Dysregulated 5-HT2A receptor binding in postmortem frontal cortex of schizophrenic subjects

Previous postmortem and neuroimaging studies have repeatedly suggested alterations in serotonin 5-HT_2A receptor (5-HT_2AR) binding associated with the pathophysiology of schizophrenia. These studies were performed with ligands, such as ketanserin, altanserin and LSD, that may bind with high-affinity to different structural or functional conformations of the 5-HT_2AR. Interpretation of results may also be confounded by chronic antipsychotic treatment and suicidal behavior in the schizophrenia group. We quantified 5-HT_2AR density by radioligand binding assays in postmortem prefrontal cortex of antipsychotic-free (n=29) and antipsychotic-treated (n=16) schizophrenics, suicide victims with other psychiatric diagnoses (n=13), and individually matched controls. [³H]Ketanserin binding, and its displacement by altanserin or the LSD-like agonist DOI, was assayed. Results indicate that the number of [³H]ketanserin binding sites to the 5-HT_2AR was increased in antipsychotic-free (128±11%), but not in antipsychotic-treated (92±12%), schizophrenic subjects. In suicide victims, [³H]ketanserin binding did not differ as compared to controls. Aging correlated negatively with [³H]ketanserin binding in schizophrenia, suicide victims and controls. The fraction of high-affinity sites of DOI displacing [³H]ketanserin binding to the 5-HT_2AR was increased in antipsychotic-free schizophrenic subjects. Functional uncoupling of heterotrimeric G proteins led to increased fraction of high-affinity sites of altanserin displacing [³H]ketanserin binding to the 5-HT_2AR in schizophrenic subjects, but not in controls. Together, these results suggest that the active conformation of the 5-HT_2AR is up-regulated in prefrontal cortex of antipsychotic-free schizophrenic subjects, and may provide a pharmacological explanation for discordant findings previously obtained.     

Regulation of 5-HT(2A) receptor mRNA levels and binding sites in rat frontal cortex by the agonist DOI and the antagonist mianserin

In the present study we have characterized the time course of effect of administration of the serotonin(2) (5-HT(2)) receptor antagonist mianserin, or the 5-HT(2) receptor agonist (+/-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), on 5-HT(2A) receptor binding sites and mRNA levels in rat frontal cortex. Radioligand binding and ribonuclease protection assays were performed with separate hemispheres of frontal cortex from each animal to examine concomitant changes in 5-HT(2A) receptor sites and mRNA levels. The decrease in cortical 5-HT(2A) receptor sites in response to chronic DOI administration was not accompanied by changes in 5-HT(2A) receptor mRNA. A single injection of DOI produced a transient decrease in 5-HT(2A) receptor mRNA levels detected 1 h post-injection. The density of 5-HT(2A) receptor sites, however, was not significantly reduced following a single injection of DOI. The down-regulation of cortical 5-HT(2A) receptor sites in response to a single injection of mianserin was accompanied by reductions in 5-HT(2A) receptor mRNA levels. Following 4 days of mianserin administration, however, we did not observe a change in 5-HT(2A) receptor mRNA levels, although 5-HT(2A) receptor density was decreased. Thus, changes in receptor mRNA may initially contribute to the down-regulation of 5-HT(2A) receptors in response to acute mianserin administration. Sustained changes in 5-HT(2A) receptor mRNA, however, appear not to be involved in maintaining the down-regulation of 5-HT(2A) receptor number with chronic mianserin administration. Mechanisms other than the regulation of receptor mRNA levels appear to underlie the down-regulation of 5-HT(2A) receptor sites in response to chronic administration of the agonist DOI.     

Identity of inhibitory presynaptic 5-hydroxytryptamine (5-HT) autoreceptors in the rat brain cortex with 5-HT1B binding sites

In rat brain cortex slices preincubated with [3H]5-HT, the potencies of 17 5-HT receptor agonists to inhibit the electrically evoked 3H overflow and the affinities of 13 antagonists (including several beta-adrenoceptor blocking agents) to antagonize competitively the inhibitory effect of unlabelled 5-HT on evoked 3H overflow were determined. The affinities of the compounds for 5-HT1B and 5-HT2 binding sites in rat brain cortex membranes (labelled by [125I]cyanopindolol = [125I]-CYP in the presence of 30 mumol/l isoprenaline and [3H]ketanserin, respectively), for 5-HT1A binding sites in pig and rat brain cortex membranes (labelled by [3H]8-hydroxy-2-(di-n-propylamino)tetralin = [3H]8-OH-DPAT) and for 5-HT1C binding sites in pig choroid plexus membranes (labelled by [3H]mesulergine) were also determined. The affinities of the drugs for the various 5-HT recognition sites ranged over 4-5 log units (the functional experiments revealed the same range of differences between the drugs). There were no significant correlations between the affinities of the drugs at 5-HT1C and 5-HT2 binding sites and their potencies or affinities, determined for the 5-HT autoreceptors. In contrast, significant correlations were found between the potencies or affinities of the drugs for the autoreceptors and their affinities at 5-HT1A or 5-HT1B binding sites; the best correlations were obtained with the 5-HT1B binding site. Some of the drugs investigated were not included in the correlation since their agonistic or antagonistic effects on the autoreceptors were weak and pEC30 or apparent pA2 values could not be determined (less than 5.5).(ABSTRACT TRUNCATED AT 250 WORDS)     

5-HT2 receptor characteristics in frontal cortex and 5-HT2 receptor-mediated head-twitch behaviour following antidepressant treatment to mice.

The effects of repeated administration of antidepressant drugs or electroconvulsive shock on the binding of [3H]-spiperone to the 5-hydroxytryptamine 2 (5-HT2) receptor in mouse frontal cortex and the 5-HT-mediated head-twitch response have been examined. Repeated electroconvulsive shock increased both the head-twitch response and the number of 5-HT2 binding sites (Bmax). After 35 d but not 24 h or 14 d oral tranylcypromine (5.6 mg kg-1 per day) there was a marked decrease in both the behavioural response and the number of 5-HT2 receptors. Repeated oral doses of zimeldine (20 mg kg-1 per day, 14 days) also decreased the head-twitch response and the number of 5-HT2 binding sites and these effects persisted after 48 h withdrawal. Oral mianserin (2.1 mg kg-1 per day, 14 days) decreased both the behaviour and the number of 5-HT2 binding sites, but this change was also seen after acute (1 day) administration. After 48 h withdrawal from chronic treatment the head-twitch response was still decreased but the Bmax had returned to control values. Desipramine given orally (27 mg kg-1 per day, 14 days) decreased both the behaviour and number of 5-HT2 binding sites. After 48 h withdrawal, binding was still decreased but the head-twitch response was enhanced above control values. In contrast to repeated electroconvulsive shock (ECS), all drugs decreased both 5-HT2 binding and the head-twitch response, while the mice were still on treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hippocampal NMDA/phencyclidine receptor binding sites are reduced following forebrain ischaemia in the gerbil

The binding of [3H]N-(1-[2-thienyl]cyclohexyl)piperidine (TCP) to N-methyl-D-aspartate (NMDA) receptor sites in synaptic membranes prepared from the dorsal hippocampus of the ischaemic gerbil, has been studied. Forebrain ischaemia was induced by 10 min bilateral carotid occlusion and receptor binding determined in the dorsal hippocampus 1 week later. [3H]TCP binding capacity was significantly reduced by 28% in ischaemic tissue with no change in affinity. This result is consistent with the involvement of NMDA receptors in ischaemic brain damage.     

The administration of baclofen to mice increases 5-HT2-mediated head-twitch behaviour and 5-HT2 receptor number in frontal cortex

Mice were injected with baclofen (10 mg/kg) and then given baclofen in drinking water (10 mg/kg/day). After 1 day of administration of baclofen the head-twitch response to the precursor 5-hydroxytryptophan (5-HTP) was reduced but the response to the agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) was unaltered. However, after 14 days the head-twitch response to both 5-HTP and 5-MeODMT was enhanced and this enhancement was present for 14 days after drug withdrawal. After 14 days of administration of baclofen the number of 5-HT2 receptor binding sites in frontal cortex (labelled by [3H]-ketanserin) was also elevated. It is suggested that the enhanced 5-HT2 function, following longer-term administration of baclofen is the consequence of the drug inhibiting 5-HT release in vivo, as indicated by the observations after acute administration.     

Chronic administration of buspirone down-regulates 5-HT2 receptor binding sites

Buspirone (BuSpar®), a clinically effective anxiolytic, has been found in clinical trials to produce effects which suggest antidepressant efficacy. As antidepressants down-regulate type 2 serotonin (5-HT₂) receptors when given chronically to laboratory animals, we investigated whether buspirone would have similar effects; the possibility that chronic buspirone administration would affect β-adrenergic, D-2 dopaminergic, and γ-aminobutyric acid (GABA) receptor binding was also investigated. When chronically administered in a regimen which reflected activity in an animal model of anxiety, buspirone produced significant decreases in in vitro 5-HT₂ and β-adrenergic receptor binding but was without effect on D-2 dopaminergic of GABAergic binding. Ligand saturation experiments revealed that the decrease in 5-HT₂ binding was due to a decrease in the maximal concentration of binding sites. These data demonstrate that chronic administration of buspirone to animals produces effects which suggest the potential for antidepressant efficacy in clinical use.     

Pharmacokinetic-pharmacodynamic modelling of fluvoxamine 5-HT transporter occupancy in rat frontal cortex

BACKGROUND AND PURPOSE: The pharmacokinetic-pharmacodynamic (PK-PD) correlation of fluvoxamine 5-HT transporter (SERT) occupancy was determined in rat frontal cortex ex vivo. EXPERIMENTAL APPROACH: Rats (n=47) with permanent arterial and venous cannulas received a 30 min intravenous infusion of fluvoxamine (1 or 7.3 mg kg(-1)). At various time points after dosing, brains were collected for determination of fluvoxamine concentration and SERT occupancy. In addition, the time course of fluvoxamine concentration in plasma was determined up to the time of brain collection. In a separate study (n=26), the time course of fluvoxamine concentration in brain extracellular fluid (ECF) and plasma was determined. The results of the investigations were interpreted by nonlinear mixed effects modeling. KEY RESULTS: Highest SERT occupancy was reached at the first time point (10 or 15 min) and maintained for 1.5 and 7 h after 1 and 7.3 mg kg(-1), respectively. Thereafter, SERT occupancy decreased linearly at a rate of 8% h(-1). SERT occupancy could be directly related to plasma, brain ECF and brain tissue concentrations by a hyperbolic function (Bmax model). Maximal SERT occupancy (Bmax) was 95%. Estimated concentrations at half-maximal SERT occupancy (EC50) in plasma, ECF and brain tissue were 0.48, 0.22 and 14.8 ng mL(-1) respectively. The minimum value of the objective function decreased 12 points for ECF and brain tissue concentrations relative to plasma (P<0.01), presumably as a result of nonlinear brain distribution. CONCLUSIONS AND IMPLICATIONS: The proposed PK-PD model constitutes a useful basis for prediction of the time course of ex vivo SERT occupancy in behavioural studies with selective serotonin reuptake inhibitors.     

Brain 5-HT1 binding sites in depressed suicides

5-HT₁ and 5-HT_1A binding sites were measured in brain tissue obtained at postmortem from 19 suicides, with definite evidence of depression, and 19 sex and age-matched controls. Thirteen of the depressed suicides had not been prescribed psychoactive drugs recently (drug-free suicides); six had been receiving antidepressant drugs, alone or in combination with other drugs (antidepressant-treated suicides). No significant differences were found in the number or affinity of 5-HT₁ and 5-HT_1A binding sites in frontal or temporal cortex between drug-free suicides and controls. The number of 5-HT₁ sites was significantly lower (by 20%), affinity unaltered, in hippocampus and the affinity significantly lower (by 33%), number unaltered, in amygdala of drug-free suicides than controls. The number of 5-HT₁ binding sites tended to be higher and the affinity lower in the antidepressant-treated compared to drug-free suicides, and significantly so in hippocampus. The present results, together with our previous studies, provide no evidence of altered cortical 5-HT markers in depressed suicides, but further emphasise abnormalities in the hippocampus.     

The effects of the peptide-coupling agent, EEDQ, on 5-HT2A receptor binding and function in rat frontal cortex.

This ex vivo study in rat frontal cortex determined the influence of 5-HT receptor agonists and antagonists on EEDQ-induced depletion of 5-HT2A binding sites and reduction in their functional coupling to phospholipid hydrolysis. Twenty-four hours after EEDQ (6 mg/kg) administration a marked reduction (66%) of cortical 5-HT2A binding sites with no change in binding affinity was observed. The 5HT2A antagonists ritanserin (1 mg/kg), ketanserin (1 and 5 mg/kg), metergoline (3 mg/kg) or the 5HT2A agonist, DOI (3 and 10 mg/kg) also significantly reduced (by 15-44%) these binding sites 24 h after injection. Thirty minute pretreatment with ritanserin, ketanserin, metergoline or DOI (at the doses above) afforded 49-65% protection against the loss of 5-HT2A binding sites induced by EEDQ (6 mg/kg). DOI (10 mg/kg) pretreatment (-24 h) decreased by 26% the accumulation of [3H]inositol phosphates (IPs) evoked by 5-HT (100 microM), but did not affect that produced by DOI (100 microM). Ketanserin (5 mg/kg, -24 h) decreased 5-HT- and DOI-induced IP formation by 65% and 53%, respectively. The EEDQ (6 mg/kg, -24 h)-evoked reductions (-50%) of 5-HT- and DOI-induced IP formation were not altered by DOI (10 mg/kg) or ketanserin (5 mg/kg) given 30 min before EEDQ. G-protein-stimulated IP accumulation was unaffected by EEDQ (6 mg/kg). Overall, EEDQ reduces 5-HT2A binding sites and function in rat frontal cortex, whereas its effects on binding were attenuated by various 5-HT receptor antagonists and agonists, its effects on function was unaltered by these drugs.     

Clonazepam-induced up-regulation of serotonin1 binding sites in frontal cortex of rat

Chronic administration of the benzodiazepine, clonazepam, increased the number of [3H]5-hydroxytryptamine (5-HT1) binding sites in the frontal cortex of the rat. The increase reflected a change in the maximum density of binding sites (Bmax) with no change in ligand affinity (Kd). Increased binding occurred after continued exposure (10 days) to large (5.0 mg/kg) doses of clonazepam. The changes in [3H]5-HT binding were regional in that they occurred in membranes from the frontal cortex but not the brainstem. The effects were also at least partially selective for 5-HT receptors since the binding of the beta-adrenergic radioligand, [3H]dihydroalprenolol, was not affected by clonazepam. A second benzodiazepine, diazepam, did not affect the binding of [3H]5-HT at doses of 30 mg/kg per day. The latter data suggest that the effects of benzodiazepines on serotonin 5-HT1 receptors are unique to clonazepam.     

5-HT1A and 5-HT2 receptors mediate discrete behaviors in the Mongolian gerbil.

Although the ability of agonists at specific serotonin (5-HT) receptor subtypes to induce distinct behaviors has been well documented in the rat, similar studies have not been reported in the Mongolian gerbil. We have found that the 5-HT1A/5-HT2 agonist 5-methoxy,N-N dimethyltryptamine (5-MeODMT) (0.5-8 mg/kg, SC), the specific 5-HT1A agonist 8-hydroxy(di-n-propylamino)tetralin (8-OH-DPAT) (0.125-16 mg/kg, SC), and the 5-HT precursor L-5-hydroxytryptophan (L-5-HTP) (100-250 mg/kg, SC) all elicit a 5-HT syndrome in the gerbil. This syndrome, analogous to the 5-HT syndrome in the rat, consists of reciprocal forepaw treading (RFT), hindleg abduction (HA), body tremors (BT), and Straub tail (ST). The putative 5-HT1A antagonist NAN-190 (0.25-8 mg/kg, SC) when dosed 15 min prior to either 5-MeODMT (4 mg/kg, SC) or 8-OH-DPAT (16 mg/kg, SC) blocked both RFT and HA in a dose-dependent manner, suggesting these 5-HT syndrome behaviors are mediated via 5-HT1A receptor activation. We also identified a unique, dose-responsive behavior in the gerbil, induced selectively by 5-HT1A agonists such as quipazine (2-16 mg/kg, SC) and (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.125-8 mg/kg, SC). This reciprocal hindleg body scratch (RHBS) behavior is dose dependently inhibited by pretreatment with the selective 5-HT2 antagonist ritanserin (0.0125-0.2 mg/kg, SC). RHBS behavior is also potently inhibited by pretreatment with the selective 5-HT1A agonist 8-OH-DPAT (0.005-0.04 mg/kg, SC), demonstrating a 5-HT1A/5-HT2 receptor subtype interaction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Regulation by 5-HT1A receptors of the in vivo release of 5-HT and DA in mouse frontal cortex

This study examines the effects of serotonin (5-HT)_1A receptor ligands on the in vivo release of 5-HT and dopamine (DA) in the prefrontal cortex of mice. Oral MKC-242 and 8-OH-DPAT, selective 5-HT_1A receptor agonists, decreased cortical 5-HT release at low and high doses, while the receptor agonists increased cortical DA release only at a high dose. Local application of the selective 5-HT_1A receptor antagonist, WAY100635, via a dialysis probe, antagonized oral MKC-242-induced increase in cortical DA release, but did not affect the decrease in cortical 5-HT release. Local application of 8-OH-DPAT at 100 and 300 nM via a dialysis probe increased cortical DA release, but did not affect cortical 5-HT release. The effects of oral MKC-242 and 8-OH-DPAT on 5-HT release were blocked by low and high doses of WAY100635, while blocking the agonist-induced increase in DA release required a high dose of WAY100635. These results suggest that 5-HT release and DA release in the frontal cortex of mice are regulated by pre- and postsynaptic 5-H_1A receptors, respectively, and that the presynaptic 5-HT_1A receptor-mediated response is more sensitive to inhibition by WAY100635 than the postsynaptic 5-HT_1A receptor-mediated response in mice.     

5-HT1B and 5-HT2 serotonin binding sites in cultured Wistar-Kyoto rat aortic smooth muscle cells

We studied [3H]serotonin [( 3H]5-HT) binding on cultured arterial smooth muscle cells from rat aorta. We found a high and low affinity binding site. Binding to the higher affinity site could be displaced by drugs in an order corresponding most closely with the 5-HT1B subtype, and high affinity [125I]iodo-cyanopindolol binding was also found. We found evidence for a 5-HT2 subtype using [3H]ketanserin binding, with similar results whether specific binding was determined using unlabelled ketanserin, methysergide or mianserin.     

Effect of ACTH,adrenalectomy and the combination treatment on the density of 5-HT2 receptor binding sites in neocortex of rat forebrain and 5-HT2 receptor-mediated wet-dog shake behaviors

The effect of ACTH and/or adrenalectomy on serotonin (5-HT)₂ receptor binding sites was evaluated in the neocortex of rat forebrain. One day after the adrenalectomy or sham operation, ACTH (50 µg/day) was injected subcutaneously into adult male SD rats for 10 consecutive days. Saturation analysis showed that subchronic ACTH treatment significantly increased the B_max values for³H-ketanserin binding without any change in the K_d values. Moreover, this ACTH-induced increase in the B_max values was prevented by adrenalectomy. The concentrations of 5-HT and 5-hydroxyindole acetic acid (5-HIAA) measured by HPLC-ECD were not altered by these manipulations. Ten-day administration of corticosterone (20 and 50 mg/kg) also increased 5-HT₂ receptor density in the neocortex of rat forebrain. 5-HT₂ (and 5-HT_1C) receptor agonist, (±)DOI-induced wet-dog shakes in ACTH and/or adrenalectomy-treated rats were also examined. Ten-day administration of ACTH enhanced (±)DOI-induced wet-dog shakes and this increase was prevented by adrenalectomy. These results indicate that subchronic adrenocorticotropinadrenal axis activation of rats increases both the number of 5-HT₂ receptors in neocortex of forebrain and the wet-dog shake responses induced by (±)DOI.     

3H]MK-801 binding sites in post-mortem human frontal cortex

The binding of [3H]MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate) was investigated in extensively washed homogenates of post-mortem human frontal cortex. The association of [3H]MK-801 proceeded slowly (t1/2 = 553 min) and reached equilibrium only after a prolonged incubation (greater than 24 h). The dissociation of [3H]MK-801 from the binding site was also slow (t1/2 = 244 min). Glutamate, glycine and magnesium markedly increased the rate of association (t1/2 = 14.8 min) and dissociation (t1/2 = 36.5 min). At equilibrium, the binding was not altered by these substances. Specific binding was linear with protein concentration, was saturable, reversible, stereoselective, heat-labile and was nearly absent in the white matter. Scatchard analysis of the saturation curves obtained at equilibrium indicated that there was a high-affinity (Kd1 1.39 +/- 0.21 nM, Bmax1 0.483 +/- 0.084 pmol/mg protein) and a low-affinity (Kd2 116.25 +/- 50.79 nM, Bmax2 3.251 +/- 0.991 pmol/mg protein) binding site. All competition curves obtained with (+)-MK-801, (-)-MK-801, phencyclidine and ketamine had Hill coefficients of less than unity and were best explained by a two-site model. Thus, our results demonstrate the presence of binding sites for MK-801 in post-mortem human brains and provide evidence for binding site heterogeneity. Furthermore, glutamate, glycine and magnesium accelerate the association and dissociation of [3H]MK-801 to and from its binding sites. The results add support to the hypothesis that MK-801, glutamate, glycine and magnesium all bind to different sites on the NMDA receptor-ion channel complex.     

Effects of a selective 5-HT2 agonist, DOI, on 5-HT neuronal firing in the dorsal raphe nucleus and 5-HT release and metabolism in the frontal cortex.

Systemic administration of the 5-HT2 agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (50 and 100 micrograms kg-1, i.v.) inhibited dorsal raphe neuronal firing. DOI (100 micrograms kg-1, i.v.) also produced a decrease in extracellular 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in the frontal cortex measured by microdialysis. However, local administration of DOI into the frontal cortex produced no change in extracellular 5-HT and 5-HIAA at any dose given (1, 10 and 100ng). The results demonstrate that DOI is a potent inhibitor of 5-HT neuronal firing and terminal release and that the effects on release are not mediated by an action within the terminal region. The site of action and the receptor involved in the inhibition remains to be determined.     

Irreversible blockade of central 5-HT binding sites by 8-methoxy-2'-chloro-PAT

We have synthesized 8-methoxy-2-(N-2'-chloropropyl, N-propyl) aminotetralin (8-methoxy-2'-chloro-PAT), an alkylating agent derived from the potent 5-HT agonist, 8-hydroxy-2-(N,N-dipropyl)-aminotetralin (PAT). As expected for an irreversible ligand, the blockade of 3H-PAT or 3H-5-HT binding to post-synaptic 5-HT1 (A and B) sites in rat hippocampal membranes pretreated with 8-methoxy-2'-chloro-PAT could not be prevented by extensive washing of membranes. Prior occupancy of 5-HT1 sites by 5-HT or PAT prevented any subsequent irreversible blockade by the alkylating agent. Similar irreversible blockade by 8-methoxy-2'-chloro-PAT was found on 3H-PAT binding to striatal membranes suggesting that presynaptic 5-HT binding sites (see Gozlan et al., Nature, Lond. 305, 140, 1983) were sensitive also to the alkylating agent. In contrast, the modifying agent N-ethylmaleimide (NEM) reduced markedly 3H-PAT binding to postsynaptic hippocampal 5-HT1 sites, but did not alter 3H-PAT binding to striatal presynaptic 5-HT sites. Although 8-methoxy-2'-chloro-PAT bound irreversibly to different classes of 5-HT binding sites (5-HT1A, 5-HT1B, presynaptic sites), it can be considered a selective alkylating agent, since it exerted no action on 3H-spiperone binding to 5-HT2 sites, 3H-muscimol binding to GABA sites, or 3H-flunitrazepam binding to benzodiazepine sites.     

Cerebral 5-HT2A receptor binding is increased in patients with Tourette's syndrome

Experimental and clinical data have suggested that abnormalities in the serotonergic neurotransmissions in frontal-subcortical circuits are involved in Tourette's syndrome. To test the hypothesis that the brain's 5-HT2A receptor binding is increased in patients with Tourette's syndrome, PET imaging was performed. Twenty adults with Tourette's syndrome and 20 healthy control subjects were investigated with PET-[18F]altanserin using a bolus-infusion protocol. Regions of interest were delineated automatically on co-registered MRI images, and partial volume-corrected binding parameters were extracted from the PET images. Comparison between control subjects and Tourette's syndrome patients showed increased specific [18F]altanserin binding, not only in the a-priori selected brain regions hypothesized to be involved in Tourette's syndrome, but also post-hoc analysis showed a global up-regulation when testing for a overall difference with a randomization test (p<0.03). Increased 5-HT2A receptor binding was found not only in regions closely related to subcortical regions in patients with Tourette's syndrome, but also in most other brain regions. Our data suggest that the serotonergic transmitter system is pathophysiologically involved in Tourette's syndrome and that a clinical trial with 5-HT2A receptor antagonists may be justified.