[Validation of the QFS measuring the frequency and satisfaction in social behaviours in psychiatric adult population]. / Validation du Questionnaire de fonctionnement social (QFS), un autoquestionnaire mesurant la fréquence et la satisfaction des comportements sociaux d'une population adulte psychiatrique.

INTRODUCTION: Although everyone working in routine mental health services recognizes the scientific and ethical importance to ensure that treatments being provided are of highest quality, there is a clear lack of consensus regarding what outcome domains to include, what measure of assessment to use and, moreover, who to question when assessing. LITERATURE FINDINGS: Since the fifties, social functioning is considered as an important dimension to take into account for treatment planning and outcome measuring. But for many years, symptoms scales have been considered as sufficient outcome measures and social functioning improvement expected on the basis of symptoms alleviation. As symptoms and social adjustment sometimes appear relatively independent, no accurate conclusion concerning the patient's social functioning can so be driven on the basis of his clinical symptoms. More attention has then been directed toward the development of instruments specifically intended to measure the extent and nature of social functioning impairments observed in most psychiatric syndromes. Many of these instruments are designed to be completed by caregivers or remain time consuming and difficult to use routinely. Presently, in clinical practice, there is a need to rely on simple and brief instruments considering patients'perspective about their social adjustment as a function of time. AIM OF THE STUDY: The aim of this study is to present a new instrument, the QFS, initially developed in order to assess social functioning in patients involved in group psychotherapy programs conducted in a specialist mental health setting, as well as its psychometric characteristics. METHODOLOGY: It was designed to be completed in less than 10 minutes and the questions are phrased in a simple and redundant way, in order to limit problems inherent to illiteracy or language comprehension. The QFS is a 16 items self-report instrument that assesses both the frequency of (8 items) and the satisfaction with (8 items) various social behaviours adopted during the 2 weeks period preceding the assessment. It yields three separate indexes of social functioning, defined a priori and labelled "frequency", "satisfaction" and "global". The higher the scores, the better the social functioning. The QFS was administered to 457 subjects, aged between 18 and 65, including 176 outpatients (99 with anxious or depressive disorders, 25 with personality disorders and 52 with psychotic disorders) and 281 healthy control subjects. RESULTS: No significant difference was found between patients and controls according to age or gender distribution. Acceptance rate was high (>95%). Moreover, the QFS was generally acceptable to the clinicians who used it. Internal consistency calculated for each index ranged from 0.65 to 0.83 (Cronbach alpha). Test-retest reliability, calculated within a 15 days time interval on a sample of 49 healthy controls, ranged from 0.69 to 0.71 (intraclass correlation coefficient). Discriminant validity was calculated on healthy controls and patients divided into sub-groups according to their diagnosis. It showed to be excellent, with significantly higher scores in control subjects than in psychiatric patients and significant differences across diagnostic categories (Kruskal-Wallis ANOVA with post-hoc tests, all p<0.05). The convergent validity of the QFS with other measures of social functioning was calculated, using the Social Adaptation Self-Evaluation Scale (SASS) and the Social Adjustment Scale Self-Report (SAS-SR). With the SASS, the convergent validity was higher among patients (Spearman rS 0.71 to 0.92, p<0.01) than controls (rS from 0.49 to 0.66, p<0.001). In healthy controls, correlation with the SAS-SR was moderate but statistically significant (rS from - 0.21 to - 0.44, p<0.05). When comparing QFS scores with self-rated symptoms severity, lower levels of social functioning were significantly associated with more severe symptoms according to the Brief Symptom Inventory (BSI: rS from - 0.38 to - 0.65, p<0.001). The QFS indexes demonstrated sensitivity to change (Wilcoxon: all p<0.05) on a sample of 27 out-patients suffering from anxious-depressive disorders questioned before and after 4 months of cognitive behavioural group therapy running on a weekly basis during 16 sessions of 2 hours each.The factorial validity of the QFS was measured through 3 separate factor analysis conducted using the data of 457 subjects. The first analysis considered only Frequency items; 7 out of 8 items had loadings above 0.5 on Factor 1 accounting for 30.7% (unrotaded) of the variance. The second analysis considered only Satisfaction items; all items had loadings above 0.6 on Factor 1 explaining 43.4% (unrotaded) of the variance. And finally, in the third factor analysis, all QFS items were included; 15 out of 16 items had loadings above 0.4 on Factor 1 accounting for 30% (unrotated) of the variance. Concerning the factorial validity of the instrument, these results suggest that all QFS items belong to the same underlying dimension. DISCUSSION: Finally, provisional norms for the QFS are provided for healthy controls, in order to characterise individual patients or patient subgroups. In conclusion, the need for assessment in clinical routine, in order to estimate different aspects of patients conditions as well as the quality of the treatment provided, has contributed to the development of a large variety of instruments measuring several domains. Concerning the level of social functioning, many instruments fail to meet chief criterion of feasibility, remaining often too complex or time onsuming. Moreover, only few of them are available in French. CONCLUSION: The QFS presented here is a brief, simple and easy to administer self-rating scale that displays satisfactory psychometric properties. It seems to be a valuable instrument for the monitoring of social functioning in psychiatric patients which, from a therapeutic point of view, may have a clear impact as it sets up expectation of change and allows both to reality test patients and therapists beliefs about the presence of progress or not and to identify if therapy is working on this specific outcome domain. Though, to date, the administration of the QFS to other populations and treatment modalities requires further investigation.

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.

Acute and chronic effects of morphine and naloxone on the phosphorylation of neurofilament-H proteins in the rat brain.

Increased amounts of phosphorylated neurofilaments (pNF-H and pNF-M) are found in postmortem brains of opioid addicts. Because of the potential relevance of aberrant pNF in opioid addiction (alterations of neuronal cytoskeleton and associated functions), the effects of opiate drugs on pNF-H were investigated in rat brain. Acute morphine (30 mg/kg, 2 h) induced a marked increase in the immunodensity of pNF-H in the cerebral cortex (93%). Chronic morphine (10-100 mg/kg for 5 days) followed by opiate withdrawal resulted in a time-dependent decline in pNF-H (induction of tolerance). Thus, 2 h after the last dose of morphine, the abundance of pNF-H was still increased (27%), which was followed (6-24 h) by down-regulation of pNF-H (5% increase at 6 h; 5% decrease at 12 h, and 29% decrease at 24 h). The acute (10 mg/kg for 2 h) and chronic (2 x 10 mg/kg for 14 days) treatments with naloxone, an opioid receptor antagonist, did not alter pNF-H in the cerebral cortex, suggesting that the opioid receptors (probably the mu-type) modulating the phosphorylation state of NF-H are not tonically activated by endogenous opioids. The results indicate that morphine addiction is associated with an aberrant hyperphophorylation of NF-H in the rat brain.

Cyclic AMP-mediated signaling components are upregulated in the prefrontal cortex of depressed suicide victims.

The components of cyclic AMP signaling cascade (catalytic (Calpha) subunit of cyclic AMP-dependent protein kinase (PKA) and cyclic AMP response element binding protein (CREB)) were quantitated by Western blotting in the prefrontal cortex of depressed suicide victims (n=23) and their matched controls (n=14). There was a significant increase in the levels of CREB, both in total (tCREB; 121+/-8% (mean+/-S.E.M.), P<0.02) and phosphorylated (pCREB; 128+/-9%, P<0.01) forms, but not in PKA Calpha levels (109+/-9%, ns), in brains of depressed suicides compared to those in control subjects. The increases in CREB were specifically observed in antidepressant drug-free subjects (tCREB: 137+/-11%, P<0.01; pCREB: 136+/-12%, P<0.02; n=9), but not in the antidepressant-treated subjects (tCREB: 108+/-18%, ns; pCREB: 111+/-17%, ns; n=8). There were significant correlations between the levels of PKA and those of tCREB and pCREB in the prefrontal cortex of depressed suicides. These results indicate that the components of cyclic AMP signaling are upregulated in a coordinated manner in brains of depressed suicides and that this alteration is not related to antidepressant treatment.

Relationships between beta- and alpha2-adrenoceptors and G coupling proteins in the human brain: effects of age and suicide.

Interactions between brain alpha2- and beta-adrenoceptors are of interest in physiological (aging) and pathological (major depression) processes involving both receptors. In this study, total beta-adrenoceptors and beta1/2-subtypes were quantitated in postmortem human brains to investigate their relationships with alpha2A-adrenoceptors and specific G proteins during the process of aging and in brains of suicide victims. Analysis of [3H]CGP12177 binding, in the presence of CGP20712A (beta1-antagonist), indicated that the predominant beta-adrenoceptor in the frontal cortex is the beta1-subtype (65-75%). The density of total beta- (r=-0.60, n=44) or beta1-adrenoceptors (r=-0.78, n=22), but not the beta2-subtype, declined with aging (3-80 years). The density of total beta- or beta1-adrenoceptors, but not the beta2-subtype, correlated with the number of alpha2-adrenoceptors quantitated in the same brains with the agonist [3H]UK14304 (r=0.71-0.81) or the antagonist [3H]RX821002 (r=0.61-0.66). Interestingly, the ratios alpha2/beta- or alpha2/beta1-adrenoceptors did not correlate with the age of the subject at death, indicating that the proportion of alpha2/beta-adrenoceptors in brain remains rather constant during the process of aging. The density of beta-adrenoceptors correlated with the immunodensity of G(alpha)s (r=0.55) and Gbeta (r=0.61) proteins, and that of alpha2-adrenoceptors with those of G(alpha)i1/2 (r=0.88) and Gbeta (r=0.65). In brains of suicides, compared to controls, the ratio between alpha2- and beta- or beta1-adrenoceptors (alpha2-full agonist sites/beta-sites) was greater (1.3- to 2.0-fold; P<0.05). The results demonstrate a close interdependence between brain alpha2- and beta-adrenoceptors during aging, and in brains of suicides. The quantitation of the alpha2A/beta-adrenoceptor ratio could represent a relevant neurochemical index in the study of brain pathologies in which both receptors are involved.

Regulation of nonphosphorylated and phosphorylated forms of neurofilament proteins in the prefrontal cortex of human opioid addicts.

The neurofilament (NF) proteins (NF-H, NF-M, and NF-L for high, medium, and low molecular weights) play a crucial role in the organization of neuronal shape and function. In a preliminary study, the abundance of total NF-L was shown to be decreased in brains of opioid addicts. Because of the potential relevance of NF abnormalities in opioid addiction, we quantitated nonphosphorylated and phosphorylated NF in postmortem brains from 12 well-defined opioid abusers who had died of an opiate overdose (heroin or methadone). Levels of NF were assessed by immunoblotting techniques using phospho-independent and phospho-dependent antibodies, and the relative (% changes in immunoreactivity) and absolute (changes in ng NF/microg total protein) amounts of NF were calculated. Decreased levels of nonphosphorylated NF-H (42-32%), NF-M (14-9%) and NF-L (30-29%) were found in the prefrontal cortex of opioid addicts compared with sex, age, and postmortem delay-matched controls. In contrast, increased levels of phosphorylated NF-H (58-41%) and NF-M (56-28%) were found in the same brains of opioid addicts. The ratio of phosphorylated to nonphosphorylated NF-H in opioid addicts (3.4) was greater than that in control subjects (1.6). In the same brains of opioid addicts, the levels of protein phosphatase of the type 2A were found unchanged, which indicated that the hyperphosphorylation of NF-H is not the result of a reduced dephosphorylation process. The immunodensities of GFAP (the specific glial cytoskeletol protein), alpha-internexin (a neuronal filament related to NF-L) and synaptophysin (a synapse-specific protein) were found unchanged, suggesting a lack of gross changes in glial reaction, other intermediate filaments of the neuronal cytoskeletol, and synaptic density in the prefrontal cortex of opioid addicts. These marked reductions in total NF proteins and the aberrant hyperphosphorylation of NF-H in brains of opioid addicts may play a significant role in the cellular mechanisms of opioid addiction.

mu-opioid receptor and alpha2-adrenoceptor agonist stimulation of [35S]GTPgammaS binding to G-proteins in postmortem brains of opioid addicts.

Repeated opioid administration has been associated in human brain with unaltered density of mu-opioid receptors (agonist radioligand binding sites and immunodetected receptor protein). These receptors are coupled to Gi/Go-proteins, which are increased in brain of heroin addicts. To assess the activity of G-proteins and their coupling to receptors after chronic opioid abuse, [35S]GTPgammaS binding was quantified in postmortem prefrontal cortices of 15 opioid-dependent subjects and 15 matched controls. The stimulation of [35S]GTPgammaS binding by the mu-opioid receptor agonist DAMGO or the alpha2-adrenoceptor agonist UK14304 was used as a functional measure of the status of the receptor-G-protein coupling. [35S]GTPgammaS binding basal values were similar in opioid addicts (819+/-83 fmol mg-1 of protein) and controls (918+/-106 fmol mg(-1) of protein). In opioid addicts, [35S]GTPgammaS binding stimulation by DAMGO showed a maximal effect (62+/-8%) and a potency (EC50 = 1.09+/-0.26 microM) that did not differ from the maximal effect (60+/-12%) and potency (EC50 = 2.01+/-0.58 microM) in controls. In opioid addicts, [35S]GTPgammaS binding stimulation by UK14304 was not different in maximal effect (28+/-3%) from controls (32+/-8%), but the potency of the agonist was decreased (EC50 = 4.36+/-1.81 microM) when compared with controls (EC50 = 0.41+/-0.15 microM). The results provide a direct evidence of an apparent normal functional activity of brain mu-opioid receptors (Gi/Go-protein coupling) during the opioid dependence process in humans. The data also demonstrate a functional uncoupling of alpha2-adrenoceptors from G-proteins, which indicates a heterologous desensitization of these receptors. This finding could represent an adaptive mechanism against the decreased noradrenergic activity induced by the chronic presence of opioid drugs.

Association between bipolar disorder and monoamine oxidase A gene polymorphisms: results of a multicenter study.

OBJECTIVE: Although genetic factors have been implicated in the etiology of bipolar disorder, no specific gene has been conclusively identified. Given the link between abnormalities in serotonergic neurotransmission and bipolar disorder, a candidate gene association approach was applied to study the involvement of the monoamine oxidase A (MAOA) gene, which codes for a catabolic enzyme of serotonin, in the susceptibility to bipolar disorder. METHOD: In France and Switzerland, 272 patients with bipolar disorder and 122 healthy subjects were typed for three polymorphic markers of the MAOA gene: the MAOA-CA repeat, the MAOA restriction fragment length polymorphism (RFLP), and a repeat directly adjacent to the variable number of tandem repeats (VNTR) locus. RESULTS: A significant difference in the distribution of the alleles for the MAOA-CA repeat was observed between the female bipolar patients and comparison group. CONCLUSIONS: The results obtained in the French and Swiss population confirm findings from two studies conducted in the United Kingdom.

Wavelet analysis of dynamic PET data: application to the parametric imaging of benzodiazepine receptor concentration.

Receptor density and ligand affinity can be assessed using positron emission tomography (PET). Biological parameters (B(max)('), k(1), k(2), k(on)/V(R), k(off)) are estimated using a compartmental model and a multi-injection protocol. Parametric imaging of the ligand-receptor model has been shown to be of special interest to study certain brain disorders. However, the low signal-to-noise ratio in kinetic curves at the pixel level hampers an adequate estimation of model parameters during the optimization procedure. For this reason, mapping requires a spatial filter, resulting in a loss of resolution. Filtering the kinetic curves in the frequency domain using the Fourier transform is not appropriate, because of difficulties in choosing a correct and efficient cutoff frequency. A wavelet-based filter is more appropriate to such tracer kinetics. The purpose of this study is to build up parametric images at the pixel level while conserving the original spatial resolution, using wavelet-based filtering. Data from [(11)C]flumazenil studies, mapping the benzodiazepine receptor density, were used. An invertible discrete wavelet transform was used to calculate the time-frequency signals of the time-concentration PET curves on a pixel-by-pixel basis. Kinetic curves observed from large regions of interest in high and low receptor-density regions were used to calibrate the threshold of wavelet coefficients. The shrunken wavelet coefficients were then transformed back to the original domain in order to obtain the filtered PET signal. Maps of all binding parameters were obtained at the pixel level with acceptable coefficients of variation of less than 30% for the B(max)(') parameter in most of the gray matter. A strong correlation between model parameter estimates using the usual regions of interest and parametric imaging was observed for all model parameters (r = 0.949 for the parameter B(max)(')). We conclude that wavelet-based filters are useful for building binding parameter maps without loss of the original spatial resolution of the PET scanner. The use of the wavelet-based filtering method can be extended far beyond the multi-injection protocol. It is likely to be also effective for other dynamic PET studies.

Private psychiatry in Switzerland.

INTRODUCTION: Two-thirds of Swiss psychiatrists are engaged, either exclusively or partially, in private practice, a proportion that is higher than in other countries. METHOD: A questionnaire survey of 1000 psychiatrists was carried out. RESULTS: Psychiatrists in private practice display a greater degree of clinical activity, mainly with individuals, than do psychiatrists employed by public institutions; and they work principally within two practice profiles, psychoanalytical and generalist, and much less in the biological profile. They show a preference for the psychological model, mostly in a psychoanalytical orientation. Psychiatrists who have a mixed privatepublic practice - more than half of them - are even more psychoanalytically oriented than psychiatrists working exclusively in private practice. They act as an interface between the public and private sectors, playing a pivotal role as guardians of psychoanalysis, proclaiming its principles to psychiatric residents. CONCLUSION: With the transformations taking place in the health care system, new care concepts are being developed, there is a wider variety of theoretical orientations, and the profession is therefore undergoing substantial changes. ( Int J Psych Clin Pract 2000; 4: 227 - 232).

Objectives for the undergraduate teaching of psychiatry: survey of doctors and students.

OBJECTIVES: The principal aim was to assess the psychiatric topics that doctors and students considered most important for undergraduate teaching. Differences between doctors and students, men and women, physicians/students with or without an interest in psychiatry were examined. DESIGN: A mailed questionnaire was used concerning the knowledge and skills of psychological/psychiatric medi- cine considered to be needed in medical practice. SETTING: The Medical School of the University of Geneva. SUBJECTS: Doctors and undergraduate medical students in their last 2 years of medical training. RESULTS: Both doctors and students agreed on most topics, even though the students tended to give all items a higher rating. Both groups agreed on the importance of the following main topics: the doctor-patient relationship, identification and management of the principal psychiatric disorders and their associated risks and problems of a psychosocial nature. Those doctors showing an interest in psychiatry tended to accentuate the importance attached to interpersonal skills. The male and female doctors and students expressed very similar opinions. The female doctors, however, tended to attach greater importance to relational-emotional aspects and to disorders affecting children and adolescents than did their male colleagues, which is probably a reflection of the specific role that women still play within our society. When asked to assess the current teaching they received in medical school, the students considered that certain important aspects of psychiatry were insufficiently taught. CONCLUSION: These results confirm the importance of teaching psychiatry with an emphasis on problems encountered in general practice.

Imidazoline receptors and human brain disorders.

Major depression, opioid addiction, neurodegenerative diseases, and glial tumors are associated with disturbances of imidazoline receptors (IR) in the human brain. In depression, the level of a 45-kD IR protein (putative I1-IR) is increased in the brain of suicide victims (51%) and in platelets of depressed patients (40%). The density of platelet I1-IR ([125I]-p-iodoclonidine binding) is also increased in depression (135%). The 29/30-kD IR protein (putative I2B-IR) is downregulated (19%) in suicide victims in parallel with a reduction (40%) in the density of I2B-IR ([3H]idazoxan binding). Antidepressant drugs induce downregulation of 45-kD IR protein and I1-sites in platelets of depressed patients and upregulation of I2-sites in rat brain. The densities of I2B-IR and the related 29/30-kD IR protein are decreased (39% and 28%) in the brain of heroin addicts. The density of I2B-IR is increased in Alzheimer's disease (63%) and decreased in Huntington's disease (56%). Brain I2B-IR is not altered in Parkinson's disease. The level of I2-IR in glial tumors is increased (two-fivefold) in parallel with the abundance of the related 29/30-kD IR protein (39%), whereas the level of 45-kD IR protein is decreased (39%). The possible functional relevance of these findings in the context of the pathogenesis of these disorders remains to be elucidated.

[Professional practice and theoretical orientation of women and men psychiatrists]. / Pratiques et orientations théoriques des femmes et des hommes psychiatres.

RESEARCH QUESTIONS: Differences between male and female psychiatrists in their careers, professional and clinical activities, and clinical orientations, in general and in contrasted settings for the practice of psychiatry. METHODS: Survey by mailed questionnaire to psychiatrists working in private practice or in institutions. RESULTS: Male and female psychiatrists share some similar characteristics (age, many interests, etc.). However, female psychiatrists differ from male psychiatrists in numerous respects: more frequently engaged in private practice, shorter work-weeks, less diversification of clinical activities, more frequent reference to a psychological model. In women occupying hierarchic positions, these differences disappear, whilst they are maintained in private practice for those using the psychological model. The differences can be interpreted in part in terms of gender-specific socialization, but their origin could mainly arise from the existence of different systems of gender-based constraints in the management of professional and personal, or family, spheres. CONCLUSIONS: Adjusting the training period and working conditions in institutions could facilitate career diversification for both male and female psychiatrists.

Up-regulation of immunolabeled alpha2A-adrenoceptors, Gi coupling proteins, and regulatory receptor kinases in the prefrontal cortex of depressed suicides.

Suicide and depression are associated with an increased density of alpha2-adrenoceptors (radioligand receptor binding) in specific regions of the human brain. The function of these inhibitory receptors involves various regulatory proteins (Gi coupling proteins and G protein-coupled receptor kinases, GRKs), which work in concert with the receptors. In this study we quantitated in parallel the levels of immunolabeled alpha2A-adrenoceptors and associated regulatory proteins in brains of suicide and depressed suicide victims. Specimens of the prefrontal cortex (Brodmann area 9) were collected from 51 suicide victims and 31 control subjects. Levels of alpha2A-adrenoceptors, Galphai1/2 proteins, and GRK 2/3 were assessed by immunoblotting techniques by using specific polyclonal antisera and the immunoreactive proteins were quantitated by densitometry. Increased levels of alpha2A-adrenoceptors (31-40%), Galphai1/2 proteins (42-63%), and membrane-associated GRK 2/3 (24-32%) were found in the prefrontal cortex of suicide victims and antidepressant-free depressed suicide victims. There were significant correlations between the levels of GRK 2/3 (dependent variable) and those of alpha2A-adrenoceptors and Galphai1/2 proteins (independent variables) in the same brain samples of suicide victims (r = 0.56, p = 0.008) and depressed suicide victims (r = 0.54, p = 0.041). Antemortem antidepressant treatment was associated with a significant reduction in the levels of Galphai1/2 proteins (32%), but with modest decreases in the levels of alpha2A-adrenoceptors (6%) and GRK 2/3 (18%) in brains of depressed suicide victims. The increased levels in concert of alpha2A-adrenoceptors, Galphai1/2 proteins, and GRK 2/3 in brains of depressed suicide victims support the existence of supersensitive alpha2A-adrenoceptors in subjects with major depression.

Imidazoline receptor proteins in brains of patients with Alzheimer's disease.

Imidazoline receptors (29/30- and 45-kDa proteins) were quantitated in postmortem brains of patients with Alzheimer's disease (AD) by using immunoblotting techniques and a specific antiserum. Increased levels of the 29/30-kDa protein (30%), 45-kDa protein (36%) and glial fibrillary acidic protein (88%) were found in the frontal cortex of AD patients. These findings are in line with the reported higher density of imidazoline receptors labelled by [3H]idazoxan in AD brains, suggesting that these imidazoline receptor proteins are related to the I2-imidazoline receptor located in mitochondria of glial (astrocyte) cells.

Density of imidazoline receptors in platelets of euthymic patients with bipolar affective disorder and in brains of lithium-treated rats.

BACKGROUND: Platelet imidazoline receptors have been shown to be up-regulated in patients with unipolar major depression. This study examines the status of imidazoline receptor proteins in platelets of euthymic bipolar patients and in brains of lithium-treated rats. METHODS: Platelets were collected from 12 bipolar patients (lithium-treated or drug-free) and brains from chronic lithium-treated rats. Imidazoline receptors were quantitated by immunoblotting, using a specific antiserum, and/or radioligand binding. RESULTS: No changes in platelet imidazoline receptors (35-kDa and 45-kDa proteins) were found. Lithium treatment did not alter brain imidazoline receptors (29/30-kDa, 45-kDa, and 66-kDa proteins or density/affinity of [3H]-idazoxan binding sites). CONCLUSIONS: Imidazoline receptor proteins are not altered in platelets of euthymic patients with bipolar affective disorder.

Cerebral cortex pathology in aging and Alzheimer's disease: a quantitative survey of large hospital-based geriatric and psychiatric cohorts.

In order to explore the relationships between the involvement of specific neuronal populations and cognitive deterioration, and to compare the hierarchical patterns of cortical involvement in normal brain aging and Alzheimer's disease, over 1200 brains from elderly subjects without cognitive deficits, as well as from patients with age-associated memory impairment and Alzheimer's disease, were examined. Our results suggest that the neuropathological changes associated with normal brain aging and Alzheimer's disease affect select cortical circuits at different points in time. Extensive hippocampal alterations are correlated with age-associated memory impairment, whereas substantial neurofibrillary tangle formation in neocortical association areas of the temporal lobe is a prerequisite for the development of Alzheimer's disease. Despite several lines of evidence involving amyloid deposit in the pathogenesis of Alzheimer's disease and Down's syndrome, our observations indicate that there is no correlation between senile plaque densities and degree of dementia in both disorders. In contrast to younger elderly cases, in the ninth and tenth decades of life, there is a differential cortical involvement in that parietal and cingulate areas are early affected in the course of Alzheimer's disease, and neocortical senile plaques densities are strongly correlated with the severity of dementia. Moreover, Alzheimer's disease symptomatology is characterized in these very old patients by high neurofibrillary tangle densities in the anterior CA1 field, but not in the entorhinal cortex and inferior temporal cortex. These observations are discussed in the light of the hypothesis of global corticocortical disconnection and with respect to the notion of selective neuronal vulnerability in Alzheimer's disease.

Density of guanine nucleotide-binding proteins in platelets of patients with major depression: increased abundance of the G alpha i2 subunit and down-regulation by antidepressant drug treatment.

The aim of this study was to quantitate the density of guanine nucleotide-binding (G) protein subunits (inhibitory G alpha i, stimulatory G alpha s, G alpha q/11, and G beta) in platelets of unipolar depressed patients to assess the status of these signal transduction proteins in depression and the effects of antidepressant drug treatment. Blood platelets were collected from 22 drug-free depressed patients and 22 age- and sex-matched healthy controls. The levels of the various G protein subunits were assessed by immunoblotting techniques. The immunoreactivity of G alpha 12 was increased (41%) and that of G alpha i3 decreased (25%) in platelets of depressed patients. The levels of other G protein subunits (G alpha s, G alpha q/11, G beta) did not change significantly with respect to those of control subjects. Chronic administration of cyclic antidepressant drugs (citalopram, clomipramine, imipramine) decreased the immunoreactivity of the up-regulated G alpha i2 protein (31%). Since platelet G alpha i2 is in line with the existence of supersensitivity of these receptors in major depression.

Marked decrease of immunolabelled 68 kDa neurofilament (NF-L) proteins in brains of opiate addicts.

NEUROFILAMENT (NF) proteins, the major components of the neuronal cytoskeleton, have been shown to represent previously unknown targets for the chronic effects of morphine in rats. This study was designed to evaluate the abundance of immunoreactive NF-L (68 kDa) proteins in post-mortem brains of chronic opiate addicts who had died of a heroin or methadone overdose. Levels of NF-L proteins were assessed by immunoblotting techniques. Levels of immunoreactive NF-L proteins were markedly decreased (47%, n = 17) in the frontal cortex. The reduced abundance of brain NF-L proteins was not related to the post-mortem delay or to the plasma concentrations of opiates, suggesting that the observed changes represent a specific long-term effect of opiate drugs. Because of the functions associated with NF proteins (e.g. axonal transport), this finding suggests that opiate drugs may induce neuronal damage after chronic abuse in humans.

Regulation of immunolabelled mu-opioid receptors and protein kinase C-alpha and zeta isoforms in the frontal cortex of human opiate addicts.

To assess the status of opioid receptors in the human brain during the process of opiate addiction, the abundance of immunoreactive mu-opioid receptors was quantitated in postmortem brains of chronic opiate addicts who had died of a heroin or methadone overdose. The immunoreactive levels of the associated enzyme protein kinase C (PKC-alpha and zeta isoforms) and G proteins (G alpha(i1/2) subunits) were also assessed in the same brains. In the frontal cortex of opiate addicts, the abundance of mu-opioid receptors was not different from that obtained in matched controls. The level of Ca2+-dependent PKC-alpha was decreased (25%), whereas that of the atypical PKC-zeta remained unchanged. The density of G alpha(i1/2) proteins also was found to be increased (40%). The results indicate that opiate addiction in humans does not appear to be associated with a reduced density of brain mu-opioid receptors. The sustained down-regulation of PKC-alpha in the brain of opiate addicts would allow the up-regulation of G alpha(i1/2) proteins aimed at compensating the postulated desensitization of the mu-opioid receptor system.