The dynorphin system has been associated with the regulation of mood. The expression of the prodynorphin mRNA was currently studied in the amygdaloid complex, a brain region critical for emotional processing, in subjects (14–15 per group) diagnosed with major depression, bipolar disorder, or schizophrenia and compared to normal controls. In situ hybridization histochemistry was used to characterize the anatomical distribution and expression levels of the prodynorphin mRNA within the amygdaloid complex. High prodynorphin mRNA levels were expressed in the parvicellular division of the accessory basal, posterior cortical, periamygdaloid cortex, and amygdalohippocampal area in normal subjects. Individuals with major depression had significantly reduced (41–68%) expression of the prodynorphin mRNA in the accessory basal (both parvicellular and magnocellular divisions; P < 0.01) and amygdalohippocampal area (P < 0.001) as compared to controls. The bipolar disorder group also showed a significant reduction (37–38%, P < 0.01) of the mRNA expression levels in the amygdalohippocampal area and in the parvicellular division of the accessory basal. No other amygdala nuclei studied showed any significant differences for the prodynorphin mRNA levels measured in the major depression and bipolar disorder subjects. Additionally, the prodynorphin mRNA expression levels did not differ significantly between the schizophrenic and normal control subjects in any of the amygdala areas examined. These findings indicate specific prodynorphin amygdala impairment in association with mood disorder.
The dynorphin opioid neuropeptide system is involved in motor, cognitive, and endocrine functions as well as in the regulation of mood. In the human brain, the prodynorphin gene is highly expressed in limbic-related areas such as the amygdala, hippocampus, ventral striatum, patch compartment of the dorsal striatum, entorhinal cortex, and hypothalamus.1 Administration of dynorphinergic drugs to humans induces dysphoria and psychotomimetic symptoms.2,3 Very few studies have examined the levels of dynorphin peptides or the precursor, prodynorphin, in individuals with psychiatric illnesses. An increase of dynorphin A peptides was detected in the cerebrospinal fluid (CSF) of drug-free schizophrenics,4,5 and reduced CSF levels of dynorphin (1–8) immunoreactivity was reported in patients diagnosed with schizophrenia.6 Although activation of the dynorphin system is normally associated with negative mood states, dynorphin peptides have not been studied in patients with affective disorders. However, prodynorphin mRNA levels were found to be elevated in the limbic-related patch compartment of the dorsal striatum in suicide victims.7
The amygdaloid complex is considered a key limbic brain region for processing emotional information.8,9,10 Both clinical and experimental animal studies have shown a strong involvement of the amygdala in anxiety, fear, emotional memory, emotional social responses, and stimulus-reward association.10,11,12,13,14,15,16,17,18,19 A number of in vivo studies have also provided evidence indicating impaired amygdala function in depressed patients.20,21,22 The amgydaloid complex has one of the highest expressions of the prodynorphin gene in the human brain1 with the prodynorphin mRNA expressed preferentially in superficial nuclei such as the cortical, amygdalohippocampal area (AHA), and periamygdaloid cortex in normal subjects.1,23 There is also high prodynorphin mRNA expression in the accessory basal (AB) nucleus, the most medial of the deep amygdaloid nuceli. Considering that impairment of amygdaloid function can lead to dysfunction of the regulation of emotional states and that the dynorphin system has been linked with negative mood, the present study investigated the prodynorphin mRNA expression in the amygdaloid complex in individuals with mood disorders. In situ hybridization histochemistry was used to measure prodynorphin mRNA expression levels in post-mortem brain specimens from subjects diagnosed with major depression or bipolar disorder and compared to schizophrenics and normal controls.
Material and methods
Human amgydala specimens (mid to caudal level; 14 μm-thick frozen sections cut in the coronal plane) were obtained from the Stanley Foundation Neuropathology Consortium that collected the brains under approved ethical guidelines. Four groups were studied from this collection: schizophrenia (n = 14), bipolar disorder (n = 14; 10 with psychotic features), major depression without psychotic features (n = 14), and normal controls (n = 15). Psychiatric diagnosis had been established independently by two psychiatrists using DSM-IV criteria as described by Torrey and colleagues.24 The detailed demographic information on these subjects has been previously described.24 In brief, schizophrenic subjects (nine males/five females; 12 white/two Asians): 43.6 ± 3.5 years old (range 25–62 years), postmortem interval (PMI) of 34.2 ± 4.01 (range 12–61 h). Bipolar subjects (nine males/six females; 14 white/one black): 42.3 ± 3.0 years old (range 25–61 years), PMI of 32.5 ± 4.2 (range 13–62 h). Major depression subjects (nine males/ six females; 15 white): 46.5 ± 2.4 years old (range 30–65 years), PMI of 27.5 ± 2.8 (range 7–47 h). Normal control subjects (nine males/six females; 14 white, one black): 48.1 ± 2.8 (range 29–68 years), PMI of 23.7 ± 2.6 (range 8–42 h). The groups had been matched for age, sex, PMI, and brain hemisphere. The brains studied had also been matched for mRNA stability (GAPdH and actin) and for pH.24 All demographic and toxicological (limited) information as well as documented medical data (lifetime antipsychotic (fluphenazine) treatment and history of drug abuse) about the subjects were provided by the Stanley Foundation Neuropathology Consortium. No information was available regarding the lifetime antidepressant medication treatment. CNS medication at the time of death: Major Depression subjects: tricyclic (TCA; n = 3), selective serotonin reuptake inhibitors (SSRI; n = 4), lithium (n = 2), and anxiolytics (n = 5). Bipolar disorder subjects: tricyclic (n = 2), SSRI (n = 1), SNRI (n = 1), lithium (n = 4), antipsychotic (n = 7), valproate (n = 4), anxiolytic (n = 5), and antidyskinetic (n = 1). Schizophrenic subjects: antipsychotic (n = 11), SSRI (n = 2), TCA (n = 3), anxiolytic (n = 2). One major depression, three bipolar disorder, and three schizophrenics were medication-free at the time of death. Normal subjects also showed negative toxicology for CNS medication. The in situ hybridization experiments (described below) were carried out blinded as to the diagnosis of the subjects. In addition to the above specimens, coronal sections were taken from fresh frozen amygdala brain specimens collected from the Forensic Medicine Department at the Karolinska Institute under approved guidelines approved by the human ethics committee and the Swedish Board of Health and Social Welfare from five normal subjects (three males, two females, 41.2 ± 9.2 years old (range 17–65 years), PMI > 9 < 24 h). These specimens were used to validate the hybridization conditions and the pattern of mRNA expression in the Stanley specimens.
Riboprobes preparation and in situ hybridization
Prodynorphin riboprobes were complementary to a 1.2-kb fragment containing most of exon 4 of the human prodynorphin cDNA (termed preproenkephalin B)25 in a SP65 vector (courtesy of Dr Jim Douglas) or to a 400-bp (exon 4) subcloned into PGEM vector. The riboprobes were transcribed from their templates using SP6 or T3 polymerase and [35S]-UTP (New England Nuclear, Belgium).
The hybridization procedure was carried out as previously described.7 In brief, the labeled probe was added to the hybridization cocktail in a concentration of 20 × 103 cpm per μl, and 0.2 ml of this hybridization mixture was applied to the brain sections. Hybridization was carried out overnight at 55°C in a humidified chamber. Following the hybridization procedure the slides were exposed to Hyperfilm (Amersham, Bucks, UK) along with 14C standards for a period of 3–5 weeks. The slides were subsequently dipped in Kodak emulsion and exposed for 6 weeks at 4°C, developed and counterstained with cresyl violet. Adjacent brain sections were Nissl stained with thionin.
Film autoradiograms were scanned at a resolution of 300 dpi with a ScanMaker III (Microtek Electronics, Düsseldorf, Germany). Light transmittance values were measured from the digitalized images with a Macintosh-based image analysis software system (NIH Image, Wayne Rasband, NIMH). Measurements were taken within discrete amygdala subnuclei (Figure 1; amygdala nomenclature according to Pitkänen and colleagues26) with the help of the Nissl stains and published sources on the human amygdala.26,27,28 Background signal in the adjacent white matter was subtracted. Based on the known radioactivity in the 14C standards relative to their transmittance levels, the light transmittance values were converted to dpm mg−1 using a Rodbard calibration curve (NIH Image). The dorsal portion of the amygdaloid complex was cut off in some of the specimens from the Stanley Foundation collection, so nuclei such as the medial, cortical, assessory basal, and periamygdala cortex, were not visible in all subjects.
Microscopic visualization of the emulsion-dipped slides and Nissl-stained sections were carried out by the use of an Optiphot-2 microscope (Nikon, Tokyo, Japan). The total number of neurons within a square 0.2 × 0.2 mm ocular grid were counted under brightfield illumination at ×40 magnification.
Parametric or non-parametric analysis was used depending on whether there was an approximate normal distribution of the dpm mg−1 (mRNA expression) values. For parametric analysis, multivariate analysis was used to determine group differences in dpm mg−1 (mRNA expression) levels measured. Independent variables (age, PMI, sex, hemisphere side, and documented history of stimulant (cocaine/amphetamine), marihuana, or alcohol use) were included in the model if results from univariate analysis (ANOVA) showed a P-value of <0.250.29 Significant (P ≤ 0.05) differences in the multivariate analysis were further assessed by Tukey–Kramer post-hoc comparison. The association between suicide as a cause of death, age of disease onset, and duration of the disease on the mRNA expression levels was determined only in the psychiatric groups. Kruskal–Wallis non-parametric analysis was used for dpm mg−1 values not normally distributed. All the statistical evaluations were carried out using the JMP (3.1 v) statistical software package.
No differences were observed between the prodynorphin mRNA distribution patterns in the normal human brain specimens obtained from the different brain collections. The same hybridization patterns were obtained using either the 1.2 or the 0.4-kb antisense riboprobes, but the signal intensity was greater with the 1.2-kb probe. No signal above background was observed in the hybridization tests carried out with the sense riboprobe (Figure 2). The complete study of the psychiatric brain specimens and respective controls was subsequently carried out under conditions using the 1.2-kb riboprobe. Consistent with previous studies,1,23 at the amygdala levels examined, the highest prodynorphin hybridization signals were observed in the posterior cortical nucleus, amygdalohippocampal area, parvicellular division of the accessory basal (ABpc), and periamygdaloid cortex (except in the sulcal portion which showed low expression; Figures 2 and 3). Low to moderate expression levels were detected in the lateral nucleus, except in two individuals (one diagnosed with schizophrenia, the other with major depression) who showed an unusual prodynorphin mRNA expression pattern in the amygdala with very high hybridization signals in the lateral nuclei; no known demographic or toxicological information could account for this finding. Very weak to low mRNA levels were observed in the magnocellular division of the AB (ABmc). No positive signals above background were detected in the intermediate or magnocellular division of the basal nucleus, though scattered weak signals were periodically evident in the parvicellular division. Notably, one of the subjects (major depression) with very high mRNA levels in the lateral nucleus also showed very high expression throughout the basal nuclear group. Very low, often not above background, levels of the prodynorphin mRNA hybridization signal were found at the level of the central or medial nuclei examined. Due to their unusual prodynorphin mRNA expression patterns in the amygdala, two individuals were excluded from further study.
In examining the Stanley Foundation specimens, there was no significant relationship between PMI, age, sex, or history of alcohol, marihuana, or stimulant use on the prodynorphin mRNA expression levels measured in any of the amygdala nuclei studied. Only diagnosis in the multivariate analysis had a significant main effect for the prodynorphin mRNA expression levels. Significant diagnosis effects were evident in the ABpc (F3,43 = 5.3010; P = 0.0034) and in the AHA (F3,46 = 8.0930; P = 0.0002). Post-hoc analysis revealed that the bipolar and major depression disorder groups had significantly lower prodynorphin mRNA expression as compared to the control group in these regions (Figures 3 and 4). For subjects diagnosed with major depression, the average reduction compared to the normal group was 41.9% (P < 0.01) in the ABpc and 55.7% (P < 0.001) in the AHA (Figure 4). For subjects diagnosed with bipolar disorder, the reduction was 38.03% (P < 0.01) in the ABpc and 37.42% (P < 0.01) in the AHA (Figure 3). A similar pattern was also evident in the ABmc (F3,42 = 3.6013; P = 0.0210) with a 68.9% (P < 0.01) reduction in the major depression group as compared to control (Table 1). Microscopic examination of the brain sections verified that reduction in the prodynorphin mRNA evident with the film analysis was associated with a reduction in the silver grains overlying the cells. To assess whether the reduction in the prodynorphin mRNA expression levels, most evident in the major depression group, related to neuronal loss, the number of neurons in the accessory basal (within a 2 mm total area) were counted in the major depression and control subjects. No significant (F1,22 = 0.2731; P = 0.6065) difference in the number of neurons was found between the major depression (73.94 ± 7.25) and the normal control (69.34 ± 5.21) groups. Although some major depression and bipolar disorder subjects had positive toxicology for CNS medication, this did not directly relate to the reduced prodynorphin mRNA expression levels observed in the AB or AHA. All but three subjects in the bipolar disorder group had a positive toxicology of antidepressant or mood stabilizing medication at the time of death, but some subjects expressed very low prodynorphin mRNA and others showed prodynorphin mRNA levels similar to the normal group. No documented clinical information or familial history of psychiatric disorder was found to explain the variability in the prodynorphin mRNA expression levels evident particularly in the affective disorder groups. At least 80% of the subjects diagnosed with major depression had a positive family history (primary relative) of mood disorder yet the prodynorphin mRNA expression levels differed over 2-fold between some of these subjects.
No significant effects were observed in the other nuclei (periamygdala cortex 3/ posterior cortex, basal, or lateral) that were studied (Table 1). Overall, there was no significant association between suicide as a cause of death and the prodynorphin mRNA expression levels measured in the psychiatric groups. In addition, no significant correlation was found in regard to the age of disease onset and the duration of the disease in any of the amgydaloid nuclei examined. Moreover, no significance was observed in relation to the dpm mg−1 values and the lifetime antipsychotic treatment (fluphenazine) in the schizophrenic and bipolar disorder groups.
In the present study, a selective reduction of the prodynorphin mRNA expression levels was found in the AB and AHA of subjects diagnosed with mood disorders, but not in schizophrenic individuals. Based on the fact that elevation of dynorphin tone is associated with dysphoria and negative mood states, one would hypothesize that the prodynorphin mRNA expression would be elevated in the individuals with major depression and bipolar disorder. However, it is feasible that the reduced prodynorphin mRNA levels currently observed could compensate for an elevation of dynorphin peptides in these subjects, but it was not possible to measure peptide levels in the current specimens. The decreased levels of the prodynorphin mRNA expression could also be speculated to be due to antidepressant treatment since it is most likely that individuals in both the major depression and bipolar groups had received antidepressant medication at some time in the course of their disease. Although there was no direct association between the limited available toxicological information and the prodynorphin mRNA expression levels measured in the amygdala, the history of long-term antidepressant medication (which was unknown in this study) cannot be ruled out. Very few experimental animal studies have examined the effects of antidepressant drugs on the prodynorphin mRNA expression in the amygdala. In rats, administration of imipramine was shown to increase brain dynorphin levels.30 There were, however, no discrete subregional measurements of the peptide levels in that study. The lack of detailed toxicological information related to the antidepressant treatment history is a limitation of the current study and the paucity of experimental studies regarding the amygdala dynorphin system also makes it difficult to speculate on how the observed alterations in the prodynorphin mRNA expression would be expected to relate to behavior and psychopathology.
A generalized neuronal loss in the amygdala might account for the reduced prodynorphin mRNA signal in the affective disorder subjects, but no significant difference was currently found in the number of neurons in the accessory basal nucleus in the major depression group as compared to normal controls. Although glial loss has been reported in the amygdala of subjects diagnosed with mood disorder, no neuronal loss was detected.31 Nevertheless, more detailed pathological analysis of the amygdaloid complex of subjects with major depression or bipolar disorders should be carried out in future studies.
It has long been hypothesized that major depression is characterized by a decrease of serotonin activity.32,33,34 Depletion of serotonin levels by destruction of serotonin cell bodies has been shown to reduce prodynorphin mRNA expression levels in the mesolimbic ventral striatal region.35 The amygdala has a high serotonin content,36 but no experimental studies have as yet examined dynorphin peptide or mRNA expression levels following reduction of serotonin in this region. If a similar serotoninergic regulation of the dynorphin system does exist in the amygdala as in the ventral striatum, then it is possible that the reduced prodynorphin mRNA expression levels observed in subjects with mood disorder may be related to reduced serotoninergic activity. However, reduced serotonin tone is a common feature of suicidal behavior37,38,39 and the prodynorphin mRNA expression levels in the amygdala were not associated with suicide as a cause of death in the psychiatric groups, only with the mood disorder diagnosis.
A growing body of evidence has been accumulated implicating a hyperactive glutamatergic system in depression. Administration of antidepressant agents decreases glutamate levels in the prefrontal cortex40 and there are long lasting reductions of glutamatergic activity after chronic, but not acute antidepressant treatments.41,42 Antagonists at the N-methyl-D-aspartate (NMDA) glutamate receptor have been shown to improve depressive symptoms in subjects diagnosed with major depression43 and NMDA antagonists are effective in animal models of depression.44,45 Dynorphin is known to inhibit excitatory glutamatergic neurotransmission (assessed primarily in the hippocampus).46,47 Reduced prodynorphin mRNA levels, and possibly of dynorphin peptides, would be expected to increase glutamate tone in line with the theory of enhanced glutamateric circuits in depression. However, it has to be considered that administration of dynorphin-like drugs, which would be expected to inhibit glutamate tone, is associated with negative mood states.2,3 The specific interaction between amygdala dynorphin and glutamatergic systems in depression behavior has to be directly examined.
The current results point to subregional specificity of the prodynorphin mRNA alterations in the amgydaloid complex. Although prodynorphin mRNA was expressed in various amygdala nuclei, only the AHA and the AB showed significant changes. The specificity of the prodynorphin changes is probably linked to the diverse anatomical, neurochemical, and functional organization of the amgydaloid complex and its role in regulating specific behaviors involved in regulating emotional processing. Although damage of more superficial parts of the human amygdala, which express the highest prodynorphin mRNA expression, has been associated with emotional blunting,48 very little is, however, known about how discrete damage to specific amygdaloid subnuclei is related to the pathogenesis of psychiatric disorders.
The AB has more extensive efferent targets than the AHA innervating brain areas such as the hippocampus, ventral striatum, basal forebrain, and entorhinal, medial prefrontal, and orbitofrontal cortices in primates.49 Thus, the AB nuclei can be involved in cognitive, motivation, and reward behaviors. Based on the fact that a common neuroanatomical target of both the AB and AHA in primates is the ventromedial hypothalamus,49 it is feasible that the prodynorphin alterations could contribute to the modulation of endocrine and autonomic mechanisms in subjects with affective disorder. A reduced dynorphin output from the AB and AHA in subjects with mood disorder would be expected to result in a release of the inhibitory dynorphin tone in the ventromedial hypothalamus thereby leading to a decrease in food intake,50 a feature common to depressed individuals.
In conclusion, the present study revealed significant reductions of the prodynorphin mRNA expression in the ABpc and AHA in individuals diagnosed with major depression and bipolar disorder, but normal levels in schizophrenic subjects. These findings indicate that there may be a link between prodynorphin neuronal populations in discrete amygdala nuclei and pathological alterations that are common to subjects with mood disorder.
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This work was funded by the Karolinska Institute, Swedish Medical Research Council (11252), and the Stanley Foundation. Post-mortem brains were donated by the Stanley Foundation Brain Consortium courtesy of Drs Llewellyn B Bigelow, Juraj Cervenak, Mary M Herman, Thomas M Hyde, Joel E Kleinman, José D Paltán, Robert M Post, E Fuller Torrey, Maree J Webster, and Robert H Yolken. Mrs Barbro Berthelsson and Miss Pia Eriksson are thanked for their valuable technical assistance and Elisabeth Berg (Karolinska Institute Statistical Department) for helpful statistical support.
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Hurd, Y. Subjects with major depression or bipolar disorder show reduction of prodynorphin mRNA expression in discrete nuclei of the amygdaloid complex. Mol Psychiatry 7, 75–81 (2002) doi:10.1038/sj.mp.4000930
- mood disorder
- opioid neuropeptide
- in situ hybridization
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