Autoradiographic Analysis of [3H]Imipramine Binding in the Human Brain Postmortem: Effects of Age and Alcohol

In vitro quantitative autoradiography of high-affinity [3H]imipramine binding sites was performed on 16 human brains postmortem. The densities of binding sites were highest in the hypothalamus. Next, in descending order, were the basal and lateral nuclei of the amygdala; substantia innominata; insular cortex; the central nucleus of the amygdala; the anterior nucleus of the thalamus; the head of the caudate nucleus; portions of the frontal, parietal, and temporal cortex; claustrum; the granular layer of the dentate gyrus; substantia nigra; the pyramidal layer of CA fields; globus pallidus; red nucleus; and white matter. Imipramine binding was found to increase with age in a region-specific manner. The presence of alcohol had a similar effect, which was most pronounced in the hippocampus. Sex and time from death to autopsy did not affect imipramine binding, in our sample.     

Concentration-dependent changes of perceived odor quality

In order to assess the dependence of perceived odor qualityon odorant concentration, we studied 21 subjects. For eightsubjects all possible pairs from a pool of six odorants at threedecimal dilutions were presented, and subjects were requestedto state whether members of the pair were qualitatively ‘similar’or ‘different’ It was found that while pairs withthe same odorant at identical concentrations were judged ‘similar’in >90% of the cases by all subjects, scores went down to10% ‘similar’ judgements in some cases when thesame odorant was presented at a 100-fold concentration difference.Large time-invariable differences were found among subjectsand among odorants. For the additional 13 subjects, all possiblepairs from a pool of four odorants at three decimal dilutionswere presented. Subjects were instructed to state whether membersof the pair were qualitatively ‘same’ or ‘different’,and were also requested to rank the degree of difference ona visual analogue scale. Results for this group were, in general,similar to the results of the former group of subjects and goodagreement between the two tasks was found. The results suggestthat variations in olfactory stimulus magnitude may be perceivedas quality differences, as previously shown for vision and audition.     

Mutations in olfactory signal transduction genes are not a major cause of human congenital general anosmia

Anosmia affects the western world population, mostly the elderly, reaching to 5% in subjects over the age of 45 years and strongly lowering their quality of life. A smaller minority (about 0.01%) is born without a sense of smell, afflicted with congenital general anosmia (CGA). No causative genes for human CGA have been identified yet, except for some syndromic cases such as Kallman syndrome. In mice, however, deletion of any of the 3 main olfactory transduction components (guanidine triphosphate binding protein, adenylyl cyclase, and the cyclic adenosine monophosphate-gated channel) causes profound reduction of physiological responses to odorants. In an attempt to identify human CGA-related mutations, we performed whole-genome linkage analysis in affected families, but no significant linkage signals were observed, probably due to the small size of families analyzed. We further carried out direct mutation screening in the 3 main olfactory transduction genes in 64 unrelated anosmic individuals. No potentially causative mutations were identified, indicating that transduction gene variations underlie human CGA rarely and that mutations in other genes have to be identified. The screened genes were found to be under purifying selection, suggesting that they play a crucial functional role not only in olfaction but also potentially in additional pathways.