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Increased Corticotropin-Releasing Hormone Immunoreactivity in Monoamine-Containing Pontine Nuclei of Depressed Suicide

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Increased Corticotropin-Releasing Hormone Immunoreactivity in Monoamine-Containing Pontine Nuclei of Depressed Suicide Molecular Psychiatry (2003) 8, 324–332 & 2003 Nature Publishing Group All rights reserved 1359-4184/03 $25.00 www.nature.com/mp ORIGINAL RESEARCH ARTICLE Increased corticotropin-releasing hormone immunoreactivity in monoamine-containing pontine nuclei of depressed suicide men MC Austin1, JE Janosky2 and HA Murphy1 1Department of Psychiatry, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA; 2Department of Family Medicine and Clinical Epidemiology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA A number of clinical investigations and postmortem brain studies have provided evidence that excessive corticotropin-releasing hormone (CRH) secretion and neurotransmission is involved in the pathophysiology of depressive illness, and several studies have suggested that the hyperactivity in CRH neurotransmission extends beyond the hypothalamus involving several extra-hypothalamic brain regions. The present study was designed to test the hypothesis that CRH levels are increased in specific brainstem regions of suicide victims with a diagnosis of major depression. Frozen tissue sections of the pons containing the locus coeruleus and caudal raphe nuclei from 11 matched pairs of depressed suicide and control male subjects were processed for radioimmunocytochemistry using a primary antiserum to CRH and a [125]I-IgG secondary antibody. The optical density corresponding to the level of CRH- immunoreactivity (IR) was quantified in specific pontine regions from the film autoradio- graphic images. The level of CRH-IR was increased by 30% in the locus coeruleus, 39% in the median raphe and 45% in the caudal dorsal raphe in the depressed suicide subjects compared to controls. No difference in CRH-IR was found in the dorsal tegmentum or medial parabrachial nucleus between the subject groups. These findings reveal that CRH-IR levels are specifically increased in norepinephrine- and serotonin-containing pontine nuclei of depressed suicide men, and thus they are consistent with the hypothesis that CRH neurotransmission is elevated in extra-hypothalamic brain regions of depressed subjects. Molecular Psychiatry (2003) 8, 324–332. doi:10.1038/sj.mp.4001250 Keywords: axons; corticotropin-releasing factor; locus coeruleus; mood disorders; norepine- phrine; postmortem; raphe; serotonin Introduction fluid (CSF) levels,9–11 increased numbers of CRH- immunoreactive12 and CRH mRNA-containing para- Corticotropin-releasing hormone (CRH) is the primary ventricular hypothalamic neurons13 and decreased chemical regulator mediating the stress-induced binding sites of CRH receptors in the frontal cortex of activation of the hypothalamic–pituitary–adrenal depressed subjects14 represent some of the biochem- (HPA) axis stimulating the secretion of adrenocortico- ical changes that support the hypothesis of hyper- tropin hormone (ACTH) from the anterior pituitary activity of CRH function in depression. However, which in turn stimulates cortisol release from the other studies have failed to document changes in CSF adrenal gland. Hyperactivity of the HPA axis resulting CRH levels,15–17 brain tissue levels of CRH18,19 or CRH in increased circulating cortisol levels is one of the receptor binding sites in the cortex of depressed most consistent biological alterations reported in subjects19,20 and thus do not support the CRH depressed patients.1–5 Several lines of evidence hyperactivity hypothesis of depression. With the support the theory that excessive secretion of CRH exception of the reports documenting alterations in is involved in the hypercortisolism in depressed CRH substrates in the paraventricular nucleus of the patients, and that the anatomical sites of CRH hypothalamus and in the frontal cortex, there has hypersecretion include the hypothalamus and possi- been no additional direct evidence for CRH hyper- bly other extra-hypothalamic brain regions. For activity in other brain regions of depressed subjects. example, a blunted ACTH response to exogenous In addition to the hormonal role of CRH, a variety of CRH administration,6–8 increased CRH cerebrospinal rodent studies have provided evidence supporting a neurotransmitter role for CRH in the central nervous Correspondence: Dr MC Austin, PhD, Department of Psychiatry, system. In particular, both electrophysiological and Western Psychiatric Institute and Clinic, University of Pittsburgh biochemical studies have shown that CRH is involved Medical Center, W1645 Biomedical Science Tower, Pittsburgh, PA in mediating the effects of stress on norepinephrine 15213, USA. E-mail: [email protected] Received 20 January 2002; revised 31 January 2002; accepted 7 neurotransmission specifically at the level of the July 2002 noradrenergic neurons in the locus coeruleus Increased CRH in pons of depressed subjects MC Austin et al 325 (LC).21–23 Furthermore, recent electrophysiological revealed a few senile plaques in subjects 598, 600, studies have found that CRH has both excitatory 685, 699 and 795 but clinical and neuropathological and inhibitory effects on serotonin neurons in the criteria to establish a diagnosis of Alzheimer’s disease dorsal raphe nucleus.24–26 Given the evidence from were not met. Toxicological screens were positive animal studies supporting a functional role of CRH on for chlordiazepoxide for one depressed subject (598) LC and raphe neurons, it is interesting that both and CO for two other depressed subjects (614, 628). clinical and postmortem brain studies have docu- Also, three depressed subjects (598, 689, 698) were mented alterations in various noradrenergic27–29 and receiving antidepressants at the time of death and two serotonergic30–32 parameters in depressed subjects. of these depressed subjects (689, 698) were treated Perhaps CRH has a similar functional role in the with antipsychotics at the time of death. Three human brain and may contribute to the alterations in depressed subjects (614, 596, 613) had been off the monoamine systems in depressed patients? antidepressant medication for 0.6, 1.8 and 7.1 years, Indeed, recent immunocytochemical studies have respectively, and one subject (613) off antipsychotic shown that several monoaminergic nuclei in the medication for 7.6 years. The other five depressed human brainstem are innervated by CRH-containing subjects had no documented history of antidepressant axons including the locus coeruleus and raphe medication. nuclei.33,34 Given the evidence for alterations in CRH, norepinephrine and serotonin neurotransmis- Tissue preparation and radioimmunocytochemistry sion in depressive illness together with the anatomi- Upon removal of the brain from the cranium, the cal data suggesting an interaction of CRH on LC and cerebellum was removed and the brainstem was raphe neurons in the human brainstem, we sought to separated by a transverse cut at the rostral border of test the hypothesis that the concentration of CRH the superior colliculi. The brainstems were then cut immunoreactivity is increased in specific pontine into midbrain/pons and caudal medulla blocks, nuclei in subjects with major depression who com- immediately frozen in isopentane and then stored at mitted suicide. À801C. The frozen midbrain/pontine blocks were sectioned transversely at 20 mm, sections were thaw- mounted onto gelatin-coated microscope slides and Materials and methods every 10th tissue section stained for Nissl substance Tissue collection with cresyl violet. The slides were stored at À801C All procedures in our study were approved by the until processed. University of Pittsburgh’s Institutional Review Board Slide-mounted tissue sections of the pons were for Biomedical Research. Human brain specimens selected for assay based on the anatomical distribu- were obtained in the course of routine autopsies tion of CRH-immunoreactive (IR) axons previously conducted at the Allegheny County Coroner’s Office, reported in the human brainstem.33 The radioimmu- Pittsburgh, PA, after obtaining consent from a surviv- nocytochemical assay was performed as previously ing family member. A total of 11 subjects who died by described35 with some modifications. Four tissue suicide and had a diagnosis of depression were each sections were selected at 200 mm intervals from each matched with one control subject for sex and as case and placed into 4% paraformaldehyde for closely as possible for age and postmortem interval approximately 17 h. The sections were then rinsed (Table 1). Of the pairs, 10 were also matched for race. twice for 15 min in PBS containing 0.4% Triton X-100 For each subject, a consensus DSM-IV diagnosis was and then incubated for 60 min in PBS with 1.5% made by an independent panel of experienced normal goat, 0.5% normal human serum and 0.4% clinicians after reviewing medical records and the Triton X-100 to reduce background. results of structured interviews conducted with The CRH primary antiserum (rabbit anti-CRH family members of the deceased. Of the suicide (human, rat), Pennisula Laboratories, San Carlos, subjects, 10 had a diagnosis of major depression, CA, USA) was preadsorbed with natural melanin as and one had a depressive disorder NOS. Three of the previously described.33 The concentration of the CRH depressed subjects also had an Axis II diagnosis of primary antiserum used on the tissue sections from obsessive–compulsive personality disorder and one the subject pairs was determined from a dilution depressed subject had an Axis II diagnosis of curve constructed from control brainstem tissue paranoid personality disorder. Three
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