Quantitative autoradiographic mapping of serotonin 5-HT1 and 5-HT2 receptors and uptake sites in the neocortex of the rhesus monkey

The in vitro autoradiographic technique was used to characterize the distribution of serotonin 5-HT1 and 5-HT2 receptors and uptake sites in 11 cortical areas of frontal, parietal, and occipital lobes in the rhesus monkey; 5-HT1 receptors were labeled with [3H]5-HT; 5-HT2 receptors were labeled with [3H]ketanserin; and 5-HT uptake sites were labeled with [3H]citalopram. Five-HT1 and 5-HT2 receptors and 5-HT uptake sites were found in every cortical area examined with the absolute concentration of 5-HT1 receptors higher than that of 5-HT2 receptors in all areas. In eight regions of prefrontal and parietal as well as in prestriate cortex, 5-HT1 and 5-HT2 receptors had complementary distribution profiles: 5-HT1 receptors were concentrated in layers I and II and the upper strata of layer III, while 5-HT2 receptors had their highest concentration throughout layers III and IV. Only the primary motor and visual cortex had receptor distributions different from that described above. Thus, in the primary visual cortex, both 5-HT1 and 5-HT2 receptors were found in high concentration in sublayer IVc beta, though the density of 5-HT1 receptor was also high in other subdivisions of layer IV and in layers III, V, and VI. In the primary motor cortex, both receptor subtypes were concentrated in layers I and II and the upper strata of layer III. The pattern of distribution of serotonin uptake sites did not match the patterns of distribution of either 5-HT1 or 5-HT2 receptors alone; rather it approximated the combined patterns of distribution of both receptor subtypes. The complementary patterns of distribution of 5-HT1 and 5-HT2 receptors in most areas of the monkey cerebral cortex suggest that these two receptor subtypes may make differential contributions to cortical functions.     

Cortical serotonin-S2 receptor binding in Lewy body dementia, Alzheimer's and Parkinson's diseases.

The binding of the selective 5-HT2 antagonist [3H]ketanserin has been investigated in the temporal cortex of patients with Alzheimer's disease (SDAT), Parkinson's disease (PD), senile dementia of Lewy body type (SDLT) and neuropathologically normal subjects (control). 5-HT2 binding was reduced in SDAT, PD with dementia and SDLT. SDAT showed a 5-HT2 receptor deficit across most of the cortical layers. A significant decrease in 5-HT2 binding in the deep cortical layers was found in those SDLT cases without hallucinations. SDLT cases with hallucinations only showed a deficit in one upper layer. There was a significant difference in cortical layers III and V between SDLT without hallucinations and SDLT with hallucinations. The results confirm an abnormality of serotonin binding in various forms of dementia and suggest that preservation of 5-HT2 receptor in the temporal cortex may differentiate hallucinating from non-hallucinating cases of SDLT.     

Frequency of long allele in serotonin transporter gene is increased in depressed suicide victims.

BACKGROUND: There is evidence indicating that serotonin uptake and density of 5-HT2A receptors are altered in brain regions of depressed suicide victims and in platelets of depressed suicidal subjects. The present investigation tested the hypothesis that these changes in the serotonergic system in depressed suicide victims are trait rather than state markers and associated with a polymorphism in respective candidate genes. METHODS: Two polymorphic variants (102T/C polymorphism and His452Tyr functional polymorphism) of the 5-HT2A receptor gene and a functional polymorphism in the 5' regulatory region of the 5-HT transporter gene, have been determined in genomic DNA obtained from postmortem brain samples of 24 depressed suicide victims and 31 control subjects of the same ethnic background. In a subset of subjects, density (Bmax) of 5-HT uptake sites (labeled with 3H-paroxetine) and of 5-HT2A receptors (labeled with 3H-ketanserin) was also determined in prefrontal cortex samples. RESULTS: The major finding of this study was a significantly higher frequency of the 5-HT transporter gene long (L) allele (chi 2 = 3.9, df = 1; p = .048) in depressed suicides. No significant differences between suicides and controls were observed for the 102T/C polymorphism and His452Tyr polymorphism of 5-HT2A receptor gene. The density of 3H-paroxetine binding sites tended to be higher in subjects expressing the short (S) allele of 5-HT transporter gene. Furthermore, there was a significant difference in serotonin transporter binding sites between the genotype S/S and combined genotypes S/L and L/L. CONCLUSIONS: Our finding provides the first evidence suggesting that a functional polymorphism in the regulatory region of serotonin transporter gene may be associated with suicide in depressed subjects.     

Increased serotonin2 and beta-adrenergic receptor binding in the frontal cortices of suicide victims

A statistically significant 28% increase in the mean (+/- SD) number of serotonin2 receptors (127.8 +/- 13.4 vs 99.6 +/- 11.1 fmol/mg of protein) and a 73% increase in beta-adrenergic receptor binding (14.5 +/- 1.5 vs 8.4 +/- 1.5 fmol/mg) was found in the frontal cortices of violent suicide victims compared with matched controls. No significant differences were found in the number of serotonin1 binding sites (109.5 +/- 13.4 vs 99.9 +/- 8.8 fmol/mg). We have previously reported a reduced density of presynaptic tritiated imipramine binding sites on serotonergic nerve terminals in the frontal cortices of suicide victims. These data support the hypothesis that suicide completed by violent methods is associated with reduced presynaptic serotonergic activity that has generated compensatory upregulation of the postsynaptic serotonin2 receptor sites. The increase observed in beta-adrenergic binding suggests that there may also be a concomitant reduction in presynaptic noradrenergic activity associated with suicide. If antidepressant pharmacotherapies specifically downregulate cortical beta-adrenergic and/or serotonin2 receptors in depressed subjects, as has been demonstrated in animal studies, and since these effects would be in the opposite direction of the receptor changes found in suicide victims, they may account for the therapeutic action of antidepressants on suicidal behavior and depressive disorders.     

Brain 5-HT2 receptor binding sites in depressed suicide victims

5-HT2 receptor binding sites were measured (by saturation binding of [3H]ketanserin) in brain tissue obtained at postmortem from 19 suicide victims with definite evidence of depression and 19 sex and age-matched control subjects. Five of the suicide victims were receiving antidepressant drugs prior to death; 13 suicide victims had not been prescribed antidepressant or other psychoactive drugs recently and none were found in their blood at postmortem. The number of serotonin-2 (5-HT2) binding sites in frontal, temporal and occipital cortex and amygdala did not differ significantly between the depressed suicide victims and controls, either in the total suicide group or in the antidepressant drug-free suicides. The number of 5-HT2 binding sites in the hippocampus did not differ from controls in the total suicide group but was significantly lower (by 23%) in the antidepressant-free suicide group. The affinity of [3H]ketanserin binding did not differ from controls in the antidepressant-free suicides but was lower (increased Kd) in those subjects receiving antidepressant drugs. No correlation was found between the time of death and storage of tissue or the duration of tissue storage prior to assay and the number or affinity of 5-HT2 binding sites. A significant negative correlation was found between age of the subject and the number of 5-HT2 binding sites in the frontal and occipital cortex. The present study of suicide victims with definite evidence of depression do not confirm previous studies of increased numbers of 5-HT2 binding sites in suicide victims and suggest that these previous findings may be related to factors other than depression.     

Higher postmortem prefrontal 5-HT2A receptor binding correlates with lifetime aggression in suicide.

BACKGROUND: In vivo studies find altered serotonin function associated with aggressive and suicidal behaviors. Postmortem studies also reveal serotonergic alterations in suicide subjects but have not reported on the relationship between aggression and the serotonin system. We measured 5-hydroxytryptamine 2A (5-HT(2A)) receptor binding in prefrontal cortex of suicide and nonsuicide subjects and explored the relationship between 5-HT(2A) receptor binding, lifetime aggression, and suicide. METHODS: The 5-HT(2A) receptor binding in coronal sections of prefrontal cortex was quantified by autoradiography with [(3)H] ketanserin in 37 suicide subjects and 73 nonsuicide subjects. The relationship between [(3)H] ketanserin binding and lifetime aggression, rated on the Brown-Goodwin Aggression History Scale, was assessed controlling for age and sex. RESULTS: In suicide subjects, lifetime aggression scores correlated positively with [(3)H] ketanserin binding in all prefrontal Brodmann areas examined, after adjusting for age and sex. This was not the case in nonsuicide subjects. We found no significant differences in aggression scores or [(3)H] ketanserin binding between the suicide subjects and nonsuicide subjects. CONCLUSIONS: The relationship between aggression and 5-HT(2A) receptor binding in suicide subjects, but not in nonsuicide subjects, may reflect differences in the regulation of the 5-HT(2A) receptor related to suicidal behavior and perhaps other proaggressive changes in brains of suicide subjects.     

Neurotransmitter receptor-mediated activation of G-proteins in brains of suicide victims with mood disorders: selective supersensitivity of alpha(2A)-adrenoceptors

Abnormalities in the density of neuroreceptors that regulate norepinephrine and serotonin release have been repeatedly reported in brains of suicide victims with mood disorders. Recently, the modulation of the [(35)S]GTPgammaS binding to G-proteins has been introduced as a suitable measure of receptor activity in postmortem human brain. The present study sought to evaluate the function of several G-protein coupled receptors in postmortem brain of suicide victims with mood disorders. Concentration-response curves of the [(35)S]GTPgammaS binding stimulation by selective agonists of alpha(2)-adrenoceptors, 5-HT(1A) serotonin, mu-opioid, GABA(B), and cholinergic muscarinic receptors were performed in frontal cortical membranes from 28 suicide victims with major depression or bipolar disorder and 28 subjects who were matched for gender, age and postmortem delay. The receptor-independent [(35)S]GTPgammaS binding stimulation by mastoparan and the G-protein density were also examined. The alpha(2A)-adrenoceptor-mediated stimulation of [(35)S]GTPgammaS binding with the agonist UK14304 displayed a 4.6-fold greater sensitivity in suicide victims than in controls, without changes in the maximal stimulation. No significant differences were found in parameters of 5-HT(1A) serotonin receptor and other receptor-mediated [(35)S]GTPgammaS binding stimulations. The receptor-independent activation of G-proteins was similar in both groups. Immunoreactive densities of G(alphai1/2)-, G(alphai3)-, G(alphao)-, and G(alphas)-proteins did not differ between suicide victims and controls. In conclusion, alpha(2A)-adrenoceptor sensitivity is increased in the frontal cortex of suicide victims with mood disorders. This receptor supersensitivity is not related to an increased amount or enhanced intrinsic activity of G-proteins. The new finding provides functional support to the involvement of alpha(2)-adrenoceptors in the pathogenesis of mood disorders.     

The neuroscience of suicide

Various postmortem brain studies have provided evidence that reduced serotonin (5-HT) transmission in the ventrolateral prefrontal cortex (vlPFC) is associated with depression-related suicide. Suicide victims have fewer 5-HT transporter sites and a large number of postsynaptic 5-HT1A and 5-HT receptors in the vlPFC, which are implicated in behavioral inhibition and impulsivity. These could be compensatory changes in response to 5-HT hypofunction in depression and suicide. Selective serotonin reuptake inhibitors (SSRIs) are commonly used for the treatment of depression and suicidal ideation. 5-HT innervation of the PFC arises predominantly from 5-HT neurons in the brainstem dorsal raphe nucleus (DRN). In the DRN of suicide cases, 5-HT1A autoreceptors are increased and the levels of 5-HT biosynthetic enzyme, tryptophan hydroxylase (TPH), are reduced. Reduced 5-HT1A feedback inhibition and increased TPH may reflect compensatory changes in response to 5-HT hypofunction in depression-related suicide. Genetic polymorphisms in TPH, 5-HT transporter (5-HTTLPR allele), and 5-HT2A receptor were examined for their association with depression-related suicide, but no consistent associations were found. Stress is a risk factor for depression and is linked to hyperactivity of the hypothalamo-pituitary-adrenal axis and suicide. Corticotropin-releasing factor (CRF)-immunoreactive varicose fibers were detected in the DRN of suicide victims, suggesting that CRF neurons in the paraventricular nucleus of the hypothalamus and 5-HT neurons in the DRN may form a circuit in stress-induced depression. Alcoholics are at a significantly greater risk of suicide than the general population. Alcoholism is associated with alterations in the 5-HT system.     

Serotonin-1A autoreceptor binding in the dorsal raphe nucleus of depressed suicides

Serotonergic dysfunction is present in mood disorders and suicide. Brainstem 5-HT1A somatodendritic autoreceptors regulate serotonin neuron firing but studies of autoreceptor binding in the dorsal raphe nucleus (DRN) in depressed suicides report conflicting results. We sought to determine: (1) the anatomical distribution of 5-HT1A receptor binding in the DRN in depressed suicides and psychiatrically normal controls; and (2) whether sex differences in 5-HT1A binding in the DRN contribute to differences between depressed suicides and controls. Previously collected quantitative receptor autoradiograms of [3H]8-hydroxy-2-(di-n-propyl)aminotetralin (3H-8-OH-DPAT) in postmortem tissue sections containing the DRN from drug-free suicide victims (n=10) and matched controls (n=10) were analyzed. Less total receptor binding (fmol/mg tissuexmm3) was observed in the entire DRN in depressed suicides compared with controls (p<0.05). Group differences along the rostrocaudal extent of the DRN were observed for cross-sectional 5-HT(1A) binding (fmol/mg tissue) and receptor binding (fmol/mgxmm3, p<0.05). Cross-sectional 5-HT1A DRN binding in depressed suicides compared with controls was higher rostrally and lower caudally. The differences between depressed suicides and controls were present in males and females, although females had more binding than males. Less autoreceptor binding in the DRN of depressed suicides may represent a homeostatic response to less serotonin release, increasing serotonin neuron firing. More autoreceptor binding in rostral DRN might contribute to deficient serotonin release in ventromedial prefrontal cortex by lower neuronal firing.     

Prefrontal cortex 5-HT2 receptors in depression: an [18F]setoperone PET imaging study.

OBJECTIVE: Widespread disturbances of serotonin (5-HT) are implicated in the pathophysiology of depression. Of 5-HT receptor abnormalities reported, the most replicated finding is increased 5-HT2 receptor binding in the postmortem prefrontal cortex of depressed suicide victims. The extent to which these findings exist in depressed persons without recent suicide attempts is uncertain. The objective of this study was to evaluate 5-HT2 receptors in depressed patients who were medication-free and who had not made recent suicide attempts. METHOD: With the use of [18F]setoperone and positron emission tomography (PET), 5-HT2 receptor binding potential was assessed in 14 depressed and 19 healthy subjects. Exclusion criteria for depressed patients included use of antidepressant medication within the past 6 months, a history of suicide attempts within the past 5 years, other current axis I disorders including bipolar disorder, and the presence of psychotic symptoms. The 5-HT2 (setoperone) binding potential in the two groups of subjects was compared by analysis of covariance with age as the covariate. RESULTS: Age had a significant effect on 5-HT2 binding potential, but depression did not. The interaction of age and depression was not significant. CONCLUSIONS: The 5-HT2 binding potential is not increased in untreated depressed subjects who have not made recent suicide attempts. This negative finding does not rule out the possibility that there is a role for 5-HT2 receptors in treatment or that 5-HT2 receptors are increased in highly suicidal states.     

Serotonin1A receptors at the axon initial segment of prefrontal pyramidal neurons in schizophrenia

OBJECTIVE: Inhibition mediated by gamma-aminobutyric acid at the axon initial segment of pyramidal neurons appears to be altered in the prefrontal cortex in schizophrenia. This study examined the densities and laminar distribution of axon initial segments labeled with an antibody against the serotonin(1A) (5-HT(1A)) receptor, which also mediates inhibitory regulation of pyramidal neurons, in subjects with schizophrenia. METHOD: The densities and laminar distribution of axon initial segments with 5-HT(1A)-like immunoreactivity were assessed in postmortem tissue from the prefrontal cortex (Brodmann's area 46) of 14 matched triads of subjects with schizophrenia, subjects with major depressive disorder, and comparison subjects with no psychiatric disorder. RESULTS: The relative densities of the labeled axon initial segment in both the superficial and the deep cortical layers did not differ across the three subject groups. CONCLUSIONS: The findings do not support a role for altered serotonin transmission by means of the 5-HT(1A) receptor in dysfunction of prefrontal cortex pyramidal neurons in schizophrenia.     

Autoradiographic analysis of tritiated imipramine binding in the human brain post mortem: effects of suicide

In vitro quantitative autoradiography of high-affinity tritiated imipramine binding sites was performed on brains of 12 suicide victims and 12 matched controls. Region-specific differences in imipramine binding were found between the two groups. Thus, the pyramidal and molecular layers of the cornu ammoni hippocampal fields and the hilus of the dentate gyrus exhibited 80%, 60%, and 90% increases in binding in the suicide group, respectively. The postcentral cortical gyrus, insular cortex, and claustrum had 45%, 28%, and 75% decreases in binding in the suicide group, respectively. No difference in imipramine binding was observed in prefrontal cortical regions, in the basal ganglia, and in mesencephalic nuclei. No sex and postmortem delay effects on imipramine binding were found. Imipramine binding was positively correlated with age, the effect of age being most pronounced in portions of the basal ganglia and temporal cortex.     

Lower3H-paroxetine binding in cerebral cortex of suicide victims is partly due to fewer high affinity,non-transporter sites

Summary Suicide has been associated with decreased serotonin transmission. Measurement of concentrations of serotonin, its precursors tryptophan (TRY) and 5-hydroxytryptophan (5-HTP) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), have been used as indices of serotonin activity, and with serotonin transporter binding, are indices of the integrity of serotonin nerve terminals. Most previous studies have not distinguished high affinity transporter binding from a very similar nontransporter binding site, where binding is not dependent on Na⁺ or Cl^– and that does not have a known functional role. We therefore, assayed binding kinetics in prefrontal (PFC) and temporal cortex (TC) in matched pairs of suicide victims and controls using the selective ligand³H-paroxetine, and employing 1 M sertraline to define specific binding to the transporter and 10 M sertraline which also displaces binding to the high affinity, nontransporter site. In addition, we measured concentrations of TRY, 5-HTP, serotonin and 5-HIAA in the same brain areas. The total number of³H-paroxetine transporter and nontransporter binding sites (B_max), was lower in the suicide group compared to controls in both Brodmann area 9 (prefrontal cortex; p=0.02) and in Brodmann area 38 (temporal cortex, p=0.01). In contrast, no differences were found in the number of high affinity transporter binding sites and concentrations of serotonin, 5-HIAA, 5-HTP or TRY (p > 0.05). We conclude that the number of serotonin transporter sites is not altered in Brodmann area 9 in suicide, and that fewer³H-paroxetine and³H-imipramine binding sites found in this region of cerebral cortex of suicides may be explained by a reduction in the nontransporter binding sites.     

Altered serotonin 2C receptor RNA splicing in suicide: association with editing

In an earlier study, we showed increases in serotonin 2C receptor (5-HT2CR) pre-mRNA editing in prefrontal cortex that were specific to suicide victims irrespective of associated psychiatric diagnoses. Here we demonstrate that the ratio between the two 5-HT2CR splice variants is increased in people who committed suicide, but does not vary among the diagnostic groups. This provides further evidence for suicide-specific neurobiology and suggests that, as it was previously shown in vitro, 5-HT2CR editing modulates its splicing in human brain. The association analysis indicates, however, that the efficiency of 5-HT2CR editing is an imperfect predictor of the splicing outcome, and that splice site selection is only partially controlled by the level of editing in vivo.     

Localization of serotonin 5-HT2 receptors in living human brain by positron emission tomography using N1-([11C]-methyl)-2-Br-LSD

N1-([11C]-Methyl)-2-Br-LSD ([11C]-MBL) has been developed as a positron emission tomography (PET) imaging agent for serotonin 5-HT2 receptors. In vitro receptor binding assays with nonradioactive MBL show high-affinity binding to serotonin 5-HT2 receptors (Ki = 0.5 nM), a secondary interaction of 8-fold lower affinity with dopamine D2 receptors, and low-affinity interactions with alpha 1-adrenergic as well as serotonin 5-HT1 receptors. Intravenous injection of [11C]-MBL in a baboon led to selective labeling of cortical regions that was markedly blocked by prior administration of ketanserin, a selective 5-HT2 receptor antagonist. Clinical trials with [11C]-MBL have been conducted in seven normal human volunteers, and the regional distribution of radioactivity in the brain was distinctly serotonergic. Labeling was highest in frontal, temporal, and parietal cortex with lower levels observed in caudate and putamen. The tracer rapidly washed from the cerebellum and the low levels of activity in this brain region were used to define nonspecific binding. The maximum specificity was reached between 30 and 60 minutes postinjection when frontal cortex to cerebellum ratios ranged from 1.7 for a 52-year-old male to 2.7 for a 30-year-old male. In agreement with previous studies, a trend towards lower ratios (lower serotonin 5-HT2 receptor levels) was observed in older volunteers. These studies indicate that [11C]-MBL is a selective radioligand that can be used to monitor serotonin 5-HT2 receptor densities in vivo in most regions of the human brain.     

Serotonergic mechanisms in brains of suicide victims

Serotonergic mechanisms have been investigated in postmortem brain samples from controls and suicide victims. The concentrations of 5-hydroxytryptamine (serotonin; 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined in occipital cortex and hippocampus and the high-affinity binding of ligands to the 5-HT₁, 5-HT₁ and imipramine-binding sites was assessed in frontal cortex, occipital cortex and hippocampus. The only significant difference between the two groups was a modest increase in 5-HIAA levels in the hippocampus of suicide victims. There was no evidence to suggest that those suicide victims with a clinical history of depression represented a subgroup with altered metabolite levels or binding values. The storage conditions of the samples were not related to the metabolite levels or binding values. There was, however, a significant positive correlation between [³H]imipramine binding and age in some brain regions. The results do not provide any evidence of gross alterations in 5-HT mechanisms in suicide or depression.     

Prediction of level of serotonin 2A receptor binding by serotonin receptor 2A genetic variation in postmortem brain samples from subjects who did or did not commit suicide.

OBJECTIVE: Postmortem studies have indicated that suicide victims have greater serotonin receptor 2A (5-HTR2A) binding in prefrontal brain regions. However, there remains some controversy regarding the biological specificity of these findings. The authors hypothesized that the variance observed in brain 5-HTR2A binding is genetically mediated, at least in part. METHOD: Postmortem data from 56 subjects who had committed suicide and 126 normal comparison subjects were studied; brain tissue was available from 11 subjects who committed suicide and 11 comparison subjects. Homogenate binding assays were carried out with [3H]ketanserin. Variation at the 5-HTR2A gene (HTR2A) was investigated by means of two polymorphisms: T102C and A-1438G. RESULTS: 5-HTR2A binding was greater in the prefrontal cortex of the subjects who committed suicide. In addition, the findings suggest that HTR2A variation significantly affects 5-HTR2A binding. However, no interaction between suicidal behavior and this locus was observed. CONCLUSIONS: These results confirm previous reports of greater 5-HTR2A binding in subjects who committed suicide; they also provide preliminary evidence suggesting that the number of 5-HTR2A receptors is genetically mediated.     

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.     

Autoradiographic analysis of [3H]ketanserin binding in the human brain postmortem: effect of suicide

In vitro quantitative autoradiography of 5-HT2 receptors, using [3H]ketanserin as a ligand, was performed on 24 human brains postmortem. Twelve brains were donated by suicide victims and 12 by matched controls. We found a characteristic decline in 5-HT2 receptors with age in several brain regions of the control group. This age dependence of ketanserin binding was not present in some of these brain regions of the suicide group. We also found a significant but anatomically selective reduction in the density of ketanserin binding sites in the young suicide group, compared to age-matched controls. This reduction was evident in portions of the prefrontal cortex. Homogenate binding assays on prefrontal cortex samples from a large group of suicides (n = 20) and controls (n = 23) showed that the difference in age dependence of ketanserin binding and the reduced binding in the young suicide group were explained by differences in Bmax values. No differences were observed in Kd. Sex, presence of alcohol and time from death to autopsy did not affect ketanserin binding, in our sample, as measured by either autoradiography or homogenate binding assay.