5-HT1A Binding Research Articles

Use of LC/MS to assess brain tracer distribution in preclinical, in vivo receptor occupancy studies: Dopamine D2, serotonin 2A and NK-1 receptors as examples

High performance liquid chromatography combined with either single quad or triple quad mass spectral detectors (LC/MS) was used to measure the brain distribution of receptor occupancy tracers targeting dopamine D2, serotonin 5-HT2A and neurokinin NK-1 receptors using the ligands raclopride, MDL-100907 and GR205171, respectively. All three non-radiolabeled tracer molecules were easily detectable in discrete rat brain areas after intravenous doses of 3, 3 and 30 μg/kg, respectively. These levels showed a differential brain distribution caused by differences in receptor density, as demonstrated by the observation that pretreatment with compounds that occupy these receptors reduced this differential distribution in a dose-dependent manner. Intravenous, subcutaneous and oral dose–occupancy curves were generated for haloperidol at the dopamine D2 receptor as were oral curves for the antipsychotic drugs olanzapine and clozapine. In vivo dose–occupancy curves were also generated for orally administered clozapine, olanzapine and haloperidol at the cortical 5-HT2A binding site. In vivo occupancy at the striatal neurokinin NK-1 binding site by various doses of orally administered MK-869 was also measured. Our results demonstrate the utility of LC/MS to quantify tracer distribution in preclinical brain receptor occupancy studies.

Brain Serotonin 1A Receptor Binding in Major Depression Is Related to Psychic and Somatic Anxiety

The anxious phenotype of the 5-HT1A receptor knockout mouse and the anxiolytic properties of 5-HT1A agonists suggest that the 5-HT1A receptor modulates anxiety. We investigated the relationship of anxiety expressed in major depressive disorder (MDD) to regional 5-HT1A binding. Positron emission tomography with [carbonyl-11C]WAY-100635 was used to estimate regional 5-HT1A binding potential (BP) in 28 medication-free MDD subjects. Stepwise linear regression assessed the predictive capacity of three anxiety components, derived from a larger MDD sample and termed psychic, somatic, and motoric anxiety, on regional 5-HT1A BP. Higher psychic (beta >or= .63) and lower somatic (beta <or= -.70) anxiety predicted over 50% of the variance in 5-HT1A BP in multiple cortical regions, but not in amygdala, hippocampus, or autoreceptors of the raphe nuclei. The psychic and somatic anxiety components were not related to depression severity. Comorbid panic disorder was associated with lower cortical and subcortical 5-HT1A BP. The 5-HT1A receptor in the same brain regions has different relationships to psychic anxiety versus somatic anxiety. Lower 5-HT1A BP in panic disorder may be accounted for by higher somatic and lower psychic anxiety. Further study of the pathobiology of these anxiety components may identify distinct therapeutic targets or mechanisms.

Differential effects of paroxetine on raphe and cortical 5-HT1A binding: A PET study in monkeys

Positron emission tomography (PET) ligands that are sensitive to transient changes in serotonin (5-HT) concentration are desirable for studies of neuropsychiatric diseases. Few studies, however, have sought to demonstrate that variations in 5-HT concentration can be closely tracked with available serotonergic ligands. Microdialysis studies in rats have shown a maximal increase in 5-HT concentration in raphe nuclei after systemic infusion of selective serotonergic re-uptake inhibitors (SSRIs). We performed PET scans with [18F]FPWAY, an intermediate-affinity antagonist of 5-HT1A receptors, in 4 anesthetized rhesus monkeys in control studies and after systemic paroxetine administration (5 mg/kg, i.v.). In addition, a paired [11C]DASB study revealed that this paroxetine regimen produced an occupancy of 54–83% of the serotonin transporters. According to the conventional receptor competition model, increased 5-HT concentration produces decreased binding of the radioactive ligand. Over a 3-h period following paroxetine infusion, a progressively increasing reduction (ranging from 8 ± 6% to 27 ± 10%) of [18F]FPWAY-specific binding was found in the raphe nuclei. This result is interpreted as an SSRI-induced increase in 5-HT concentration, potentially combined with reduced binding to internalized 5-HT1A receptors. In addition, a transient (1 h) increase in cerebral cortical binding was observed, attributed primarily to a reduction in cortical 5-HT due to the effects of raphe autoreceptor inhibition. This study is the first demonstration of the feasibility of quantifying dynamic changes in 5-HT neurotransmission in the raphe and the cortex with PET. These results lend promise to the use of these serotonergic neuroimaging techniques to study neuropsychiatric disorders.

Differences of cortical 5-HT 2A receptor binding index with SPECT in subtypes of anorexia nervosa: Relationship with personality traits?

Using single photon emission computed tomography and the 5-HT2A receptor antagonist, 123I-5-I-R91150, we explored differences in 5-HT2A binding index in anorexia nervosa patients with and without bulimic features. We also searched for associations between temperament dimensions and cortical 5-HT2) binding. About 9 restrictive and 7 bulimic anorexia nervosa patients were examined and cortical 123I-5-I-R91150 binding index values were compared between the two subgroups. Open explorative correlation analysis was used to examine any relationships between binding index values and temperament scores, as assessed with the Temperament and Character Inventory. 5-HT2A binding index was significantly reduced in the parietal cortex in bulimic anorexia nervosa patients in comparison with restrictive anorectics. Further, a positive correlation was documented between reward dependence and parietal 5-HT2A binding index across patients in the two subgroups. Restrictive anorexia nervosa patients differ from binging/purging anorexia nervosa patients on the basis of a reduced parietal 5-HT2A binding index in the latter. We speculate that the finding of a positive correlation between parietal 5-HT2A binding and reward dependence might reflect an association between these two variables, at least in anorexia nervosa patients.

11C]-WAY100635 PET demonstrates marked 5-HT1A receptor changes in sporadic ALS

The pathogenesis of amyotrophic lateral sclerosis (ALS) remains obscure, but it is now clear that neuronal loss is not confined to the motor cortex, even in cases without dementia. A reliable method of assessing cortical involvement in vivo remains elusive. WAY100635 binds selectively to the 5-hydroxytryptamine (5-HT1A) receptor, which is expressed on pyramidal neurones present throughout the cortex. [11C]-WAY100635 PET is, therefore, a potential marker of cerebral neuronal loss or dysfunction in ALS. Twenty-one ALS subjects and 19 healthy volunteers underwent [11C]-WAY100635 PET of the brain. A cortical template consisting of multiple volumes of interest (VOI) was applied to each individual's [11C]-WAY100635 binding potential (BP) image to determine the regional reduction in binding in ALS patients compared to controls. There was a marked reduction (21%) in both the global cortical and raphe BP of [11C]-WAY100635 in ALS patients (P < 0.001), with regional variations in the VOI analysis that ranged from 16% to 29% decrease compared with the control group, and trends to greater reductions in those with bulbar involvement. To clarify the significance of the global cortical reductions, statistical parametric mapping was used as an alternative method to identify the cortical regions with the most significant decreases in [11C]-WAY100635 binding. SPM analysis revealed the greatest differences between ALS cases and controls in frontotemporal regions, cingulate and lateral precentral gyri. The reductions in cortical [11C]-WAY100635 binding were not related to depression, riluzole or other drug use. We postulate that the reduction of 5-HT1A binding represents loss of, or damage to, neurones bearing these receptors although we cannot exclude the possibility that these reductions reflect alterations in receptor expression or function. Further investigation into the role of the 5-HT1A receptor and the potential of [11C]-WAY100635 PET as a marker of cortical dysfunction in ALS is warranted.

Association of serotonin 5-HT2A receptor binding and the T102C polymorphism in depressed and healthy Caucasian subjects.

Serotonin 5-HT2A receptor (5-HT2A) binding is reported to be altered in individuals with suicidal behavior, mood disorders, and aggressive-impulsive traits. Genetic association with major depression, suicidal behavior, and aggressive-impulsive traits has not been established. This study examines the possible association of the 5-HT2A gene C102T polymorphism with the receptor binding kinetics, and clinical overt phenotypes. The study population included 63 healthy volunteers and 152 subjects with mood disorders, 56 of whom had a history of suicide attempts. All were Caucasian. Platelet 5-HT2A binding kinetics (Bmax and KD) were assayed and adjusted for seasonal variation. All subjects were genotyped for the T102C polymorphism. Clinical phenotype was determined by structured clinical interview. The TT genotype was associated with higher Bmax in all subjects (F=3.53, df=2,211; p=0.03), controlling for diagnosis. Bonferroni-adjusted post hoc testing showed higher binding in the TT compared with TC genotype in the control group (F=7.56, df=2,60, p=0.001), but not in the mood-disordered subjects. No difference was found in genotype and allele distribution between the mood-disordered subjects, with and without suicide attempt history, and controls. Bmax was not related to a diagnosis of mood disorders. The TT genotype appears associated with higher platelet 5-HT2A Bmax in the healthy population, but this genotypic effect appears absent in mood disorders and unrelated to psychopathology.

Human 5-HT1A receptor C(-1019)G polymorphism and psychopathology.

Dysfunction of the serotonin (5-HT1A) receptor (5-HTR1A) has been implicated in mood disorders, anxiety disorders, psychosis and the action of antidepressants. A common C(-1018)G [C(-1019)G] functional polymorphism in the promoter region of the human 5-HT1A receptor gene has been reported, which may be useful in identifying psychopathology associated with altered function of the human 5-HT1A receptor. We studied the relationship of this polymorphism to psychopathology and 5-HT1A binding in prefrontal cortex. The 5-HT1A receptor genotype for the C(-1019)G polymorphism was typed in 696 unrelated psychiatric subjects, 107 unrelated healthy volunteers, and in post-mortem brain samples from 241 cases. 5-HT1A receptor binding was assayed in post-mortem prefrontal cortex using [3H]8-OH-DPAT, and specific binding determined by 1 microM 5-HT. An association of genotype distribution and allele frequency of the 5-HTR1A C(-1019)G locus was observed in schizophrenia (chi2=9.51, d.f.=2, p=0.009; chi2=9.52, d.f.=1, p=0.002; Armitage's trend test: chi2=9.07, d.f.=1, p=0.003), in substance use disorder (chi2=8.41, d.f.=2, p=0.015; chi2=8.35, d.f.=1, p=0.004; Armitage's trend test: chi2=6.27, d.f.=1, p=0.0012), and in panic attack (chi2=6.31, d.f.=2, p=0.043; chi2=6.14, d.f.=1, p=0.013; Armitage's trend test: chi2=6.27, d.f.=1, p=0.012). An association of the 5-HTR1A C(-1019)G locus with schizophrenia, substance use disorder, and panic attack was suggested by our results. In post-mortem brain samples, 5-HT1A receptor binding in prefrontal cortex and suicide were not associated with genotype. The relationship does not appear to be explained by binding differences, although we cannot rule out altered receptor affinity and transduction.

P3.044 Alttered 5HT1A binding in panic disorderdemonstrated by positron emission tomography

It is now well accepted that graphic methods are a poor choice of analytical technique for analyzing radioligand binding data given the complexity of some radioligand-binding site interactions; this is true not only for studies performed at equilibrium but also for those examining kinetic properties of the radioligand. As a consequence the computer plays an important role in all forms of radioligand binding experiments because it reduces the labor-intensive calculations associated with such experiments and it allows the use of more appropriate weighted nonlinear curve-fitting techniques that more accurately describe the radioligand-binding site interaction. This paper describes a collection of four programs (klnetic, ebda, ligad, and lowry) that can be used to analyze most forms of radioligand binding experiments. The programs have been adapted for use on an IBM PC, which is a popular, inexpensive microcomputer and which is well suited to the analysis of radioligand binding data.

Comparison of Cortical 5-HT2A Receptor Binding in Bulimia Nervosa Patients and Healthy Volunteers

OBJECTIVE: Bulimia nervosa has been associated with alterations in central serotonergic (5-HT) function. This study investigated iodine-labeled 4-amino-N-[1-[3-(4-fluorophenoxy) propyl]-4-methyl-4-piperidinyl]-5-iodo-2-methoxybenzamide (123I-5-I-R91150) binding to the 5-HT2A receptor in the brain by using single photon emission computed tomography in acutely ill bulimia nervosa patients. METHOD: Cortical 123I-5-I-R91150 binding in 10 normal-weight patients with bulimia nervosa, purging type, was compared with that of 11 healthy volunteers. RESULTS: The 5-HT2A binding index of the bulimia nervosa patients, with and without correction for age, was not significantly different from that of the comparison group. CONCLUSIONS: As a group, acutely ill bulimia nervosa patients cannot be discriminated from healthy subjects on the basis of cortical 123I-5-I-R91150 binding to the 5-HT2A receptor.

Altered 5-HT2A and 5-HT4 Postsynaptic Receptors and Their Intracellular Signalling Systems IP3 and cAMP in Brains from Depressed Violent Suicide Victims

Serotonin 5-HT2A and 5-HT4 binding parameters and their second messengers 1,4,5-inositol triphosphate (IP₃) and cyclic adenosyl monophosphate (cAMP) were studied in the frontal cortex, hippocampus, caudate nucleus and amygdala of 19 control subjects and 19 antidepressant-free, violent suicide victims. A significantly higher number of 5-HT4 receptors and higher second messenger cAMP concentrations were found in the frontal cortex and caudate nucleus of the depressed suicide victims as compared with the control group. Furthermore, significantly increased 5-HT2A binding sites and IP₃ concentrations were noted in the caudate nucleus of the suicide victims, together with a significantly reduced number of 5-HT2A binding sites, higher binding affinity and increased IP₃ concentrations in the hippocampus. No significant alterations in 5-HT4 and cAMP or in 5-HT2A and IP₃ concentrations were observed in the amygdala. The caudate nucleus of depressed suicide victims seems to be the brain region with the highest alteration of the serotonergic system, and hence with the most diagnostic sensitivity. Further studies on suicidality and depression should focus on the functionality of the caudate nucleus.

Platelet Serotonergic Predictors of Clinical Improvement in Obsessive Compulsive Disorder

Serotonin reuptake inhibitors (SRIs) are the most efficient pharmacological treatment of obsessive-compulsive disorders (OCD). Previous studies have suggested that some peripheral serotonergic parameters can be used to predict the clinical outcome of the treatment of OCD patients with SRIs. We tried to identify further peripheral serotonergic parameters that could help predict the clinical outcome of SRI treatment in a sample of patients with OCD. We compared 19 OCD patients before and after 8 weeks of SRI treatment with 19 sex-matched and age-matched controls. We assessed clinical improvement and whole-blood serotonin (5-HT) concentration, platelet 5-HT transporter (5-HTT) and 5-HT2A receptor binding characteristics and platelet IP3 content. Before treatment, OCD patients had higher platelet IP3 content and fewer 5-HTT binding sites than the controls. Treatment with SRIs further lowered the number of 5-HTT binding sites, normalized platelet IP3 contents, and lowered the number of platelet 5-HT2A binding sites and whole-blood 5-HT concentrations below control values. The patients who improved most following SRI treatment had higher whole-blood 5-HT concentrations before treatment. Our results confirm that whole-blood 5-HT concentration is a predictor for clinical improvement and indicate that abnormal intracellular mechanisms may be involved in OCD patients, in particular, the overstimulation of the phosphoinositide signaling system.

S.25.01 Psychotropic drugs in the prevention of suicide

Superfusion of hemisected lumbar spinal cord of the neonatal rat with solutions containing 10−6 to 10−3 M 5-hydroxytryptamine (5-HT) elicited depolarizations of graded amplitude which were recorded from motorneurones through a ventral root. Maximum responses (amplitude 1.0 ± 0.1 mV, mean ± SEM, n = 30) were evoked by 10−4 M 5-HT. Repeated concentration-response curves could be determined from the same preparation.There was no involvement of 5-HT2 receptors in the depolarizing response to 5-HT, since neither ritanserin nor ICI 169, 369 showed any antagonist action.Amongst agents with activity at 5-HT1A sites, the selective 5-HT1A receptor agonist, 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT), neither mimicked the action of 5-HT nor antagonised it, while spiperone (10−8-10−7 M) antagonised responses to 5-HT in a concentration-related manner. Responses to 10−4 M noradrenaline, used as a control depolarizing agent, were unaffected by spiperone. The onset of blockade by spiperone was slow, 1 hr being required for equilibration of the tissue with antagonist. The blockade was surmountable by larger concentrations of 5-HT. Concentration-response curves to 5-HT were shifted to the right in an approximately parallel manner by spiperone. The dose ratios measured from these curves at the EC50 level, yielded an apparent pA2 of 8.24 ±0.14 (mean ± SEM, n = 15), although the Schild plot of the data had a slope less than unity.The lack of activity of the selective 5-HT1B receptor agonist, RU 24969, and the 5-HT1B receptor antagonists, (±) cyanopindolol and quipazine, indicated that 5-HT1B receptors were not involved in the 5-HT response of motorneurones to 5-HT.Mesulergine, metergoline and cyproheptadine also antagonised responses of motorneurones to 5-HT, producing a surmountable blockade. Mesulergine (10−8, 3 × 10−8 and 10−7 M) caused a progressive rightward shift of the concentration-response curves, but 10−7 M depressed the maximum response to 5-HT. Responses to noradrenaline were not affected by these concentrations of mesulergine. The apparent pA2 for blockade of 5-HT responses by mesulergine, calculated from experiments in which there was a parallel displacement of the concentration-response curves, was 8.75 ± 0.11 (mean ± SEM, n = 10). Metergoline (10−7 M) produced a modest degree of antagonism, the apparent pA2 being 7.2 ± 0.2(mean ± SEM, n = 6). Cyproheptadine (10−9 and 10−8 M) induced rightward, parallel shifts of the concentration-response curves to 5-HT and the apparent pA2 was 8.88 ± 0.24 (mean ± SEM, n = 10). Responses to noradrenaline were unaffected by these concentrations of cyproheptadine.The pharmacological profile of the 5-HT receptor of the motorneurone from this and previous results (Connell and Wallis, 1988) is, thus: (a) 5-HT, α-Me-5-HT, 5-carboxamidotryptamine (5-CT) and 5-methoxytryptamine (5-MeOT) were full agonists, the order of agonist potency being 5-HT > α-Me-5-HT > 5-CT > 5-MeOT ⪢ tryptamine. The compounds 8-OH-DPAT, RU 24969 and 2-Me-5-HT were inactive as agonists, (b) Methysergide, spiperone, mesulergine, cyproheptadine and metergoline were antagonists active at nM concentrations. Ketanserin was a weak antagonist, while ritanserin, methiothepin, (±) cyanopindolol, MDL 72222, ICS 205-930, quipazine, ICI 169, 369, yohimbine, 8-OH-DPAT and RU 24969 were without antagonist activity.This profile cannot be equated with the CNS 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D or 5-HT2 binding sites, nor with 5-HT3 receptors. It is also distinguishable from a number of other functional 5-HT, -like receptors which do not conform to an identified 5-HT binding site.

Impaired Repression at a 5-Hydroxytryptamine 1A Receptor Gene Polymorphism Associated with Major Depression and Suicide

Inhibition of serotonergic raphe neurons is mediated by somatodendritic 5-HT1A autoreceptors, which may be increased in depressed patients. We report an association of the C(-1019)G 5-HT1A promoter polymorphism with major depression and suicide in separate cohorts. In depressed patients, the homozygous G(-1019) allele was enriched twofold versus controls (p = 0.0017 and 0.0006 for G/G genotype and G allele distribution, respectively), and in completed suicide cases the G(-1019) allele was enriched fourfold (p = 0.002 and 0.00008 for G/G genotype and G allele distribution, respectively). The C(-1019) allele was part of a 26 bp imperfect palindrome that bound transcription factors nuclear NUDR [nuclear deformed epidermal autoregulatory factor (DEAF-1)]/suppressin and Hairy/Enhancer-of-split-5 (Drosophila) (Hes5) to repress 5-HT1A or heterologous promoters, whereas the G(-1019) allele abolished repression by NUDR, but only partially impaired Hes5-mediated repression. Recombinant NUDR bound specifically to the 26 bp palindrome, and endogenous NUDR was present in the major protein-DNA complex from raphe nuclear extracts. Stable expression of NUDR in raphe cells reduced levels of endogenous 5-HT1A protein and binding. NUDR protein was colocalized with 5-HT1A receptors in serotonergic raphe cells, hippocampal and cortical neurons, and adult brain regions including raphe nuclei, indicating a role in regulating 5-HT1A autoreceptor expression. Our data indicate that NUDR is a repressor of the 5-HT1A receptor in raphe cells the function of which is abrogated by a promoter polymorphism. We suggest a novel transcriptional model in which the G(-1019) allele derepresses 5-HT1A autoreceptor expression to reduce serotonergic neurotransmission, predisposing to depression and suicide.

Endocrine, cognitive and hippocampal/cortical 5HT 1A/2A receptor changes evoked by a time-dependent sensitisation (TDS) stress model in rats

Post traumatic stress disorder (PTSD) is characterised by hyperarousal, anxiety and amnesic symptoms. Deficits in explicit memory recall have been causally related to volume reductions of the hippocampus and prefrontal cortex. While stress-related glucocorticoid secretion appears involved in this apparent atrophy, there is also evidence for low plasma cortisol in PTSD. Prior exposure to trauma is an important risk factor for PTSD, suggesting a role for sensitisation. Using Sprague–Dawley rats, we studied the effects of a time-dependent sensitisation (TDS) model of stress on spatial memory deficits, 1 week post-stress, using the Morris water maze. Basal and 7-day post-stress plasma corticosterone levels were also determined. Due to the putative role of serotonin in anxiety and stress, and in the treatment of PTSD, hippocampal 5HT 1A and prefrontal cortex 5HT 2A radioligand binding studies were performed. TDS stress evoked a marked deficit in spatial memory on day 7 post TDS stress, coupled with significantly depressed plasma corticosterone levels. Cognitive and endocrine changes at day 7 post stress were associated with a significant increase in receptor density ( B max) and a significant decrease in receptor affinity ( K d) for hippocampal 5HT 1A receptors. The B max of prefrontal cortex 5HT 2A receptors were unaffected, but K d was significantly increased. We conclude that TDS stress evokes cognitive and endocrine changes characteristic of PTSD. Moreover, TDS stress induces diverse adaptive 5HT receptor changes in critical brain areas involved in emotion and memory that may underlie the effect of stress on cognitive function.

Data Back Relationship Between Serotonin Binding, Suicide Attempts

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessData Back Relationship Between Serotonin Binding, Suicide AttemptsJoan Arehart-TreichelJoan Arehart-TreichelSearch for more papers by this authorPublished Online:20 Jun 2003https://doi.org/10.1176/pn.38.12.0026aDo serotonin abnormalities in the brain underlie suicidal thoughts and behavior? Postmortem evidence from the brains of suicide completers indicates yes. So has cerebrospinal fluid evidence from suicide attempters. And now evidence from the brains of a handful of suicide attempters indicates yes as well.Kees van Heeringen, M.D., Ph.D., chair of psychiatry at the University Hospital Gent in Belgium, and his coworkers have found that serotonin receptors in the prefrontal cortex of nine suicide attempters did not bind as well as did serotonin receptors in the prefrontal cortex of 13 control subjects. They reported their finding in the April Journal of Affective Disorders.“These results compliment our findings,” Maria Oquendo, M.D., an associate professor of clinical psychiatry at Columbia University, told Psychiatric News. In the January Archives of General Psychiatry, Oquendo and her team reported that they had found less serotonergic response to a chemical challenge in the prefrontal cortexes of 16 very suicidal depressed subjects than in the prefrontal cortexes of nine less suicidal depressed subjects.Still another strength of the study, Oquendo pointed out, is that the researchers focused on those serotonin receptors that have been found to be involved in suicide completion—the 5-HT2a receptors. The study also links poor 5-HT2a binding with hopelessness—a well-documented risk factor for suicide.The suicidal subjects whom van Heeringen and his colleagues selected for their study were persons who had been admitted to the University Hospital Gent Department of Psychiatry following a suicide attempt. Seven were male, two female. For at least six months before the study, all were free of psychotropic drugs, except for benzodiazepines, barbiturates, or anti-epileptic drugs that were ingested during the suicide attempt. None were substance abusers. Control subjects consisted of seven males and six females who were recruited from the hospital staff and screened for personal and familial psychiatric histories as well as medical histories. None used psychotropic medications or abused substances.The suicidal subjects were assigned a psychiatric diagnosis according to DSM-IV criteria. Four were diagnosed with major depressive disorder, two with narcissistic personality disorder, one with borderline personality disorder, one with dependent personality disorder, and one with brief psychotic disorder. Then both suicidal subjects and control subjects were assessed for personality characteristics using a Dutch version of Cloninger’s 240-item Temperament and Character Inventory and for hopelessness according to Beck’s Hopelessness Scale. After that, a radioactively labeled chemical that binds selectively to 5-HT2a receptors and brain imaging were used to visualize 5-HT2a receptor binding in all the subjects’ frontal cortexes.The researchers then compared serotonin receptor binding in the suicide attempters with that in the controls. They found that the suicide attempters had a significantly lower binding potential of 5-HT2a receptors in the prefrontal cortex than had the control subjects, especially in the dorsolateral area of the prefrontal cortex, which is involved in anticipation and planning.The investigators then looked to see whether they could identify any personality traits that characterized the suicide attempters compared with the controls. The suicidal subjects scored significantly higher on harm avoidance and hopelessness and significantly lower on self-directedness and cooperativeness than had the controls.Finally, the scientists attempted to see whether they could make any statistically significant connections between the low serotonin-binding potential in the prefrontal cortexes of the suicidal subjects and particular personality characteristics that the subjects possessed. A significant link was found between harm avoidance and binding potential and also between hopelessness and binding potential.Thus, “lower central serotonergic function, hopelessness, and harm avoidance are interrelated phenomena, which may increase the probability of the occurrence of attempted suicide,” van Heeringen and his team concluded.The results, van Heeringen told Psychiatric News, also imply that drugs that enhance serotonin activity in the brain might possibly “prevent the occurrence of suicidal behavior through their effect on hopelessness and anxiety regulation.”In fact, Oquendo and her coworkers are exploring the possible value of the SSRIs, as well as of some other medications, in preventing suicidal behavior (Psychiatric News, October 18, 2002).The study by van Heeringen and his colleagues was financed by the Fund for Scientific Research–Flanders.An abstract of the study, “Prefrontal 5-HT2a Receptor Binding Index, Hopelessness, and Personality Characteristics in Attempted Suicide,” can be accessed on the Web at www.sciencedirect.com by clicking on “Browse A-Z of journals,” then “j,” then Journal of Anxiety Disorders. ▪ ISSUES NewArchived

Altered platelet serotonin 5-HT2A receptor density but not second messenger inositol trisphosphate levels in drug-free schizophrenic patients

The 5-HT2A receptor binding parameters using [ 3H]ketanserine and its intracellular signal inositol 1,4,5 trisphosphate (IP3) concentrations were determined in platelets from schizophrenic patients so as to assess differences with respect to a control group and to a standardized antipsychotic drug treatment. Seventy-five antipsychotic-free patients with a DSM-IV diagnosis of paranoid schizophrenia were included in the study. Blood samples were collected before the onset of antipsychotic treatment (baseline values) and after 3 weeks of treatment. Antipsychotic-free schizophrenic patients showed significantly increased basal 5-HT2A densities in comparison to the control group, together with a significantly increase (23%) in the 5-HT2A binding density in those patients treated with risperidone. These changes could be attributed to an up-regulation of 5-HT2A receptors caused by previous treatment with antipsychotic drugs, which is consistent with the chronic effect of 5-HT2A antagonists to up-regulate the number of binding sites. With regard to second messenger IP3 concentrations, basal concentrations in schizophrenic patients were not significantly different from control values, nor was there any significant difference between basal vs. posttreatment values. These results are possibly related to failure of second messenger systems of ‘translating’ extracellular messages generated presynaptically into effective neurotransmitter signals in schizophrenic patients.

A synthetic overview of new molecules with 5-HT1A binding affinities.

The present review discusses the synthetic strategies of new ligands exhibiting mainly 5-HT(1A)binding affinities. Specifically we focused our attention in the synthesis of compounds structurally related to arylpiperazine, 2-aminotetralin, and benzopyran derivatives.

Ovarian Steroid Regulation of 5-HT1A Receptor Binding and G protein Activation in Female Monkeys

Serotonin 5-HT1A receptors play an important role in serotonin neurotransmission and mental health. We previously demonstrated that estradiol (E) and progesterone (P) decrease 5-HT1A autoreceptor mRNA levels in macaques. In this study, we questioned whether E and P regulate 5-HT1A binding and function and Gα subunit protein expression. Quantitative autoradiography for 5-HT1A receptors and G proteins using [3H]8-OH-DPAT and [35S]GTP-γ-S, respectively, was performed on brain sections of rhesus macaques from four treatment groups: ovariectomized controls (OVX), E (28 d), P (28 d), and E (28 d) plus P (the last 14 d) treated. Western blot analysis for Gα subunits was performed on raphe extracts from cynomolgus macaques that were OVX or OVX treated with equine estrogens (EE, 30 months). In the hypothalamus, E or E + P but not P alone decreased postsynaptic 5-HT1A binding sites. In the dorsal raphe nucleus (DRN), E, P, and E + P treatments decreased 5-HT1A autoreceptor binding. The Kd values for 8-OH-DPAT were the same for each treatment group. Both the basal and the R-(+)-8-OH-DPAT stimulated [35S]GTP-γ-S binding were decreased during hormone replacement whereas the coupling efficiency between the receptor and G proteins was maintained. Finally, EE treatment reduced the level of Gαi3, but not Gαi1, Gαo, and Gαz in the DRN. In conclusion, these observations suggest that ovarian hormones may increase serotonin neurotransmission, in part, by decreasing 5-HT1A autoreceptors, 5-HT1A postsynaptic receptors, and the inhibitory G proteins for intracellular signal transduction.

A Database of [11C]WAY-100635 Binding to 5-HT1A Receptors in Normal Male Volunteers: Normative Data and Relationship to Methodological, Demographic, Physiological, and Behavioral Variables

PET studies of [11C]WAY-100635 binding are proving to be a useful tool to evaluate 5-HT1A receptor function in vivo in humans. We describe the pattern of [11C]WAY-100635 binding in 61 healthy male brains and examine its variability. For all PET scans, binding potential (BP) values for [11C]WAY-100635 in different regions were calculated using a simplified reference tissue model, with the cerebellum as reference region. Specifically we describe (1) region of interest and SPM databases of PET [11C]WAY-100635 binding, including test–retest variability; (2) the sensitivity of [11C]WAY-100635 binding to manipulations of endogenous 5-HT; and (3) correlations between [11C]WAY-100635 binding and radiochemical, demographic, physiological, and behavioral variables. The regional distribution of [11C]WAY-100635 binding in healthy human brain was similar to that reported in vitro. The test–retest variability was ∼12% (range 9–16%) and was similar for all methods of regional sampling. The binding of [11C]WAY-100635 was insensitive to changes in brain 5-HT induced by tryptophan infusion and depletion. Although BP values varied greatly across subjects (range 2.9–6.8), there were no significant correlations of regional and global BP with common radiochemical, demographic, physiological, and personality variables. Specifically, in contrast with two recent small studies, we found no decline of [11C]WAY-100635 binding with age in our large cohort over the age range of 24 to 53 years. Assessment of 5-HT1A receptors in vivo using PET and [11C]WAY-100635 gives reliable measures of 5-HT1A binding. The large between-subject variability observed could not be explained by common methodological, physiological, or behavioral factors and hence the biological basis of this variability remains to be clarified.

Serotonin 1A Receptors, Serotonin Transporter Binding and Serotonin Transporter mRNA Expression in the Brainstem of Depressed Suicide Victims

Suicide and depression are associated with reduced serotonergic neurotransmission. In suicides, there is a reduction in serotonin transporter (SERT) sites and an increase in postsynaptic 5-HT1A receptors in localized regions of the prefrontal cortex. In depression, there is a diffuse decrease in SERT binding throughout the dorsoventral extent of the prefrontal cortex. Serotonergic innervation of the prefrontal cortex arises predominantly from neurons in the brainstem dorsal raphe nucleus (DRN). We, therefore, examined postmortem SERT binding and mRNA expression, as well as 5-HT1A autoreceptor binding in the DRN of 10 matched pairs of controls and depressed suicide victims. The concentration of SERT sites, SERT mRNA, and 5-HT1A binding was not different between controls and suicides (p > .05). In the DRN of suicides, the volume of tissue defined by 5-HT1A binding was 40% smaller than controls. An index of the total number of 5-HT1A receptors (receptor binding × volume of receptor distribution) was 43.3% lower in the DRN of suicides, compared with controls. The suicide group had 54% fewer DRN neurons expressing SERT mRNA compared with controls. In the serotonin neurons that expressed the SERT gene, expression per neuron was greater in suicides. Less total 5-HT1A and SERT binding is consistent with results of in vivo studies in depression. Less feedback inhibition of serotonin DRN firing via 5-HT1A autoreceptors and enhancement of serotonin action due to less uptake of serotonin, is consistent with compensatory changes in response to hypofunction in depressed suicides.