection neurons also known as the MSNs and (b) the interneurons subdivided into three classes dependent on the abundance of the proteins parvalbumin (PV), calretinin, and somatostatin. Unlike glutamatergic neurons, which initially form contacts with all possible targets in close geometric proximity and thereafter rearrange their network via activity-dependent mechanisms, GABAergic interneurons display well organized and highly branched neuronal networks (Kalisman, Silberberg, & Markram, 2005). The glutamate and GABAergic systems are closely connected. A dysfunctional interplay of glutamate, GABA, and dopamine within the CSTC circuitry might contribute to the pathophysiological basis of tics— glutamate and GABA both give input into the circuit, whereas dopamine modulates the information. Hence, an imbalance of excitation and inhibition might trigger dysfunctional signal transmission through the CSTC, which provokes the onset of TS (Harris & Singer, 2006).

5.1. Genetic, biomarker, and postmortem studies An assay of total RNA from whole blood in 26 TS patients and 23 healthy controls identified 3627 genes which correlated to tic severity (p < 0.05) and among which GABA- and ACh-related genes were significantly overrepresented (Tian et al., 2011). GABAA receptor transcripts (GABRA2–4 and GABRB1) displayed positive correlation with tic severity. Although Tian et al. reported higher expression of the GABAA receptor genes, they hypothesized lower protein levels at the synapse, because levels of the GABARAP, a gene coding for the GABA(A) receptor-associated protein, which mediates receptor trafficking to the synaptic membrane, showed negative correlation to tic severity. Furthermore, clearance of GABA from the synaptic cleft might also be faster in TS patients compared to healthy controls, since expression of the SLC6A1, the GABA reuptake transporter,

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also displayed positive correlation with tic severity. Transcript level of the GABAB receptor subunit GABBR2 also positively correlated with tic severity. The same applied to the GABA-related gene GPR156 (the G protein-coupled receptor 156), whose function is still unknown. However, expression of GABBR1 (coding for a GABAB receptor subunit) remained unaltered. In a neuropathological examination, Kalanithi et al. (2005) found a significant reduction in cell number and density of GABAergic neurons in the basal ganglia.

5.2. Imaging studies In a recent PET study, 11 patients with TS and 11 age- and gender-matched healthy controls were scanned using the GABAA receptor ligand [11C] flumazenil. Widespread abnormalities in the GABAergic system were identified in TS patients, including both decreased and increased GABAergic binding (Lerner et al., 2012). Lerner et al. (2012) found decreased GABAA receptor binding, reduced metabolic activity, and tic-related increased activity in the striatum, a region harboring 90–95% GABAergic neurons. The thalamus displayed reduced GABAA receptor activity in the centromedian and mediodorsal nuclei and the pulvinar. Especially, the latter thalamic regions have also been shown to be involved in the pathophysiology of ADHD (Ferreira et al., 2009; Gilbert et al., 2006), which is highly comorbid to TS. Regression analysis proved an association between TS and dysfunctional cerebellar lobule VI (Lerner et al., 2012), which has been reported to be crucial for cognitive and affective functions (Schmahmann, 2004). In amygdala and hippocampus, GABAA receptor activity was reduced and increased in the substantia nigra pars compacta and pars reticulata in TS patients. GABAA receptor activity was also reduced in the right insula, a cortical region discussed as an interface integrating sensational activity from all over the body (Craig, 2002).

5.3. Pharmacological interventions A small randomized, double-blind, placebo-controlled study of baclofen, an GABAB-agonist, in 10 children was inconclusive because there was a reduction in overall impairment but no changes in tic frequency or severity (Singer, Wendlandt, Krieger, & Giuliano, 2001). The anticonvulsant Vigabatrin, an analog of GABA, is an irreversible inhibitor of 4-aminobutyrate transaminase, the enzyme responsible for

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the catabolism of GABA. This compound is currently investigated in a open label safety and tolerability study for treatment in young adults with TS whose symptoms have persisted into adulthood and have not responded to usual treatment (ClinicalTrials.gov Identifier:NCT01585207). Chapter 12 Antiepileptic drugs and Tourette syndrome deals with the numerous case reports and controlled studies with other anticonvulsants (clonazepam, levetiracetam and topiramate) influencing the GABAergig system.

6. ROLE OF ACh ACh is an important neurotransmitter in the CNS that binds to nicotinic and muscarinic receptors (Lucas-Meunier, Fossier, Baux, & Amar, 2003). Since striatal dopaminergic and cholinergic systems exhibit reciprocal antagonism, it is conceivable that the cholinergic system is implicated in TS (Sandyk, 1995). The dopamine/Ach balance is essential for striatal function (Aliane, Perez, Bohren, Deniau, & Kemel, 2011).

6.1. Genetic, biomarker, and postmortem studies Activation of striatal cholinergic interneurons triggers dopamine release via activation of nicotinic receptors on dopamine neurons (Threlfell et al., 2012). Dopamine regulates Ach release through dopamine receptors that are localized directly on striatal cholinergic interneurons. An immunocytochemistry study in rodents could show that these are dopamine D2 receptors (Alcantara, Chen, Herring, Mendenhall, & Berlanga, 2003). In a postmortem study of five TS subjects, patients demonstrated a 50–60% decrease of both PV þ and choline acetyltransferase þ cholinergic interneurons in the caudate and the putamen (Kataoka et al., 2010). No other neurons were affected. The authors postulated that the selective deficit of PVþ and cholinergic striatal interneurons in TS subjects might result in an impairment of striatal neuron firing by cortical and thalamic projections. Hayslett and Tizabi (2003) investigated the possible involvement of the cholinergic system in an animal model. The administration of the selective 5-HT (2A and 2C subtype) agonist 1-(2,5-dimethoxz-4-iodophenyl)-2aminopropane (DOI) induces head twitches and might be considered to model tics. Acute and chronic administration of donezepil, an acetylcholinesterase inhibitor, significantly reduced the DOI-induced head twitches. The nicotinic antagonist mecamylamine was also effective. The authors concluded that donepezil could have therapeutical potential in treating tics.

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6.2. Imaging studies To the best of our knowledge, no PET or SPECT studies have been performed to investigate the acetylcholine metabolism in TS patients. Appropriate radiolabeled imaging agents are just developed for the two major nicotinic acetylcholine receptor subtypes, alpha4beta2 and alpha 7 (Hillmer et al., 2013; Ogawa et al., 2009; Yin et al., 2013).

6.3. Pharmacological interventions Striatal cholinergic dysfunction might play a role in the pathophysiology of TS. Therefore, cholinesterase inhibitors such as donepezil or galantamine could be beneficial in TS treatment. Cubo et al. (2008) conducted an 18-week, single-center, dose/escalating, prospective, open-label study in which 17 males and 3 females (mean age 11 years, range 8–14 years) participated. Tics were significantly reduced in week 14 compared to baseline, but 50% of the patients withdrew mainly because of adverse events. Future controlled trials are needed to prove if cholinergic modulation is a promising avenue for managing tic disorders.

7. ROLE OF ENDOCANNABINOID Since the psychopharmacological treatment of TS is so unsatisfactory, researchers and clinicians are interested in new therapeutical strategies. High densities of cannabinoid receptors were found in the basal ganglia and hippocampus, indicating a putative functional role of cannabinoids in movement and behavior (Muller-Vahl et al., 2003). Anecdotal reports suggested beneficial effects of marijuana on TS symptoms, a preliminary study of 47 TS patients, questioned by a structured interview, provided strong evidence for significant improvement of tic symptoms after the use of marijuana (Muller-Vahl, Kolbe, & Dengler, 1997; Muller-Vahl, Kolbe, Schneider, & Emrich, 1998).

7.1. Genetic, biomarker, and postmortem studies Genetic studies investigating the cannabinoid system are rare and inconclusive. One study investigating the central cannabinoid receptor (CNR1) gene did not find an association between the gene and TS (Gadzicki et al., 2004).

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7.2. Imaging studies Berding et al. (2004) performed a SPECT study of the central cannabinoid CB1 receptor before and after Delta9-tetrahydrocannabinol therapy in six adult Tourette patients. Regions of interest were an area with high CB1 density (lentiform nuclei) and reference regions. Specific over nonspecific partition coefficients V300 were calculated. No significant differences could be detected after Delta9-THC treatment on group level. Nevertheless, the only patient who clearly showed a clinical benefit from the substance also exhibited a significantly declined V300 (Berding et al., 2004).

7.3. Pharmacological interventions Although the neurobiological basis for the involvement of the cannabinoid system in TS pathophysiology is small, there are some clinical hints that TS patients might benefit from pharmacological interventions. Two controlled trials were conducted as randomized double-blind studies. One was a single dose cross-over design and the other was a parallel group design (Curtis, Clarke, & Rickards, 2009; Mu¨ller-Vahl et al., 2002; Muller-Vahl et al., 2003). In the latter, 24 TS patients were treated for a 6-week period. Delta-9-tetrahydrocannabinol (THC) was applied in oral formulation. A significant difference was found between the THC and the placebo group without any serious AEs (Muller-Vahl et al., 2003). Only these two trials were eligible for a Cochrane Review on cannabinoids for TS (Curtis et al., 2009).

8. ROLE OF CORTICOID Tic symptoms often exacerbate during periods of fatigue, stress, or excitement (Lin et al., 2007; Silva, Munoz, Barickman, et al., 1995). In addition, adolescent TS patients experience significantly higher levels of psychosocial stress if compared to their peers (Findley, Leckman, Katsovich, et al., 2003). Therefore, the hypothalamic–pituitary–adrenocortical (HPA) axis, the major human stress response system, might be relevant in the pathophysiology of tic disorders. Stress response is mediated through a cascade of events, starting with the release of corticotropin-releasing factor (CRF) from the hypophysis. CRF binds to its receptors on the pituitary gland thus inducing the secretion of adrenocorticotropic hormone (ACTH). ACTH targets the adrenal cortex, stimulating the synthesis of the downstream effectors of the HPA axis:

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glucocorticoids (i.e., corticosterone and cortisol) (Joe¨ls & BaramJoe¨ls & Baram, 2009; Smith & Vale, 2006). Glucocorticoid and mineralocorticoid receptors are expressed throughout the brain and their activation mediate both rapid and delayed neurological effects. Corticoid membrane-bound receptors can be ion channels, second-messenger activating proteins, or neurotransmitter receptors (Haller, Mikics, & Makara, 2008). Corticoid binding to the latter can mediate a rapid effect on neurotransmission. For instance, mineralocorticoid receptors located in the presynaptic neuron in hippocampal glutamatergic synapses once activated by corticoids trigger a fast glutamate release, and thus cause an increase in cell excitability (Groeneweg, Karst, de Kloet, & Joels, 2011; Popoli, Yan, McEwen, & Sanacora, 2011). When nuclear corticoid receptors are activated they relocate into the nucleus where they bind to specific DNA sites and regulate gene expression. In this case, their action is slower but lasts longer, strengthening glutamatergic transmission (Kim, Foy, & Thompson, 1996). The enhanced excitatory transmission that characterizes chronic stress eventually lead to synaptic atrophy, dendritic retraction, or spine loss (Popoli et al., 2011; Sousa et al., 2008) and is well documented in hippocampus and prefrontal cortex (Cerqueira, Mailliet, Almeida, Jay, & Sousa, 2007; Groeneweg et al., 2011). Furthermore, corticoids act synergically with catecholamines in strengthening amygdala functions (Groeneweg et al., 2011), and their crosstalk with the endocannabinoid system can indirectly influence neurotransmission, as endocannabinoid receptors appear in glutamatergic, GABAergic, cholinergic, noradrenergic, and serotonergic synapses (Hill & Tasker, 2012; Popoli et al., 2011). Exacerbation of tic disorders following stress exposition, and thus following corticoids release, might happen as a consequence of corticoids action on neurotransmission. Dopamine, which plays a central role in TS, is known to be influenced by corticoid activity especially in the mesolimbic pathway (Erickson, Drevets, & Schulkin, 2003; Oswald et al., 2005); whether corticoids are able to alter dopaminergic function in the CSTC circuitry is still unknown. Norepinephrine is also a well-established participant in stress as it is a central regulator of glucocorticoid secretion by the adrenal cortex (Tsigos & Chrousos, 2002). Evidence suggests that it might have a role in stress-caused tics exacerbation (Chappell et al., 1994, Tsigos & Chrousos, 2002).

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8.1. Genetic, biomarker, and postmortem studies Although a relationship between stress, HPA axis, altered neurotransmission, and tic exacerbation in TS has not yet been fully proven, the few related studies so far available strongly suggest its existence. TS patients had significantly higher levels of CRF in CSF than controls (Chappell et al., 1996). They secreted significantly higher levels of ACTH compared to control subjects in response to lumbar puncture stress (Chappell et al., 1994), and Corbett, Mendoza, Baym, Bunge, and Levine (2008) investigated the reactivity of the HPA axis in children with TS and reported significantly higher cortisol levels in TS patients in response to stressors compared to healthy controls. This finding supports a model of enhanced HPA responsivity rather than reduced regulation in TS, as regulation processes in TS patients matched those of healthy controls (Corbett et al., 2008; Hoekstra, Dietrich, Edwards, Elamin, & Martino, 2013). Stress-mediated tic exacerbation in TS patients seems to be due to an altered HPA axis homeostasis that might influence neurotransmission through the action of glucocorticoids.

8.2. Pharmacological interventions No controlled clinical trials have been conducted with corticoids. Kondo and Kabasawa (1978) reported about an 11-year-old boy who developed severe vocal and motor tics following an acute infection. After ineffective treatments with diazepam, carbamazepine, and haloperidol, prednisolone was administered and tics completely disappeared. However, prednisolone treatment was also observed to worsen tics in two patients suffering from tic disorder (Dietl, Ku¨mpfel, Hinze-Selch, Trenkwalder, & Lechner, 1998). In a small case series reported from Poland (Popielarska, Kuligowska, & Mazur, 1972), four patients were treated with prednisolone and three with neuroleptics. The authors observed superior therapeutic results with prednisolone.

9. CONCLUSION The number of transmitters potentially involved in generating tics suggests that they are subjected to complex modulation (Handley & Dursun, 1993). Since the different neurotransmitter systems consist of several receptor subtypes (see Table 4.2) which might mediate different effects on locomotor activity, patients with TS may respond differentially to selective agonists or antagonists. Effects of agonistic or antagonistic compounds

Table 4.2 Neurotransmitter systems involved in the Gilles de la Tourette syndrome: Their physiological role and localization NT Postsynaptic NT name (symbol) Structure transporters NT receptors effect Function Distribution

Serotonin (5-ht)

Dopamine (DA)

Monoamine SERT

Monoamine DAT

5HT1

Excitatory

Brain, intestinal nerves Neuronal inhibition, behavioral effects, cerebral vasoconstriction

5HT2

Neuronal excitation, vasoconstriction, behavioral effects, depression, anxiety

Brain, heart, lungs, smooth muscle control, GI system, blood vessels, platelets

5HT3

Nausea, anxiety

Limbic system, peripheral neural system

5HT4

Neuronal excitation, GI

CNS, smooth muscle

5H5,6,7

Not known

Brain

Excitatory role

Brain, smooth muscle

D2

Inhibitory role

Brain, cardiovascular system, presynaptic nerve terminals

D3

Inhibitory role

Brain, cardiovascular system, presynaptic nerve terminals

D4

Inhibitory role

Brain, cardiovascular system, presynaptic nerve terminals

D5

Excitatory role

Brain, smooth muscle

D1

Excitatory

Norepinephrine (NE)

Gluatamate

Monoamine NET

Amino acids EAAT1–5

Alpha 1

Vasoconstriction, smooth muscle control

Brain, heart, smooth muscle

Alpha 2

Vasoconstriction, presynaptic effect in GI (relaxant)

Brain, pancreas, smooth muscle

Beta 1

Heart rate (increase)

Heart, brain

Beta 2

Bronchial relaxation, vasodilatation

Lungs, brain, skeletal muscle

Beta 3

Stimulation of effector cells Postsynaptic effector cells

AMPA (Ionotropic)

Excitatory

Excitatory

Fastsynaptic transmission in Brain, pre- and CNS postsynaptic nerve endings

Kainate (Ionotropic)

Postsynaptic excitation, presynaptic release of GABA

Brain, pre- and postsynaptic nerve endings

NMDA (Ionobotropic)

Synaptic plasticity and memory function, longterm potentiation

Brain, pre- and postsynaptic nerve endings, extrasynaptic

mGluR (Metabotropic)

Neuronal excitation and fine tuning of NMDARmediated signals

Brain, pre- and postsynaptic nerve endings Continued

Table 4.2 Neurotransmitter systems involved in the Gilles de la Tourette syndrome: Their physiological role and localization—cont'd NT Postsynaptic NT name (symbol) Structure transporters NT receptors effect Function Distribution

GABA

Acetylcholine

Amino acids GAT 1–4

Ester

VAChT

GABAa (Ionotropic)

Inhibitory and excitatory

Inhibition of neuronal activity by hyperpolarizing resting membrane potential, during brain development GABAa receptors have excitatory properties

Brain, pre- and postsynaptic nerve endings, extrasynaptic, endocrine tissue

GABAb Inhibitory (Metabotropic)

Brain, pre- and Inhibition of neuronal activity by hyperpolarizing postsynaptic nerve resting membrane potential endings, pancreas

M1

CNS excitation, gastric acid secretion

Excitatory

Nerves

M2

Cardiac inhibition, neural Heart, nerves, smooth inhibition muscle

M3

Smooth, muscle contraction, vasodilation

Glands, smooth muscle, endothelium

M4

Not known

Brain, salivary glands, iris/ciliary muscle

M5

Not known

Skeletal muscles neuromuscular junction

NM

Neuromuscular transmission

Skeletal muscles neuromuscular junction

NN

Ganglionic transmission

Postganglionic cell body dendrites

Histamine

Endocannabinoids

Monoamine

H1

Excitatory

Smooth muscle, Bronchoconstriction, endothelium, and CNS vasodilation, allergies, motion, sleep, and appetite suppression

H2

Vasodilatation and gastric acid secretion

H3

Decrease neurotransmitter CNS and to a lesser release extent in peripheral nervous system

H4

Chemotaxis

CB1

CB2

Inhibitory

Parietal cells and vascular smooth muscle cells

Basophils, bone marrow, thymus, small intestine, spleen, and colon

Brain Sympathetic innervation inhibition of blood vessels and suppression of neurogenic vasopressin response Antinociception, relief of pain

B and T cells, macrophages, hematopoietic cells, nerve terms and microglial cells

GPRs Continued

Table 4.2 Neurotransmitter systems involved in the Gilles de la Tourette syndrome: Their physiological role and localization—cont'd NT Postsynaptic NT name (symbol) Structure transporters NT receptors effect Function Distribution

Corticoids

Oxytocin

Steroid hormone

Peptide hormone

GRa

Stress response, immune response, regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior

Excitatory

Brain Reproduction, social recognition, pair bonding, anxiety, and maternal behaviors

GRb

OXTR

Immunoresponse system

Inhibitory

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on tic symptoms might also be dose dependent. Higher doses of an effective drug at low dosage might not lead to increased tic suppression but to the contrary. Since neurotransmitter receptors are highly plastic and are subject to a turnover whose rate might be influenced by various factors (age, maturation, endogene neurotransmitter concentration, psychopharmacological substances, other epigenetic factors), initially effective drugs might lose their effectiveness and might even lead to an opposite effect. The knowledge about the interplay of the many different neurotransmitters is just at the beginning. Especially the advancement in PET and SPECT radioligands will lead to better understanding and finally to the development of a more selective pharmacological treatment with less AEs.

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Nondopaminergic neurotransmission in the pathophysiology of Tourette syndrome.

A major pathophysiological role for the dopaminergic system in Tourette's syndrome (TS) has been presumed ever since the discovery that dopamine-recep...
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