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Subjects with major depression or bipolar disorder show reduction of prodynorphin mRNA expression in discrete nuclei of the amygdaloid complex


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.

Figure 1

Schematic drawing of the human amygdaloid complex (mid level); coronal plane. ABmc, accessory basal, magnocellular division; ABpc, accessory basal, parvicellular division; AHA, amygdalohippocampal area; Bi, basal nucleus, intermediate division; Bmc, basal nucleus, magnocellular division; Bpc, basal nucleus, parvicellular division; Ce, central nucleus; COp, posterior cortical nucleus; Me, medial nucleus; PAC3, periamygdaloid cortex 3; PACs, periamygdaloid cortex, sulcal portion; L, lateral nucleus. Scale = 10 mm.

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.

Statistical analysis

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.

Figure 2

In situ hybridization signals obtained in coronal human brain sections at the level of the amygdaloid complex using an antisense (a) and sense (b) prodynorphin riboprobe. Note positive hybridization signal with the antisense, but not sense, riboprobe. See Figure 1 for schematic organization of the amygdaloid complex. Scale = 5 mm.

Figure 3

Autoradiogram showing prodynorphin mRNA expression in the human amygdaloid complex (coronal section) in normal (a), schizophrenic (b), major depression (c), and bipolar disorder (d) subjects. Note reduction of the prodynorphin hybridization signal in the major depression and bipolar disorder subjects. ABmc, magnocellular division of the accessory basal; ABpc, parvicellular division of the accessory basal; AHA, amygdalohippocampal area; B, basal nucleus; COp, posterior cortical nucleus; EC, entorhinal cortex; PAC, periamygdaloid cortex; L, lateral nucleus. See Figure 1 for schematic organization of the amygdaloid complex. Scale = 5 mm.

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.

Figure 4

Scatterplots showing prodynorphin mRNA expression levels in the human amygdalohippocampal area (a) and parvicellular division of the accessory basal (b) amygdaloid nuclei of normal (N; n = 15), major depression (MDD; n = 9–10), bipolar disorder (BP; n = 14), and schizophrenics (Sz; n = 13), subjects. **P < 0.01; ***P < 0.001 vs normal control.

Table 1 Prodynorphin mRNA expression levels (expressed as dpm mg−1 values; mean ± SEM) in various amygdaloid nuclei in normal controls and subjects with a psychiatric diagnosis

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.


  1. 1

    Hurd YL . Differential messenger RNA expression of prodynorphin and proenkephalin in the human brain Neuroscience 1996 72: 767–783

    CAS  Article  Google Scholar 

  2. 2

    Pfeiffer A, Brandt V, Herz A . Psychotomimesis mediated by kappa opiate receptors Science 1986 233: 774–776

    CAS  Article  Google Scholar 

  3. 3

    Giuffra M, Mouradian MM, Davis TL, Ownby J, Chase TN . Dynorphin agonist therapy of Parkinson's disease Clin Neuropharmacol 1993 16: 444–447

    CAS  Article  Google Scholar 

  4. 4

    Lindström LK, Terenius L . Abnormal opioid neuropeptide processing in schizophrenia Neurosci Suppl 1987 22: S15

    Google Scholar 

  5. 5

    Heikkila L, Rimon R, Terenius L . Dynorphin A and substance P in the cerebrospinal fluid of schizophrenic patients Psychiat Res 1990 34: 229–236

    CAS  Article  Google Scholar 

  6. 6

    Zhang AZ, Zhou GZ, Xi GF, Gu NF, Xia ZY, Yao JL et al. Lower CSF level of dynorphin (1–8) immunoreactivity in schizophrenic patients Neuropeptides 1985 5: 553–556

    Article  Google Scholar 

  7. 7

    Hurd YL, Herman MM, Hyde TM, Bigelow LB, Weinberger DR, Kleinman JE . Prodynorphin mRNA expression is increased in the patch versus matrix compartment of the caudate nucleus in suicide subjects Mol Psychiatry 1997 2: 495–500

    CAS  Article  Google Scholar 

  8. 8

    Gallagher M, Bhiba AA . The amygdala and emotion Curr Opin Neurobiol 1996 6: 221–227

    CAS  Article  Google Scholar 

  9. 9

    Aggleton JP . The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction Wiley-Liss: New York 1992

    Google Scholar 

  10. 10

    LeDoux JE . Emotion circuits in the brain Ann Rev Neurosci 2000 23: 155–184

    CAS  Article  Google Scholar 

  11. 11

    Mori E, Ikeda M, Hirono N, Kitagaki H, Imamura T, Shimomura T . Amygdalar volume and emotional memory in Alzheimer's disease Am J Psychiatry 1999 156: 216–222

    CAS  PubMed  Google Scholar 

  12. 12

    Tomaz C, Dickinson-Anson H, McGaugh JL, Souza-Silva MA, Viana MB, Graeff FG . Localization in the amygdala of the amnestic action of diazepam on emotional memory Behav Brain Res 1993 58: 99–105

    CAS  Article  Google Scholar 

  13. 13

    Adolphs R, Tranel D, Damasio H, Damasio AR . Fear and the human amygdala J Neurosci 1995 15: 5879–5891

    CAS  Article  Google Scholar 

  14. 14

    Isenberg N, Silbersweig D, Engelien A, Emmerich S, Malavade K, Beattie B et al. Linguistic threat activates the human amygdala Proc Natl Acad Sci USA 1999 96: 10456–10459

    CAS  Article  Google Scholar 

  15. 15

    Adolphs R, Tranel D, Damasio AR . The human amygdala in social judgment Nature 1998 393: 470–474

    CAS  Article  Google Scholar 

  16. 16

    Morris JS, Ohman A, Dolan RJ . Conscious and unconscious emotional learning in the human amygdala Nature 1998 393: 467–470

    CAS  Article  Google Scholar 

  17. 17

    Davis M, Rainnie D, Cassell M . Neurotransmission in the rat amygdala related to fear and anxiety Trends Neurosci 1994 17: 208–214

    CAS  Article  Google Scholar 

  18. 18

    Everitt B, Robbins T . Amygdala-ventral striatal interactions and reward-related processes. In: Aggleton JP (ed) The Amygdala Wiley-Liss: New York 1992 pp 401–429

    Google Scholar 

  19. 19

    Whalen PJ, Rauch SL, Etcoff NL, McInerney SC, Lee MB, Jenike MA . Masked presentations of emotional facial expressions modulate amygdala activity without explicit knowledge J Neurosci 1998 18: 411–418

    CAS  Article  Google Scholar 

  20. 20

    Tebartz van Elst L, Woermann F, Lemieux L, Trimble MR . Increased amygdala volumes in female and depressed humans. A quantitative magnetic resonance imaging study Neurosci Lett 2000 281: 103–106

    CAS  Article  Google Scholar 

  21. 21

    Sheline YI, Gado MH, Price JL . Amygdala core nuclei volumes are decreased in recurrent major depression Neuroreport 1998 9: 2023–2028

    CAS  Article  Google Scholar 

  22. 22

    Strakowski SM, DelBello MP, Sax KW, Zimmerman ME, Shear PK, Hawkins JM et al. Brain magnetic resonance imaging of structural abnormalities in bipolar disorder Arch Gen Psychiat 1999 56: 254–260

    CAS  Article  Google Scholar 

  23. 23

    Sukhov RR, Walker LC, Rance NE, Price DL, Young WS III . Opioid precursor gene expression in the human hypothalamus J Comp Neurol 1995 353: 604–622

    CAS  Article  Google Scholar 

  24. 24

    Torrey EF, Webster M, Knable M, Johnston N, Yolken RH . The Stanley Foundation brain collection and neuropathology consortium Schizophr Res 2000 44: 151–155

    CAS  Article  Google Scholar 

  25. 25

    Horikawa S, Takai T, Toyosato M, Takahashi H, Noda M, Kakidani H et al. Isolation and structural organization of the human preproenkephalin B gene Nature 1983 306: 611–614

    CAS  Article  Google Scholar 

  26. 26

    Sorvari H, Soininen H, Paljärvi L, Karkola K, Pitkänen A . Distribution of parvalbumin-immunoreactive cells and fibers in the human amygdaloid complex J Comp Neurol 1995 360: 185–212

    CAS  Article  Google Scholar 

  27. 27

    de Olmos JS . Amygdaloid nuclear gray complex. In: Paxinos G (ed) The Human Nervous System Academic Press: San Diego, New York 1990 pp 583–710

    Google Scholar 

  28. 28

    Gloor P . The amygdaloid system. In: Gloor P (ed) The Temporal Lobe and Limbic System Oxford University Press: New York 1997 pp 591–651

    Google Scholar 

  29. 29

    Bendel RB, Afifi A-A . Comparison of stopping rules in forward regression J Amer Statistical Assoc 1977 72: 46–53

    Google Scholar 

  30. 30

    Przewlocki R, Lason W, Majeed NH, Przewlocka B . Antidepressants and endogenous opioid peptide systems Neuropeptides 1985 5: 575–578

    CAS  Article  Google Scholar 

  31. 31

    Bowley MP, Drevets WC, Öngür D, Price JL . Glial changes in the amygdala and entorhinal cortex in mood disorders Soc Neurosci Abstr 2000 26: 867.10

    Google Scholar 

  32. 32

    Mann JJ . Role of the serotonergic system in the pathogenesis of major depression and suicidal behavior Neuropsychopharmacology 1999 21 (2 Suppl): 99S–105S

    Article  Google Scholar 

  33. 33

    Meltzer HY . Role of serotonin in depression Ann NY Acad Sci 1990 600: 486–500

    CAS  Article  Google Scholar 

  34. 34

    Price LH, Charney DS, Delgado PL, Heninger GR . Lithium and serotonin function: implications for the serotonin hypothesis of depression Psychopharmacology 1990 100: 3–12

    CAS  Article  Google Scholar 

  35. 35

    Morris BJ, Reimer S, Höllt V, Herz A . Regulation of striatal prodynorphin mRNA levels by the raphe-striatal pathway Molec Brain Res 1988 4: 15–22

    CAS  Article  Google Scholar 

  36. 36

    Azmitia EC, Gannon PJ . The primate serotonergic system: a review of human and animal studies and a report on Macaca fascicularis Adv Neurol 1986 43: 407–468

    CAS  PubMed  Google Scholar 

  37. 37

    Åsberg M, Nordström P . Biological correlates of suicidal behavior. In: Möller HJ, Schmidtke A, Welz R (eds) Current Issues of Suicidology Springer Verlag: Berlin, New York 1988 pp 221–241

    Google Scholar 

  38. 38

    Nordström P, Samuelsson M, Åsberg M, Träskman-Bendz L, Åberg-Wistedt A, Nordin C et al. CSF 5-HIAA predicts suicide risk after attempted suicide Suicide and Life-Threatening Behav 1994 24: 1–9

    Google Scholar 

  39. 39

    Mann JJ, Malone KM, Psych MR, Sweeney JA, Brown RP, Linnoila M et al. Attempted suicide characteristics and cerebrospinal fluid amine metabolites in depressed inpatients Neuropsychopharmacology 1996 15: 576–586

    CAS  Article  Google Scholar 

  40. 40

    Michael-Titus AT, Bains S, Jeetle J, Whelpton R . Imipramine and phenelzine decrease glutamate overflow in the prefrontal cortex_a possible mechanism of neuroprotection in major depression? Neuroscience 2000 100: 681–684

    CAS  Article  Google Scholar 

  41. 41

    Paul IA, Layer RT, Skolnick P, Nowak G . Adaptation of the NMDA receptor in rat cortex following chronic electroconvulsive shock or imipramine Eur J Pharmacol 1993 247: 305–311

    CAS  Article  Google Scholar 

  42. 42

    Paul IA, Nowak G, Layer RT, Popik P, Skolnick P . Adaptation of the N-methyl-D-aspartate receptor complex following chronic antidepressant treatments J Pharmacol Exp Ther 1994 269: 95–102

    CAS  Google Scholar 

  43. 43

    Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS et al. Antidepressant effects of ketamine in depressed patients Biol Psychiat 2000 47: 351–354

    CAS  Article  Google Scholar 

  44. 44

    Trullas R, Skolnick P . Functional antagonists at the NMDA receptor complex exhibit antidepressant actions Eur J Pharmacol 1990 185: 1–10

    CAS  Article  Google Scholar 

  45. 45

    Meloni D, Gambarana C, De Montis MG, Dal Pra P, Taddei I, Tagliamonte A . Dizocilpine antagonizes the effect of chronic imipramine on learned helplessness in rats Pharmacol Biochem Behav 1993 46: 423–426

    CAS  Article  Google Scholar 

  46. 46

    Wagner JJ, Terman GW, Chavkin C . Endogenous dynorphins inhibit excitatory neurotransmission and block LTP induction in the hippocampus Nature 1993 363: 451–454

    CAS  Article  Google Scholar 

  47. 47

    Gannon RL, Terrian DM . 50,488H inhibits dynorphin and glutamate release from guinea pig hippocampal mossy fiber terminals Brain Res 1991 548: 242–247

    CAS  Article  Google Scholar 

  48. 48

    Narabayashi H, Shima F . Which is the better amygdala target, the medial or lateral nucleus for behavioral problems and paroxysms in epileptics. In: Laitinen LV, Livingston KE (eds) Surgical Approaches in Psychiatry University Park Press: Baltimore 1973 pp 129–134

    Google Scholar 

  49. 49

    Amaral DG, Price JL, Pitkänen A, Carmichael ST . Anatomical organization of the primate amygdaloid complex. In: Aggleton JP (ed) The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction Wiley-Liss: New York 1992 pp 1–66

    Google Scholar 

  50. 50

    Schulz R, Wilhelm A, Dirlich G . Intracerebral injection of different antibodies against endogenous opioids suggests alpha-neoendorphin participation in control of feeding behaviour Naunyn Schm Arch Pharmacol 1984 326: 222–226

    CAS  Article  Google Scholar 

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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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Correspondence to Y L Hurd.

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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).

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  • mood disorder
  • schizophrenia
  • opioid neuropeptide
  • in situ hybridization
  • amygdala

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