Violetta Klimek

Dopaminergic abnormalities in amygdaloid nuclei in major depression: A postmortem study

BACKGROUND A deficiency of mesolimbic dopamine (DA) is a leading candidate for the etiology of certain symptoms of depression (e.g., anhedonia and loss of motivation). Here we show amounts of dopaminergic proteins in the amygdala, a key brain structure involved in the integration of emotions and stress, in subjects with major depression and in psychiatrically normal control subjects. METHODS The specific binding of [(125)I]RTI 55 to the DA transporter, [(3)H]SCH 23390 to the D1 receptor and [(125)I]epidepride to D2/D3 receptors were measured in the right amygdaloid complex in postmortem brains from 11 subjects with major depression and 11 matched control subjects. RESULTS The binding of [(125)I]RTI 55 to DA transporter was significantly lower in the basal and central amygdaloid nuclei, whereas the binding of [(125)I]epidepride to D2/D3 receptors was significantly higher in the basal, central, and lateral amygdaloid nuclei in major depression compared with control subjects. No difference in the binding of [(3)H]SCH 23390 to D1 receptors was observed. CONCLUSIONS Given that DA depletion in rats can induce a reduction in the DA transporter and an upregulation of D2/D3 receptors, our data are consistent with the hypothesis that major depression is associated with a deficiency of mesolimbic DA.

Elevated Concentrations of CRF in the Locus Coeruleus of Depressed Subjects

Research evidence that corticotropin-releasing factor (CRF) plays a role in the pathophysiology of major depressive disorder (MDD) has accumulated over the past 20 years. The elevation of lumbar cerebrospinal fluid (CSF) concentrations of CRF decreased responsiveness of pituitary CRF receptors to challenge with synthetic CRF, and increased levels of serum cortisol in MDD subjects support the hypothesis that CRF is chronically hypersecreted in at least the endocrine circuits of the hypothalamic–pituitary–adrenal (HPA) axis and may also involve other CRF brain circuits mediating emotional responses and/or arousal. One such circuit includes the excitatory CRF input to the locus coeruleus (LC), the major source of norepinephrine in the brain. Furthermore, there are now reports of decreased levels of CRF in lumbar CSF from MDD patients after symptom relief from chronic treatment with antidepressant drugs or electroconvulsive therapy. Whether this normalization reflects therapeutic effects on both endocrine- and limbic-associated CRF circuits has not yet been effectively addressed. In this brief report, we describe increased concentrations of CRF-like immunoreactivity in micropunches of post-mortem LC from subjects with MDD symptoms as established by retrospective psychiatric diagnosis compared to nondepressed subjects matched for age and sex.

Elevated levels of tyrosine hydroxylase in the locus coeruleus in major depression

BACKGROUND Levels of tyrosine hydroxylase (TH) are regulated in the noradrenergic locus coeruleus (LC) in response to changes in the activity of LC neurons and in response to changes in brain levels of norepinephrine. To study the potential role of central noradrenergic neurons in the pathobiology of major depression, TH protein was measured in the LC from postmortem brains of 13 subjects with a diagnosis of major depression and 13 age-matched control subjects having no Axis I psychiatric diagnosis. Most of the major depressive subjects died as a result of suicide. METHODS Protein from sections cut through multiple rostro-caudal levels of LC was transferred to Immobilon-P membrane, immunoblotted for TH, and quantified autoradiographically. RESULTS The distribution of TH-immunoreactivity (TH-ir) along the rostro-caudal axis of the LC was uneven and was paralleled by a similar uneven distribution of neuromelanin-containing cells in both major depressive and psychiatrically normal control subjects. Amounts of TH-ir in the rostral, middle and caudal levels of the LC from major depressive subjects were significantly higher than that of matched control subjects. There were no significant differences in the number of noradrenergic cells at any particular level of the LC comparing major depressive subjects to control subjects. CONCLUSIONS Elevated expression of TH in the LC in major depression implies a premortem overactivity of these neurons, or a deficiency of the cognate transmitter, norepinephrine.

Elevated agonist binding to α2-adrenoceptors in the locus coeruleus in major depression

BACKGROUND Recent postmortem studies demonstrate disrupted neurochemistry of the noradrenergic locus coeruleus (LC) in major depression (MD). Increased levels of tyrosine hydroxylase and decreased levels of norepinephrine transporter implicate a norepinephrine deficiency in the LC in MD. Here we describe a study of alpha2-adrenoceptors in the LC and raphe nuclei of subjects with MD compared with psychiatrically normal control subjects. METHODS The specific binding of p-[125I]iodoclonidine to alpha2-adrenoceptors was measured at multiple levels along the rostrocaudal extent of the LC in postmortem tissue from 14 control and 14 MD subjects. In addition, p-[125I]iodoclonidine binding was measured in the dorsal and median raphe nuclei in the same tissue sections. RESULTS The specific binding of p-[125I]iodoclonidine to alpha2-adrenoceptors was significantly elevated throughout the LC from MD compared with matched control subjects. No significant differences were observed in p-[125I]iodoclonidine binding to alpha2-adrenoceptors in the raphe nuclei comparing MD and control subjects. CONCLUSIONS Given that alpha2-adrenoceptors are upregulated in laboratory animals by treatment with drugs that deplete norepinephrine, our findings implicate a premortem deficiency of brain norepinephrine in the region of the locus coeruleus in subjects with MD.

Brain Noradrenergic Receptors in Major Depression and Schizophrenia

The binding of [125I]p-iodoclonidine to alpha-2, and/or [125I]iodopindolol to beta-1 and beta-2 adrenoceptors was measured in right prefrontal cortex (Brodmanns area 10) and right hippocampus from subjects with DSM-III-R diagnoses of major depression (n = 15) or schizophrenia (n = 8) as well as from control subjects (n = 20). No significant differences between study groups were observed in binding to alpha-2 adrenoceptors in any of the six layers of prefrontal cortex or in any of the hippocampal fields. Likewise, there were no significant differences in beta-1 or beta-2 adrenoceptor binding in any of the hippocampal fields between control and major depressive subjects. In contrast, binding to beta-1 adrenoceptors, but not beta-2 adrenoceptors, was significantly lower (−13 to −27%) in most hippocampal fields of schizophrenic subjects as compared to control subjects or to major depressives. Alterations in beta-1 adrenoceptor binding in the hippocampus of schizophrenics provide further evidence for a role of central noradrenergic neurons in the neurochemical pathology of schizophrenia.

Quantitative distribution of monoamine oxidase A in brainstem monoamine nuclei is normal in major depression

An abnormal expression of noradrenergic proteins (e.g., tyrosine hydroxylase, norepinephrine transporters) in the locus coeruleus has recently been demonstrated in subjects with major depression and/or victims of suicide. Monoamine oxidase A (MAO-A) is a key enzyme in the catabolism of biogenic amines and is expressed in brain noradrenergic neurons. In this study, the binding of [3H]Ro41-1049 to MAO-A was measured by quantitative autoradiography at multiple levels along the rostral-caudal axis of the noradrenergic locus coeruleus from subjects with major depression and age- and postmortem interval-matched control subjects who were psychiatrically normal. [3H]Ro41-1049 binding to MAO-A was unevenly distributed along the axis of the locus coeruleus, paralleling an uneven number of neuromelanin-containing (noradrenergic) neurons throughout the nucleus. Accordingly, there was a significant correlation between the number of neuromelanin-containing neurons per section and the specific binding of [3H]Ro41-1049 at any particular level of the locus coeruleus in control subjects (r(2)=0.25; p<0.001) and in subjects with major depression (r(2)=0.14; p<0. 001). Moderate levels of [3H]Ro41-1049 binding were observed in regions surrounding the locus coeruleus, including the central gray and the dorsal and median raphe nuclei. No significant differences in [3H]Ro41-1049 binding to MAO-A were observed at any level of the locus coeruleus, or raphe nuclei, comparing subjects with major depression to psychiatrically normal control subjects. These findings demonstrate that the pathophysiology of major depression is not likely to involve abnormalities in MAO-A.

Serotonin transporter and MAO-B levels in monoamine nuclei of the human brainstem are normal in major depression

Neurochemical imbalance between noradrenergic and serotonergic systems has been postulated to underlie the pathophysiology of psychiatric illnesses involving mood disorders. The present study was designed to examined the possibility that serotonergic innervation of the locus coeruleus (LC) is abnormal in major depression, by measuring two proteins expressed by serotonergic neurons, but not by noradrenergic neurons, in the region of the LC. The specific binding of [(3)H]paroxetine to serotonin transporter (SERT) and of [(3)H]lazabemide to monoamine oxidase (MAO-B) were measured autoradiographically in tissue sections cut transversely at multiple levels along the rostro-caudal extent of the LC, as well as in the caudal portion of the dorsal raphe nucleus, from psychiatrically normal subjects and age-matched subjects with major depression. Under the conditions of the assays, [(3)H]paroxetine binding in the LC was specific for the SERT, based on the rank order of affinity of compounds for inhibiting [(3)H]paroxetine binding in the LC, i.e. citalopram > imipramine > desipramine > mazindol. The binding of [(3)H]paroxetine to SERT and [(3)H]lazabemide to MAO-B were higher in the raphe nuclei than in the LC. Comparison of control subjects to major depressive subjects revealed no differences in the amount of [(3)H]paroxetine binding to SERT and [(3)H]lazabemide to MAO-B in the LC, as well as in the raphe nuclei. These findings imply that serotonergic innervation of the LC is intact in major depression.

Noradrenergic pathology in psychiatric disorders: postmortem studies.

In this paper, we review research utilizing postmortem brain tissue in order to investigate the potential neuropathology of the noradrenergic system in psychiatric disorders. The postmortem tissue approach to the study of the noradrenergic system has been used primarily in investigations of the biology of suicide and depression. Findings from postmortem studies provide data generally consistent with the hypothesis that a norepinephrine deficiency exists in depression, and possibly in the victims of suicide. However, postmortem studies do not presently provide irrefutable evidence of noradrenergic neuropathology. Technical shortcomings, issues of reproducibility, and the strengths of postmortem research are reviewed. More rigorously performed postmortem research is needed to aid researchers in pinpointing specific neuropathologies associated with psychiatric disease.

Effects of depression, cigarette smoking, and age on monoamine oxidase B in amygdaloid nuclei

Altered concentrations of dopamine transporter and D2/D3 receptors have been observed in the amygdaloid complex of subjects with major depression. These findings are suggestive of neurochemical abnormalities in the limbic dopamine system in depression. Monoamine oxidase-B (MAO-B) is a key enzyme in the catabolism of biogenic amines, including dopamine, and alterations in this enzyme may underlie dopaminergic abnormalities associated with depression. The specific binding of [(3)H]lazabemide to MAO-B was measured in the right amygdaloid complex of 15 major depressive subjects and 16 psychiatrically normal controls. Subjects of the two study groups were matched as close as possible for age, sex, and postmortem interval. Examination of the regional distribution of MAO-B revealed lower [(3)H]lazabemide binding to MAO-B in the lateral and basal nuclei of the amygdala and higher binding in the medial nucleus. A modest elevation in binding to MAO-B observed in all amygdaloid nuclei in major depressive subjects as compared to control subjects failed to reach statistical significance. A significant decrease in binding to MAO-B was observed when cigarette smokers were compared to nonsmoking subjects. The amount of MAO-B binding positively correlated with the age of subjects in all nuclei investigated. A decreased amount of MAO-B in smokers further validates the pharmacological effect of tobacco smoke on this enzyme.

Distribution ofα2-adrenoceptors in the human locus coeruleus

Abstract Recent reports of specific topographic patterns of cell loss in the locus coeruleus (LC) in psychiatric and neurologic disorders underscores the need for detailed neurochemical analyses of this cell group. In this study, the anatomical distribution of α 2 -adrenoceptors and its relationship to the distribution of noradrenergic neurons in the human LC was studied. Quantitative autoradiography was used to assess the binding of [ 125 I] p -iodoclonidine ([ 125 I]PIC) to α 2 -adrenoceptors coordinately with counts of neuromelanin-containing cells in tissue sections cryocut at 10–13 levels along the rostrocaudal axis of the LC. Pontine brain tissue was obtained postmortem from 7 subjects dying of natural or accidental causes, ranging in age from 26 to 78 years. Both the binding of [ 125 I]PIC and number of neuromelanin-containing cells were differentially distributed along the LC axis ( P ) with almost identical topographical patterns. The highest concentration of binding and the greatest number of neuromelanin-containing cells per section occurred near the middle portion of the nucleus. There was a significant correlation between the number of neuromelanin-containing cells per section and the specific binding of [ 125 I]PIC at any particular level of the LC ( r 2 = 0.56; P ). The highest and lowest amounts of [ 125 I]PIC binding in the LC were observed in the youngest and oldest subjects, respectively, and this trend was parallelled by a significant negative correlation between the number of neuromelanin-containing cells at a given level and age ( r 2 = 0.85; P ). The uneven distribution of α 2 -adrenoceptors in the LC demonstrates the importance of anatomical specificity when performing quantitative studies of LC protein chemistry in psychiatric and neurologic disorders.