Ruth Gross-Isseroff

Autoradiographic analysis of serotonin 5-HT1A receptor binding in the human brain postmortem : effects of age and alcohol

Quantitative autoradiographic analysis of serotonin 5-HT1A receptors in the human brain, using [3H]8-OH-DPAT as a ligand, reveals region-specific decreases in receptor labeling with age in several cortical and hippocampal regions and in the raphe nuclei. This is due to a change in receptor density (Bmax) with no apparent change in affinity (Kd) as affirmed by saturation binding analysis on representative cortical regions. The presence of alcohol is associated with decreased binding in several cortical gyri. Suicide, gender and postmortem delay had no effect on 8-OH-DPAT binding.

Fetal human brain exhibits a prenatal peak in the density of serotonin 5-HT1A receptors.

High densities of serotonergic 5-HT1A receptors, in excess of adult levels, were found in the human fetal brain between the 16th and 22nd weeks of gestation, 5-HT1A receptors were measured by quantitative autoradiography using brain sections of fetuses aborted at gestational ages 16-22 weeks. The highest receptor concentrations were detected in the cortex and hippocampus. Two brains obtained from fetuses with Downs syndrome at 22 and 24 weeks gestation exhibited abnormal receptor levels compared to age matched controls. The presence of an early, prenatal peak of 5-HT1A receptors in fetal cortex and hippocampus suggests that these receptors play a role in human brain development and may also be involved in developmental disorders such as Downs syndrome.

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.

Alternation learning in obsessive-compulsive disorder

The Wisconsin Card Sorting Test (WCST) and an alternation learning task were administered to 15 women with obsessive-compulsive disorder (OCD) and 15 age-, sex-, education-, and intelligence-matched healthy controls. OCD patients were significantly slower on the WCST as compared to the controls. Their performance on the alternation learning task was impaired relative to the control group, though this difference was diminished when we used education as a covariate. We found a significant positive correlation between performance on the alternation task and severity of symptoms in the OCD group. Performance of similar alternation tasks is impaired by damage to the orbitofrontal cortex in nonhuman primates. Therefore the data presented support the hypothesis of orbitofrontal cortex dysfunction in OCD.

Autoradiographic analysis of age-dependent changes in serotonin 5-HT2 receptors of the human brain postmortem.

Autoradiographic analysis of 5-HT2 receptors in the human brain, using [3H]ketanserin as a ligand, reveals region-specific changes in receptor labeling as a function of age. In the prefrontal cortex and hippocampal dentate gyrus of 12 normal subjects, label density decreases sharply with age over the 2nd and 3rd decades, reaches a minimum around age 50 and then starts to increase again in the 6th and 7th decades. Other brain regions studied, including frontoparietal and temporal cortex, basal ganglia and thalamus, did not show significant changes with age. Saturation binding experiments on prefrontal cortical samples from 23 normal subjects reveal that the decrease in label density is due to changes in receptor density (Bmax) with no apparent change in affinity (Kd). Sex, presence of alcohol and postmortem delay had no effect on ketanserin binding.

Serotonergic Dissection of Obsessive Compulsive Symptoms: A Challenge Study with m-Chlorophenylpiperazine and Sumatriptan

We have conducted a pharmacological challenge experiment in 10 medication-free obsessive compulsive (OC) disorder (OCD) patients. We used a placebo-controlled paradigm for m-chlorophenylpiperazine (mCPP) and sumatriptan challenges. Endocrine, physiological and behavioral variables were assessed at baseline and over a 3-hour period after the challenge. Both cortisol and prolactin were significantly elevated in OCD patients following mCPP administration. Both mCPP and sumatriptan caused significant OC symptom exacerbation with the response to sumatriptan being more robust. We conclude that the 5-HT1Dβ receptor may play a role in the pathophysiology of OCD.

The suicide brain: a review of postmortem receptor/transporter binding studies

The present review summarizes the last 15 years of research involving postmortem receptor/transporter binding studies on brains of suicide victims. It is our working hypothesis, on the basis of psychological, behavioral and epidemiological studies, that suicidal behavior is an independent unique behavioral entity with specific neurochemical characteristics. This review tries to test this hypothesis at the level of neurotransmitter receptors by using a different approach to data analysis. We suggest that this statistical approach, involving multivariate analyses, can contribute to the formulation of new hypotheses at the level of molecular biology and genetics. Such studies if undertaken in the future, would help define suicidal behavior as a psycho-neuro-pathological entity.

Olfactory Sensitivity in Major Depressive Disorder and Obsessive Compulsive Disorder

Olfactory sensitivity to two odorants, isoamyl acetate and androsterone, was assessed in 14 obsessive compulsive disorder (OCD) patients, nine major depressive disorder (MDD) patients, and 16 sex- and age-matched healthy controls. Tests were performed during a drug-free period, and 3 and 6 weeks after initiation of antidepressant drug therapy. No difference in olfactory sensitivity, to either odorant, was found between OCD patients and controls at any time. In MDD patients, a significant increase in the sensitivity to isoamyl acetate was observed 6 weeks after initiation of treatment, compared to controls.

Neuroimaging communality between schizophrenia and obsessive compulsive disorder: a putative basis for schizo-obsessive disorder?

Summary Four major brain regions have been repeatedly implicated in the pathophysiology of obsessive compulsive disorder (OCD) in in vivo neuroimaging studies: the caudate nucleus, the orbitofrontal cortex, the anterior cingulate gyrus and the mediodorsal thalamic nucleus. The present review describes the neuroimaging studies on schizophrenia, pertaining to these brain regions. Our working hypothesis is that such common brain regions, if dysfunctional in schizophrenic patients, would be candidates for a neural network subserving the newly emerging syndrome of schizo-obsessive disorder. Findings, though, are controversial. We conclude that further studies, aimed at specific monitoring of these brain regions, in patients suffering from the schizo-obsessive syndrome are warranted.

Evidence for genetic determination in human twins of olfactory thresholds for a standard odorant

Olfactory thresholds for four odorants were determined in groups of monozygotic and dizygotic human twins. Odorants were presented in an ascending dilution series in odorless solvent, using a three-way forced choice method. For two of the tested odorants, 5 alpha-androst-16-en-3-one and isoamyl acetate, the thresholds showed a strong genetic component. This was demonstrated by respective values of 0.78 and 0.73 for the intraclass correlation difference, and of z = 3.69 and z = 2.71 in a within-pair difference analysis. The results for isoamyl acetate are novel, and suggest that genetic polymorphism in the affinity of odorant receptor proteins contributes to the (nearly normal) threshold distribution for this odorant.