On Site Link: CRF and Unipolar Depression

Gold PW, Chrousos GP.
Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states.
Mol Psychiatry 2002;7(3):254-75
"Stress precipitates depression and alters its natural history. Major depression and the stress response share similar phenomena, mediators and circuitries. Thus, many of the features of major depression potentially reflect dysregulations of the stress response. The stress response itself consists of alterations in levels of anxiety, a loss of cognitive and affective flexibility, activation of the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system, and inhibition of vegetative processes that are likely to impede survival during a life-threatening situation (eg sleep, sexual activity, and endocrine programs for growth and reproduction). Because depression is a heterogeneous illness, we studied two diagnostic subtypes, melancholic and atypical depression. In melancholia, the stress response seems hyperactive, and patients are anxious, dread the future, lose responsiveness to the environment, have insomnia, lose their appetite, and a diurnal variation with depression at its worst in the morning. They also have an activated CRH system and may have diminished activities of the growth hormone and reproductive axes. Patients with atypical depression present with a syndrome that seems the antithesis of melancholia. They are lethargic, fatigued, hyperphagic, hypersomnic, reactive to the environment, and show diurnal variation of depression that is at its best in the morning. In contrast to melancholia, we have advanced several lines of evidence of a down-regulated hypothalamic-pituitary adrenal axis and CRH deficiency in atypical depression, and our data show us that these are of central origin. Given the diversity of effects exerted by CRH and cortisol, the differences in melancholic and atypical depression suggest that studies of depression should examine each subtype separately. In the present paper, we shall first review the mediators and circuitries of the stress system to lay the groundwork for placing in context physiologic and structural alterations in depression that may occur as part of stress system dysfunction." [PDF] [Note that the authors use the atypical acronym CRH rather than the equivalent acronym CRF.]

Bissette G, Klimek V, Pan J, Stockmeier C, Ordway G.
Elevated concentrations of CRF in the locus coeruleus of depressed subjects.
Neuropsychopharmacology. 2003 Jul;28(7):1328-35. Epub 2003 May 21.
"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." [Abstract]

Austin MC, Janosky JE, Murphy HA.
Increased corticotropin-releasing hormone immunoreactivity in monoamine-containing pontine nuclei of depressed suicide men.
Mol Psychiatry. 2003 Mar;8(3):324-32.
"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 autoradiographic 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." [Abstract]

Bissette G, Klimek V, Pan J, Stockmeier C, Ordway G.
Elevated Concentrations of CRF in the Locus Coeruleus of Depressed Subjects.
Neuropsychopharmacology. 2003 Jul;28(7):1328-35.
"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." [Abstract]

Zhu MY, Klimek V, Dilley GE, Haycock JW, Stockmeier C, Overholser JC, Meltzer HY, Ordway GA.
Elevated levels of tyrosine hydroxylase in the locus coeruleus in major depression.
Biol Psychiatry. 1999 Nov 1;46(9):1275-86.
"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." [Abstract]

Ordway GA, Smith KS, Haycock JW.
Elevated tyrosine hydroxylase in the locus coeruleus of suicide victims.
J Neurochem. 1994 Feb;62(2):680-5.
"The amounts of tyrosine hydroxylase protein in locus coeruleus from nine pairs of antidepressant-free suicide victims and age-matched, sudden-death control cases were determined by quantitative blot immunolabeling of cryostat-cut sections from the caudal portion of the nucleus. In each of the nine age-matched pairs, the concentration of tyrosine hydroxylase was greater in the sample from the suicide victim, with values ranging from 108 to 172% of the matched control value (mean = 136%). By contrast, there were no differences in the concentrations of neuron-specific enolase protein in the same set of samples. Similarly, the number of neuromelanin-containing cells, counted in sections of locus coeruleus adjacent to those taken for blot immunolabeling analyses, did not differ between the two groups. These data indicate that locus coeruleus neurons from suicide victims contain higher than normal concentrations of tyrosine hydroxylase, thus raising the possibility that the expression of tyrosine hydroxylase in locus coeruleus may be relevant in the pathophysiology of suicide." [Abstract]

Brady LS, Whitfield HJ Jr, Fox RJ, Gold PW, Herkenham M.
Long-term antidepressant administration alters corticotropin-releasing hormone, tyrosine hydroxylase, and mineralocorticoid receptor gene expression in rat brain. Therapeutic implications.
J Clin Invest. 1991 Mar;87(3):831-7.
"Imipramine is the prototypic tricyclic antidepressant utilized in the treatment of major depression and exerts its therapeutic efficacy only after prolonged administration. We report a study of the effects of short-term (2 wk) and long-term (8 wk) administration of imipramine on the expression of central nervous system genes among those thought to be dysregulated in imipramine-responsive major depression. As assessed by in situ hybridization, 8 wk of daily imipramine treatment (5 mg/kg, i.p.) in rats decreased corticotropin-releasing hormone (CRH) mRNA levels by 37% in the paraventricular nucleus (PVN) of the hypothalamus and decreased tyrosine hydroxylase (TH) mRNA levels by 40% in the locus coeruleus (LC). These changes were associated with a 70% increase in mRNA levels of the hippocampal mineralocorticoid receptor (MR, type I) that is thought to play an important role in mediating the negative feedback effects of low levels of steroids on the hypothalamic-pituitary-adrenal (HPA) axis. Imipramine also decreased proopiomelanocortin (POMC) mRNA levels by 38% and glucocorticoid receptor (GR, type II) mRNA levels by 51% in the anterior pituitary. With the exception of a 20% decrease in TH mRNA in the LC after 2 wk of imipramine administration, none of these changes in gene expression were evident as a consequence of short-term administration of the drug. In the light of data that major depression is associated with an activation of brain CRH and LC-NE systems, the time-dependent effect of long-term imipramine administration on decreasing the gene expression of CRH in the hypothalamus and TH in the LC may be relevant to the therapeutic efficacy of this agent in depression." [Abstract]

EJ Nestler, A McMahon, EL Sabban, JF Tallman, and RS Duman
Chronic Antidepressant Administration Decreases the Expression of Tyrosine Hydroxylase in the Rat Locus Coeruleus
PNAS 87: 7522-7526, 1990.
"Regulation of tyrosine hydroxylase expression by antidepressant treatments was investigated in the locus coeruleus (LC), the major noradrenergic nucleus in brain. Rats were treated chronically with various antidepressants, and tyrosine hydroxylase levels were measured in the LC by immunoblot analysis. Representatives of all major classes of antidepressant medication-including imipramine, nortriptyline, tranylcypromine, fluvoxamine, fluoxetine, bupropion, iprindole, and electroconvulsive seizures-were found to decrease levels of tyrosine hydroxylase immunoreactivity by 40-70% in the LC. Decreased levels of enzyme immunoreactivity were shown to be associated with equivalent decreases in enzyme mRNA levels. Antidepressant regulation of LC tyrosine hydroxylase appeared specific to these compounds, inasmuch as chronic treatment of rats with representatives of other classes of psychotropic drugs, including haloperidol, diazepam, clonidine, cocaine, and morphine, failed to decrease levels of this protein. The results demonstrate that chronic antidepressants dramatically downregulate the expression of tyrosine hydroxylase in the LC and raise the possibility that such regulation of the enzyme represents an adaptive response of LC neurons to antidepressants that mediates some of their therapeutic actions in depression and/or other psychiatric disturbances." [Abstract]

Melia KR, Nestler EJ, Duman RS.
Chronic imipramine treatment normalizes levels of tyrosine hydroxylase in the locus coeruleus of chronically stressed rats.
Psychopharmacology (Berl). 1992;108(1-2):23-6.
"Previous studies have demonstrated that chronic stress increases and antidepressant treatments decrease levels of tyrosine hydroxylase (TH) in locus coeruleus (LC). In the present study, the influence of chronic antidepressant treatment on the induction of TH immunoreactivity in response to cold stress is examined. It was found that chronic imipramine pretreatment (18 days) attenuated the induction of TH in response to cold stress, resulting in levels of TH immunoreactivity not different from control. In contrast, imipramine pretreatment for 1 or 7 days was not sufficient to normalize the stress-induced elevation of TH immunoreactivity. These findings raise the possibility that the therapeutic action of antidepressants may be derived, in part, from the ability of these treatments to normalize levels of TH and thereby the function of the NE neurotransmitter system under conditions of stress." [Abstract]

Butterweck V, Winterhoff H, Herkenham M.
Hyperforin-Containing Extracts of St John's Wort Fail to Alter Gene Transcription in Brain Areas Involved in HPA Axis Control in a Long-Term Treatment Regimen in Rats.
Neuropsychopharmacology. 2003 Jul 16 [Epub ahead of print].
"Fluoxetine (10 mg/kg) given daily for 8 weeks, but not 2 weeks, significantly decreased levels of corticotropin-releasing hormone (CRH) mRNA by 22% in the paraventricular nucleus (PVN) of the hypothalamus and tyrosine hydroxylase (TH) mRNA by 23% in the locus coeruleus. Fluoxetine increased levels of mineralocorticoid (MR) (17%), glucocorticoid (GR) (18%), and 5-HT(1A) receptor (21%) mRNAs in the hippocampus at 8, but not 2, weeks." [Abstract]

Zeng J, Kitayama I, Yoshizato H, Zhang K, Okazaki Y.
Increased expression of corticotropin-releasing factor receptor mRNA in the locus coeruleus of stress-induced rat model of depression.
Life Sci. 2003 Jul 18;73(9):1131-9.
"Hypersecretion of corticotropin-releasing factor (CRF) has been hypothesized to occur in depression. To investigate CRF receptor (CRFR) response to the increased production of CRF in chronically stressed rats, we measured by in situ hybridization the expression of CRFR mRNA in the locus coeruleus (LC) concomitant with measuring plasma adrenocorticotropin (ACTH). The expression of both CRFR mRNA in the LC and the plasma level of ACTH increased significantly in "depression-model rats" which exhibit reduced activity following exposure to 14 days forced walking stress (FWS), but not in "spontaneous recovery rats" whose activity was restored after the long-term stress. These results suggest that the LC neurons continue to be stimulated by CRF, and that the hypothalamic-pituitary-adrenal (HPA) axis is hyperfunctioning in the depression-model rats." [Abstract]

Jezova D, Ochedalski T, Glickman M, Kiss A, Aguilera G.
Central corticotropin-releasing hormone receptors modulate hypothalamic-pituitary-adrenocortical and sympathoadrenal activity during stress.
Neuroscience. 1999;94(3):797-802.
"The role of brain corticotropin-releasing hormone receptors in modulating hypothalamic-pituitary-adrenal and sympathoadrenal responses to acute immobilization stress was studied in conscious rats under central corticotropin-releasing hormone receptor blockade by intracerebroventricular injection of a peptide corticotropin-releasing hormone receptor antagonist. Blood for catecholamines, adrenocorticotropic hormone and corticosterone levels was collected through vascular catheters, and brains were removed at 3 h for in situ hybridization for tyrosine hydroxylase messenger RNA in the locus coeruleus, and corticotropin-releasing hormone and corticotropin-releasing hormone receptor messenger RNA in the hypothalamic paraventricular nucleus. Central corticotropin-releasing hormone receptor blockade reduced the early increases in plasma epinephrine and dopamine, but not norepinephrine, during stress. Immobilization stress increased tyrosine hydroxylase messenger RNA levels in the locus coeruleus by 36% in controls, but not in corticotropin-releasing hormone antagonist-injected rats. In control rats, corticotropin-releasing hormone messenger RNA and type 1 corticotropin-releasing hormone receptor messenger RNA in the paraventricular nucleus increased after stress (P<0.01), and these responses were attenuated by central corticotropin-releasing hormone receptor blockade. In contrast, central corticotropin-releasing hormone antagonist potentiated plasma adrenocorticotropic hormone responses, but slightly attenuated plasma corticosterone responses to stress. The inhibition of plasma catecholamine and locus coeruleus tyrosine hydroxylase messenger RNA responses to stress by central corticotropin-releasing hormone receptor blockade supports the notion that central corticotropin-releasing hormone regulates sympathoadrenal responses during stress. The attenuation of stress-induced corticotropin-releasing hormone and corticotropin-releasing hormone receptor messenger RNA responses by central corticotropin-releasing hormone receptor blockade suggests direct or indirect positive feedback effects of corticotropin-releasing hormone receptor ligands on corticotropin-releasing hormone expression, whereas additional mechanisms potentiate adrenocorticotropic hormone responses at the pituitary level. In addition, changes in neural activity by central corticotropin-releasing hormone are likely to modulate adrenocortical responsiveness during stress." [Abstract]

Roy A, Pickar D, Linnoila M, Chrousos GP, Gold PW.
Cerebrospinal fluid corticotropin-releasing hormone in depression: relationship to noradrenergic function.
Psychiatry Res 1987 Mar;20(3):229-37
"We investigated the neurotransmitter regulation of corticotropin-releasing hormone (CRH). Among 21 depressed patients cerebrospinal fluid (CSF) levels of CRH significantly correlated with urinary outputs of norepinephrine and its major metabolites, and there were trends for significant correlations with both CSF and plasma levels of norepinephrine. These results suggest that CRH may be associated with the dysregulation of the norepinephrine system that is found in [depression]." [Abstract]

Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB.
The role of corticotropin-releasing factor in depression and anxiety disorders.
J Endocrinol 1999 Jan;160(1):1-12
"In the present review, we describe the evidence suggesting that CRF is hypersecreted from hypothalamic as well as from extrahypothalamic neurons in depression, resulting in hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and elevations of cerebrospinal fluid (CSF) concentrations of CRF. This increase in CRF neuronal activity is also believed to mediate certain of the behavioral symptoms of depression involving sleep and appetite disturbances, reduced libido, and psychomotor changes. The hyperactivity of CRF neuronal systems appears to be a state marker for depression because HPA axis hyperactivity normalizes following successful antidepressant treatment. Similar biochemical and behavioral findings have been observed in adult rats and monkeys that have been subjected to early-life stress. In contrast, clinical studies have not revealed any consistent changes in CSF CRF concentrations in patients with anxiety disorders; however, preclinical findings strongly implicate a role for CRF in the pathophysiology of certain anxiety disorders, probably through its effects on central noradrenergic systems. The findings reviewed here support the hypothesis that CRF receptor antagonists may represent a novel class of antidepressants and/or anxiolytics." [Abstract]

Banki CM, Bissette G, Arato M, O'Connor L, Nemeroff CB.
CSF corticotropin-releasing factor-like immunoreactivity in depression and schizophrenia.
Am J Psychiatry 1987 Jul;144(7):873-7
"To further investigate the hypothesis that hyperactivity of the hypothalamic-pituitary-adrenal axis in patients with depression may be mediated by hypersecretion of corticotropin-releasing factor (CRF), the authors measured CRF-like immunoreactivity in CSF samples from 138 neurological control, 54 depressed, and 27 nondepressed (23 schizophrenic and four manic) subjects. The CSF CRF concentration was markedly higher (almost twofold) in depressed patients than in control subjects and nondepressed psychiatric patients. The concentration of CSF CRF was slightly but significantly higher in schizophrenic patients than in control subjects. These findings provide further support for the hypothesis that CRF hypersecretion occurs in major depression." [Abstract]

Schulz C, Lehnert H.
Activation of noradrenergic neurons in the locus coeruleus by corticotropin-releasing factor. A microdialysis study.
Neuroendocrinology 1996 May;63(5):454-8
"In the present study the effects of different doses of corticotropin-releasing factor (CRF) and the CRF antagonist alpha-helical CRF on locus coeruleus (LC) neurons were studied in anesthetized male Wistar rats. To monitor the release of noradrenaline (NA) and its metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), a microdialysis probe was implanted into the parietal cortex, a major projection area of the LC. Saline, 0.17, 0.51 nmol CRF and a combination of 5.1 nmol alpha-helical CRF and 0.51 nmol CRF were applied to the LC via a fused silica capillary. While both doses of CRF augmented NA in parietal cortex dialysates (0.51 nmol CRF: from 0.0206 to 0.0266 pmol/sample; 0.17 nmol CRF: from 0.0147 to 0.0170 pmol/sample), saline did not affect NA concentration. The metabolite MHPG also increased, but in a more prolonged time course. The antagonist alpha-helical CRF attenuated the CRF effects. The increase of extraneuronal NA concentration monitored in the cortical samples indicates an augmented depolarization rate of noradrenergic LC neurons. This clearly demonstrates the activation of these neurons by CRF, suggesting physiological interactions of CRF and noradrenergic neurons." [Abstract]

Emoto H, Tanaka M, Koga C, Yokoo H, Tsuda A, Yoshida M.
Corticotropin-releasing factor activates the noradrenergic neuron system in the rat brain.
Pharmacol Biochem Behav 1993 Jun;45(2):419-22
"The effect of corticotropin-releasing factor (CRF) on central noradrenaline (NA) metabolism was examined by measuring levels of the major metabolite of NA, 3-methoxy-4-hydroxy-phenylethyleneglycol sulfate (MHPG-SO4) in several rat brain regions. Various doses of CRF ranging from 0.5-10 micrograms injected ICV significantly increased MHPG-SO4 levels in several brain regions including the hypothalamus, amygdala, midbrain, locus coeruleus (LC) region, and pons + medulla oblongata excluding the LC region. Plasma corticosterone levels were also significantly increased after ICV CRF administration up to 0.5 micrograms. The present results that CRF not only elevates plasma corticosterone levels but also increases NA metabolism in many brain regions suggest its neurotransmitter and/or neuromodulator role exerting the excitatory action on central NA neurons." [Abstract]

Emoto H, Koga C, Ishii H, Yokoo H, Yoshida M, Tanaka M.
A CRF antagonist attenuates stress-induced increases in NA turnover in extended brain regions in rats.
Brain Res 1993 Nov 5;627(1):171-6
"We investigated the effects of intracerebroventricular (i.c.v.) administration of corticotropin-releasing factor (CRF) antagonist, alpha-helical CRF9-41 (ahCRF), on increases in noradrenaline (NA) turnover caused by immobilization stress in rat brain regions. Pretreatment with ahCRF (50 or 100 micrograms) significantly attenuated increases in levels of 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4), the major metabolite of NA in rat brain, in the locus coeruleus (LC) region, and attenuated the MHPG-SO4/NA ratio after immobilization stress for 50 min in the cerebral cortex, hippocampus, amygdala, midbrain and hypothalamus. However, stress-induced increases in plasma corticosterone levels were not decreased significantly by pretreatment with ahCRF. These results suggest that CRF, released during stress, causes increases in NA release in extended brain regions of stressed rats." [Abstract]

Valentino RJ, Foote SL, Page ME.
The locus coeruleus as a site for integrating corticotropin-releasing factor and noradrenergic mediation of stress responses.
Ann N Y Acad Sci 1993 Oct 29;697:173-88
"It could be predicted that the effects of CRF neurotransmission in the LC during stress would enhance information processing concerning the stressor or stimuli related to the stressor by LC target neurons. One consequence of this appears to be increased arousal. Although this may be adaptive in the response to an acute challenge, it could be predicted that chronic CRF release in the LC would result in persistently elevated LC discharge and norepinephrine release in targets. This could be associated with hyperarousal and loss of selective attention as occurs in certain psychiatric diseases. Manipulation of endogenous CRF systems may be a novel way in which to treat psychiatric diseases characterized by these maladaptive effects." [Abstract]

Curtis AL, Valentino RJ.
Corticotropin-releasing factor neurotransmission in locus coeruleus: a possible site of antidepressant action.
Brain Res Bull 1994;35(5-6):581-7
"Hypersecretion of corticotropin-releasing factor (CRF), has been hypothesized to occur in depression. Because CRF may serve as a neurotransmitter in the locus coeruleus (LC), it was proposed that CRF hypersecretion in the LC is responsible for some characteristics of depression, and that antidepressants act by interfering with CRF neurotransmission in the LC. To test this hypothesis, the acute and chronic effects of four antidepressants and cocaine were characterized on LC spontaneous and sensory-evoked discharge, LC activation by a stressor that requires CRF release, and LC activation by exogenously administered CRF. None of the antidepressants or cocaine altered LC activation by intracerebroventricularly administered CRF (3.0 microgram) after chronic administration. However, chronic administration of desmethylimipramine and mianserin inhibited LC activation by a hypotensive stress that requires endogenous CRF release, suggesting that they decrease CRF release in the LC. Chronic administration of sertraline and phenelzine altered LC responses to repeated sciatic nerve stimulation in a manner opposite to the effect produced by CRF, suggesting that these drugs may functionally antagonize CRF actions in the LC. Cocaine did not appear to interfere with CRF actions in the LC. In conclusion, chronic administration of antidepressants may have the potential to interfere with CRF neurotransmission in the LC." [Abstract]

Valentino RJ, Curtis AL.
Pharmacology of locus coeruleus spontaneous and sensory-evoked activity.
Prog Brain Res 1991;88:249-56
"Neuroendocrine and catecholamine dysfunctions in depression may be linked by corticotropin-releasing factor (CRF) effects on locus coeruleus (LC) neurons. One consequence of CRF hypersecretion in depression would be persistent elevated levels of LC discharge and diminished responses to phasic sensory stimuli. The hypothesis that antidepressants could reverse these changes was tested by characterizing effects of pharmacologically distinct antidepressants on LC sensory-evoked discharge, LC activation by stress, and LC activation by CRF. The most consistent effect of all of the antidepressants tested was a decrease in LC sensory-evoked discharge after acute administration. However, tolerance occurs to these effects after chronic administration. With chronic administration each of the antidepressants produced effects which could potentially interfere with CRF function in the LC. Desmethylimipramine and mianserin attenuated LC activation by a stressor which requires endogenous CRF, suggesting that these antidepressants attenuate stress-elicited release of CRF and perhaps the hypersecretion that occurs in depression. The serotonin reuptake inhibitor, sertraline (SER), enhanced the signal-to-noise ratio of the LC sensory response, an effect opposite to that of CRF. Thus, SER could serve as a functional antagonist of CRF that is hypersecreted in depression. The finding that three pharmacologically distinct antidepressants share the potential to interfere with CRF function in the LC implies that this may be an important common mechanism for antidepressant activity." [Abstract]

Curtis, Andre L., Pavcovich, Luis A., Valentino, Rita J.
Long-Term Regulation of Locus Ceruleus Sensitivity to Corticotropin-Releasing Factor by Swim Stress
J Pharmacol Exp Ther 1999 289: 1211-1219
"Corticotropin-releasing factor (CRF) acts as a putative neurotransmitter in the locus ceruleus (LC) to mediate its activation by certain stressors. In this study, we quantified LC sensitivity to CRF 24 h after swim stress, at a time when behavioral depression that is sensitive to antidepressants is apparent. Rats were placed in a tank with 30 cm (swim stress) or 4 cm water and 24 h later, either behavior was monitored in a forced swim test or LC discharge was recorded. Swim stress rats were more immobile than control animals in the swim test. LC neurons of swim stress rats were sensitized to low doses of CRF (0.1-0.3 µg i.c.v.) that were ineffective in control animals and were desensitized to higher doses. Swim stress selectively altered LC sensitivity to CRF because neither LC spontaneous discharge nor responses to other agents (e.g., carbachol, vasoactive intestinal peptide) were altered. Finally, the mechanism for sensitization was localized to the LC because neuronal activation by low doses of CRF was prevented by the intracerulear administration of a CRF antagonist. CRF dose-response curves were consistent with a two-site model with similar dissociation constants under control conditions but divergent dissociation constants after swim stress. The results suggest that swim stress (and perhaps other stressors) functionally alters CRF receptors that have an impact on LC activity. Stress-induced regulation of LC sensitivity to CRF may underlie behavioral aspects of stress-related psychiatric disorders." [Full Text]

Van Bockstaele EJ, Colago EE, Valentino RJ.
Corticotropin-releasing factor-containing axon terminals synapse onto catecholamine dendrites and may presynaptically modulate other afferents in the rostral pole of the nucleus locus coeruleus in the rat brain.
J Comp Neurol 1996 Jan 15;364(3):523-534 [Abstract]

Smagin GN, Swiergiel AH, Dunn AJ.
Corticotropin-releasing factor administered into the locus coeruleus, but not the parabrachial nucleus, stimulates norepinephrine release in the prefrontal cortex.
Brain Res Bull 1995;36(1):71-6 [Abstract]

Lamberts SW, Bons E, Zuiderwijk J.
High concentrations of catecholamines selectively diminish the sensitivity of CRF-stimulated ACTH release by cultured rat pituitary cells to the suppressive effects of dexamethasone.
Life Sci 1986 Jul 14;39(2):97-102
"ACTH-release by primary cultures of rat anterior pituitary cells in response to CRF, vasopressin, epinephrine, norepinephrine and VIP is readily suppressible by dexamethasone. Rat hypothalamic extract-induced ACTH release is less sensitive to the inhibitory effect of dexamethasone than that elicited by CRF and the other secretagogues mentioned above. In studying the additive and potentiating effect on ACTH release of CRF in combination with vasopressin, VIP and the catecholamines it became evident that only the combination of micromolar concentrations of epinephrine or norepinephrine together with nanomolar concentrations of CRF will make ACTH release significantly less sensitive to the suppressive effect of dexamethasone. Other combinations of CRF and vasopressin or CRF and VIP will render ACTH release as suppressible to dexamethasone, as that elicited by each of these compounds by itself. This observation in the rat might explain at least in part the observation that a diminished suppressibility of the pituitary-adrenal axis to dexamethasone can be found in patients with psychiatric disease, especially depression." [Abstract]

Maes M, Vandewoude M, Schotte C, Martin M, Blockx P.
Positive relationship between the catecholaminergic turnover and the DST results in depression.
Psychol Med. 1990 Aug;20(3):493-9.
"In the past some workers have reported positive relationships between indices of noradrenaline activity and measures of hypothalamic-pituitary-adrenal (HPA)-axis function. In order to investigate these relations, the authors measured noradrenaline, adrenaline and vanillylmandelic acid (VMA) in 24 h urine samples of 72 depressed females. Serum adrenocorticotrophic hormone (ACTH) and cortisol concentrations were determined before and after administration of 1 mg of dexamethasone. Cortisol non-suppressors exhibited a significantly higher noradrenaline, adrenaline and VMA excretion as compared to cortisol suppressors. We determined significantly positive correlations between the postdexamethasone cortisol values and the excretion rates of noradrenaline and VMA. These indices of noradrenaline activity correlated neither with the baseline cortisol and ACTH nor with the postdexamethasone ACTH values." [Abstract]

Roy A, Pickar D, De Jong J, Karoum F, Linnoila M.
Norepinephrine and its metabolites in cerebrospinal fluid, plasma, and urine. Relationship to hypothalamic-pituitary-adrenal axis function in depression.
Arch Gen Psychiatry 1988 Sep;45(9):849-57
"Among 140 depressed and control subjects, there were significant positive correlations between indexes of noradrenergic activity in cerebrospinal fluid (CSF), plasma, and urine. Among the depressed patients, CSF levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and urinary outputs of NE and its metabolites normetanephrine, MHPG, and vanillylmandelic acid correlated significantly with plasma cortisol levels in relation to dexamethasone administration. Also, CSF levels of MHPG were significantly higher among patients who were cortisol nonsuppressors than among either patients who were cortisol suppressors or controls. Urinary outputs of NE and normetanephrine were significantly higher among patients who were cortisol nonsuppressors than among controls. Patients who were cortisol suppressors had indexes of NE metabolism similar to those of controls. These results in the depressed patients extend recent observations suggesting that dysregulation of the noradrenergic system and hypothalamic-pituitary-adrenal axis occur together in a subgroup of depressed patients." [Abstract]

Golczynska A, Lenders JW, Goldstein DS.
Glucocorticoid-induced sympathoinhibition in humans.
Clin Pharmacol Ther. 1995 Jul;58(1):90-8.
"OBJECTIVE: To test whether glucocorticoids inhibit sympathetic nerve activity or norepinephrine release in humans, as has been suggested by results in laboratory animals. METHODS: This was a double-blind, placebo-controlled, randomized crossover study performed at the Clinical Center of the National Institutes of Health. Thirteen normal volunteers received 20 mg prednisone or placebo orally each morning for 1 week, followed by a washout period of 1 week and then by treatment with the other drug for 1 week. On the last day of each treatment week, blood samples were drawn for measurements of plasma levels of catecholamines and their metabolites, of cortisol, and of corticotropin at baseline and during reflexive sympathetic stimulation elicited by lower body negative pressure (-15 mm Hg). A 24-hour urine collection was obtained at the end of each week of treatment for measurement of urinary excretion of catechols. In eight subjects, directly recorded peroneal skeletal muscle sympathetic nerve activity was also measured after both treatments. RESULTS: Prednisone significantly decreased sympathetic nerve activity by 23% +/- 6%, plasma norepinephrine levels by 27% +/- 6%, and plasma corticotropin levels by 77%. Blood pressure, heart rate, body weight, and urinary excretion of catechols and electrolytes were unaffected. Prednisone did not alter proportionate increments in sympathetic nerve activity or plasma norepinephrine levels during lower body negative pressure. Relationships between sympathetic nerve activity and plasma norepinephrine levels were unchanged. CONCLUSIONS: Glucocorticoids decrease sympathoneural outflows in humans without affecting acute sympathoneural responses to decreased cardiac filling and probably without affecting presynaptic modulation of norepinephrine release." [Abstract]

Raucoules D, Levy C, Azorin JM, Bruno M, Valli M.
[Plasma levels of MHPG, HVA and total 5-HIAA in depression. Preliminary study]
Encephale 1992 Nov-Dec;18(6):611-6
"This study was aimed at assessing monoamine catabolites plasma levels in depressed patients and healthy volunteers. Plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) of 21 control subjects and 26 depressed patients (according to DSM III-R criteria) were measured at baseline (day 0) and day 4, day 7, day 30 of prescribed antidepressant treatment. The clinical assessment, at baseline as well as during treatment, used the Hamilton depression rating scale and the BPRS. Our data show the interest of these results in predicting response. The respondent patients showed a significant decrease in plasma MHPG level at J7, contrary to non-respondent patients. Moreover, a positive correlation between plasma levels of MHPG and HVA before any prescribed antidepressants was found only with respondent patients. The lack of correlation for non-respondent patients can suggest that the relationships between this monoamine systems should be disrupted in these patients." [Abstract]

Schildkraut JJ, Orsulak PJ, LaBrie RA, Schatzberg AF, Gudeman JE, Cole JO, Rohde WA.
Toward a biochemical classification of depressive disorders. II. Application of multivariate discriminant function analysis to data on urinary catecholamines and metabolites.
Arch Gen Psychiatry 1978 Dec;35(12):1436-9
"The previous article in this series reported on the differences in urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) in patients with various clinically defined subtypes of depressive disorders. We now report that further biochemical discrimination among depressive subtypes is provided by the following equation, derived empirically by applying multivariate discriminant function analysis to data on urinary catecholamine metabolits: Depression-type (D-type) score = C1(MHPG) + C2(VMA) + C3(NE) +C4(NMN + MN)/VMA + C0. In the original derivation of this equation, low scores were related to bipolar manic-depressive depressions, and high scores were related to unipolar nonendogenous (chronic characterological) depressions. Findings from a series of depressed patients whose biochemical data had not been used to derive this equation confirmed these differences in D-type scores among subtypes of depressions. The findings presented in this report further suggest that we can discriminate three biochemically discrete subgroups of depressive disorders." [Abstract]

Roy A, Pickar D, Douillet P, Karoum F, Linnoila M.
Urinary monoamines and monoamine metabolites in subtypes of unipolar depressive disorder and normal controls.
Psychol Med 1986 Aug;16(3):541-6
"An examination was made of urinary catecholamine and metabolite outputs in 28 unipolar depressed patients and 25 normal controls. The total group of depressed patients had significantly higher urinary outputs of norepinephrine (NE) and its metabolite normetanephrine (NM), and significantly lower urinary outputs of the dopamine metabolite dihydroxyphenylacetic acid (DOPAC), than controls. Patients who met DSM-III criteria for a major depressive episode with melancholia (N = 8) had significantly higher urinary outputs of normetanephrine than controls, whereas patients with a major depressive episode without melancholia (N = 7) and dysthymic disorder patients (N = 8) had levels comparable with controls. We postulate that the higher urinary outputs of norepinephrine and its metabolite, normetanephrine, reflect dysregulation of the sympathetic nervous system in depression." [Abstract]

Roy A, Linnoila M, Karoum F, Pickar D.
Relative activity of metabolic pathways for norepinephrine in endogenous depression.
Acta Psychiatr Scand 1986 Jun;73(6):624-8
"Thirteen patients with endogenous depression, compared to 25 normal controls, had a significantly greater ratio of the urinary excretion of norepinephrine plus its metabolite normetanephrine to either the sum of the two urinary norepinephrine metabolites 3-methoxy-4-hydroxyphenylglycol plus vanillylmandelic acid or to the sum of urinary norepinephrine and all of its metabolites. As urinary levels of norepinephrine and normetanephrine are derived from an extraneuronal metabolic pathway, while levels of 3-methoxy-4-hydroxyphenylglycol and vanillylmandelic acid are more representative of total norepinephrine metabolism, these results suggest that there is a shift in endogenous depression to extraneuronal metabolic pathways for norepinephrine and its metabolites." [Abstract]

Beckmann H, Goodwin FK.
Urinary MHPG in subgroups of depressed patients and normal controls.
Neuropsychobiology 1980;6(2):91-100
"3-Methoxy-4-hydroxyphenylglycol (MHPG), the urinary metabolite thought best to reflect brain norepinephrine metabolism, was studied in a large group of hospitalized depressed patients with primary affective disorder and in normal controls, as part of an ongoing effort to evaluate the role of central amine dysfunction in affective illness. Overall there was no difference in MHPG between the depressed patients and controls. Hosever, within the depressed population the bipolar patients excreted significantly less MHPG than the unipolars and, as a group, the male bipolar patients had significantly lower MHPG than male controls. MHPG correlated positively with age, age of onset, rating of anxiety and psychosis and, most importantly, with systolic blood pressure. These data support the concept of biological heterogeneity among individuals with major depressive disorders. However, the relationship between MHPG excretion and various psychological and physiological parameters is both intriguing and complex and warrants careful interpretation." [Abstract]

Roy A, Pickar D, Linnoila M, Doran AR, Ninan P, Paul SM.
Cerebrospinal fluid monoamine and monoamine metabolite concentrations in melancholia.
Psychiatry Res 1985 Aug;15(4):281-92
"Cerebrospinal fluid levels of norepinephrine and six monoamine metabolites were measured in 28 medication-free depressed patients. Patients with a major depressive episode with melancholia (n = 15) had significantly lower levels of the three dopamine metabolites: homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC), and conjugated dihydroxyphenylacetic (CONJDOPAC), when compared with a combined group of patients with a major depressive episode or dysthymic disorder (n = 13). In patients with major depressive episode with melancholia, levels of HVA and of the serotonin metabolite 5-hydroxyindoleacetic acid significantly correlated with the severity of depression. In the total group of 28 depressed patients, cerebrospinal fluid (CSF) levels of norepinephrine significantly correlated with symptoms of anxiety. In both patients with major depressive episode and major depressive episode with melancholia, those who were non-suppressors on the dexamethasone suppression test had significantly higher CSF levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol compared to those who were suppressors." [Abstract]

Yazici O, Aricioglu F, Gurvit G, Ucok A, Tastaban Y, Canberk O, Ozguroglu M, Durat T, Sahin D.
Noradrenergic and serotoninergic depression?
J Affect Disord 1993 Feb;27(2):123-9
"The only significant finding in this study was the obvious decrease in MHPG excretion during the antidepressant treatment in the group with high pretreatment MHPG." [Abstract]

Potter WZ, Manji HK.
Catecholamines in depression: an update.
Clin Chem 1994 Feb;40(2):279-87
"Despite extensive research, the biochemical abnormalities underlying the predisposition to and the pathogenesis of affective disorders remain to be clearly established. Efforts to study norepinephrine (NE) output and function have utilized biochemical assays, neuroendocrine challenge strategies, and measures of peripheral blood cell receptors; the cumulative database points to a dysregulation of the noradrenergic system. Depressed patients (in particular, melancholic, unipolar subjects) excrete disproportionately greater amounts of NE and its major extraneuronal metabolite, normetanephrine, than do controls. Depressed patients also show subsensitive neuroendocrine (growth hormone) and biochemical (inhibition of adenylate cyclase) responses to alpha 2-adrenergic agonists, suggesting that subsensitivity of nerve terminal alpha 2 autoreceptors may underlie the exaggerated plasma NE observed in response to various challenges in affective disorders. Future advances in brain imaging techniques and in the molecular biology of adrenergic receptor-coupled signal transduction systems offer promise for meaningful advances in our understanding of the pathophysiology of affective disorders." [Abstract]

Backman J, Alling C, Alsen M, Regnell G, Traskman-Bendz L.
Changes of cerebrospinal fluid monoamine metabolites during long-term antidepressant treatment.
Eur Neuropsychopharmacol 2000 Sep;10(5):341-9
"This study describes the changes in cerebrospinal fluid (CSF) monoamine metabolites during antidepressant treatment for more than 6 months. Eight patients, who received antidepressant treatment after attempted suicide and then underwent lumbar punctures every 3 or 4 months, were included. Plasma drug concentrations and the clinical outcome were also measured. Consistent with previous reports about antidepressant treatment for between 3 and 6 weeks, both 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA) were significantly decreased after treatment for a mean of 15 weeks compared to pretreatment. However, after continued treatment for a mean of 30 weeks the MHPG concentration remained significantly lower than at pretreatment while 5-HIAA had returned to the pretreatment level. The clinical outcome was significantly correlated to the pretreatment 5-HIAA/MHPG ratio. These results suggest that the frequently reported reduction in CSF 5-HIAA after antidepressant treatment does not remain during long-term treatment." [Abstract]

Mine K, Okada M, Mishima N, Fujiwara M, Nakagawa T.
Plasma-free and sulfoconjugated MHPG in major depressive disorders: differences between responders to treatment and nonresponders.
Biol Psychiatry 1993 Nov 1;34(9):654-60
"The plasma levels of free and sulfoconjugated forms of 3-methoxy-4-hydroxyphenylglycol (MHPG) were examined before and after treatment in 16 patients with unipolar major depressive disorders without melancholia. The patients were treated with intravenous administration of clomipramine for 4 weeks. Seven depressive disorder patients who showed marked improvement (the improvement group) revealed significant reduction in their plasma sulfoconjugated MHPG levels. In 6 depressive disorder patients who showed no improvement (the no-improvement group), the plasma sulfoconjugated MHPG levels showed no significant change after treatment. The remaining 3 patients, who showed ambiguous change after treatment, were excluded from the analysis. Levels of plasma-free MHPG showed significant change after treatment in neither the improvement group nor in the no-improvement group. It is suggested that levels of plasma sulfoconjugated MHPG may serve as an indicator of brain noradrenergic activity." [Abstract]

Karege F, Bovier P, Hilleret H, Gaillard JM.
Lack of effect of anxiety on total plasma MHPG in depressed patients.
J Affect Disord 1993 Jul;28(3):211-7
"This report was undertaken to test the noradrenergic deficiency hypothesis of depression and the postulated increase in noradrenergic activity associated to anxiety states. A possible dual effect of both depression and anxiety on total plasma MHPG levels was hypothesized and assessed in anxious and non-anxious depressed patients. The findings show a decrease in plasma MHPG levels in depressed patients whatever their degree of anxiety. There was no difference in total plasma MHPG levels either between anxious and non-anxious depressed patients or between low and high anxiety to depression ratio (ADR) depressed patients. Following antidepressant drug-treatment, a decrease in plasma MHPG was found. A positive correlation between the drug-induced decrease in NA activity and the severity of depression was observed, and suggested a relationship between the severity of depression and the instability of the NA system. No correlation between the drug-induced decrease in plasma MHPG and the degree of anxiety was found. The results do not suggest out an effect of anxiety on total plasma MHPG levels in depressed patients." [Abstract]

Correa H, Duval F, Claude MM, Bailey P, Tremeau F, Diep TS, Crocq MA, Castro JO, Macher JP.
Noradrenergic dysfunction and antidepressant treatment response.
Eur Neuropsychopharmacol 2001 Apr;11(2):163-8
"The purpose of this study was to investigate differences in outcome following treatment with two different antidepressants in depressed patients according to their pretreatment hormonal response to clonidine. In all, 62 drug-free DSM-IV recurrent major depressed patients and 20 normal controls were studied. Patients were subsequently treated for 4 weeks with fluoxetine (n=28), or amitriptyline (n=34), and were then classified as responders or nonresponders according to their final Hamilton depression scale score. Compared to controls, depressed patients showed lower GH response to CLO (DeltaGH) (P<0.0002). One control (5%) and 35 depressed patients (56%) had blunted DeltaGH values. The efficacy of the two antidepressants was not significantly different: 15 patients responded to AMI (44%), seven patients responded to FLUOX (25%) (P>0.15). However, in the subgroup of patients with blunted DeltaGH levels, the rate of responders was higher for AMI (11/21) compared to FLUOX (1/14) treated patients (P<0.01). These results suggest that in depressed patients a blunted GH response to CLO could predict antidepressant response." [Abstract]

Markianos M, Alevizos B, Hatzimanolis J, Stefanis C.
Effects of monoamine oxidase A inhibition on plasma biogenic amine metabolites in depressed patients.
Psychiatry Res 1994 Jun;52(3):259-64
"The main metabolites of noradrenalin, dopamine, and serotonin-3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), respectively--were estimated in plasma of 21 depressed patients before and after 2 and 4 weeks of treatment with the monoamine oxidase-type A (MAO-A) inhibitor moclobemide (mean final daily dose = 8.9 mg/kg body weight). The treatment caused significant mean reductions in plasma MHPG and HVA (46% and 30%, respectively), while plasma 5-HIAA was unchanged. Multiple regression analysis revealed associations between reductions in MHPG and changes on the anxiety-somatization factor of the Hamilton Rating Scale for Depression (HRSD), and between reductions in HVA and changes in the HRSD factors cognitive disturbance and retardation." [Abstract]

Stout SC, Owens MJ, Nemeroff CB.
Regulation of corticotropin-releasing factor neuronal systems and hypothalamic-pituitary-adrenal axis activity by stress and chronic antidepressant treatment.
J Pharmacol Exp Ther 2002 Mar;300(3):1085-92
"In a series of experiments, we tested the hypothesis that chronic antidepressant drug administration reduces the synaptic availability of corticotropin-releasing factor (CRF) through one or more effects on CRF gene expression or peptide synthesis. We also determined whether effects of acute or chronic stress on CRF gene expression or peptide concentration are influenced by antidepressant drug treatment. Four-week treatment with venlafaxine, a dual serotonin (5-HT)/norepinephrine (NE) reuptake inhibitor, and tranylcypromine, a monoamine oxidase inhibitor, resulted in an attenuation of acute stress-induced increases in CRF heteronuclear RNA (hnRNA) synthesis in the paraventricular nucleus (PVN). Trends toward the same effect were observed after treatment with the 5-HT reuptake inhibitor fluoxetine, or the NE reuptake inhibitor reboxetine. CRF mRNA accumulation in the PVN during exposure to chronic variable stress was attenuated by concurrent antidepressant administration. Basal CRF hnRNA and mRNA expression were not affected by antidepressant treatment in the PVN or in other brain regions examined. Chronic stress reduced CRF concentrations in the median eminence, but there were no consistent effects of antidepressant drug treatment on CRF, serum corticotropin, or corticosterone concentrations. CRF receptor expression and basal and stress-stimulated HPA axis activity were unchanged after antidepressant administration. These results suggest that chronic antidepressant administration diminishes the sensitivity of CRF neurons to stress rather than alters their basal activity. Additional studies are required to elucidate the functional consequences and mechanisms of this interaction." [Abstract]

Manier DH, Shelton RC, Sulser F.
Noradrenergic antidepressants: does chronic treatment increase or decrease nuclear CREB-P?
J Neural Transm 2002;109(1):91-9
"Chronic administration of noradrenergic antidepressants causes a desensitization of the beta adrenoceptor coupled adenylate cyclase system." [Abstract]

Widmaier EP, Lim AT, Vale W.
Secretion of corticotropin-releasing factor from cultured rat hypothalamic cells: effects of catecholamines.
Endocrinology 1989 Feb;124(2):583-90
"An understanding of the regulation of CRF secretion in rats is currently incomplete, in part due to the lack of sensitive in vitro models available for studying this neuropeptide. In particular, the effects of catecholamines on CRF secretion, and the receptor subtypes mediating these actions have long been the subject of much debate. A cultured cell model has been adapted for studying secretory responses of hypothalamic cells of 1-week-old rats. Between 7-16 days in monolayer culture the cells secreted detectable levels of immunoreactive CRF, and this release was paralleled by the appearance of punctate bead-like regions of immunoreactivity along fine cellular processes. CRF secretion was increased up to 4-fold by norepinephrine (EC50, approximately 0.5 microM). The increase in CRF secretion produced by norepinephrine was blocked by the beta-receptor antagonist propranolol, but not by the alpha-antagonist prazosin. Moreover, the beta-receptor agonist isoproterenol significantly elevated CRF secretion, whereas the alpha-agonist phenylephrine was without effect, except at high concentrations. Addition of phenylephrine, however, potentiated the effect of isoproterenol, but this response was still significantly less than that produced by norepinephrine. Forskolin (EC50, approximately 0.7 microM) and the active phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (EC50, approximately 40 nM) also increased CRF secretion by 3- to 4-fold. Inactive phorbol derivatives had no effect on CRF release from these cultures. The results indicate that cultured neonatal rat hypothalamic cells are a powerful model for the study of CRF release in vitro, and that norepinephrine acts directly at the isolated cell level to stimulate secretion of this peptide, primarily by activating beta-adrenoceptors. The results also suggest that at least two functional second messenger systems (adenylate cyclase and protein kinase-C) are involved in CRF secretion and are already functional in the neonatal hypothalamus." [Abstract]

Tilders FJ, Berkenbosch F, Vermes I, Linton EA, Smelik PG.
Role of epinephrine and vasopressin in the control of the pituitary-adrenal response to stress.
Fed Proc 1985 Jan;44(1 Pt 2):155-60
"In addition to corticotropin-releasing factor (CRF) and structurally related peptides, arginine vasopressin (AVP), oxytocin, angiotensin II, vasoactive intestinal polypeptide, peptide histidine isoleucinamide, epinephrine (E), and norepinephrine induce secretion of adrenocorticotropin (ACTH) from corticotropic cells in vitro. The apparent affinity and intrinsic ACTH-releasing activity of these substances are lower than those of CRF. These substances can also act synergistically with CRF. In this paper the role of catecholamines and AVP in the control of ACTH release is discussed. Infusion i.v. of E increases plasma ACTH and corticosterone to levels that are normally found during stress. E-induced stimulation of pituitary-adrenal activity is mediated by beta adrenoceptors and involves release of CRF, because it can be prevented by beta-adrenoceptor blockers and by destruction of CRF neurons (hypothalamic lesions), blockade of CRF release (chlorpromazine, morphine, and Nembutal), or administration of CRF antiserum. Although stress can cause a vast increase in plasma E, circulating E is not essential for the acute stress-induced release of ACTH because blockade of beta (or alpha) adrenoceptors, administration of chlorisondamine, or extirpation of the adrenal medulla and sympathectomy do not prevent the pituitary-adrenal response to stress. In contrast, circulating E plays a major role in the release of intermediate-lobe peptides during emotional stress. Studies of the role of AVP in pituitary-adrenal control by the use of pressor receptor (V1) antagonists are not valuable because of the ineffectiveness of such antagonists in blocking AVP-induced release of ACTH from corticotropic cells in vitro. Treatment of rats with an antiserum to AVP reduces the ACTH response to stress. We conclude that AVP has an important role in stress-induced activation of the pituitary-adrenal system, possibly by potentiating the effects of CRF." [Abstract]

Ordway GA, Gambarana C, Frazer A.
Quantitative autoradiography of central beta adrenoceptor subtypes: comparison of the effects of chronic treatment with desipramine or centrally administered l-isoproterenol.
J Pharmacol Exp Ther 1988 Oct;247(1):379-89
"This study compares the regulation of the subtypes of central beta adrenoceptors produced by treatment of rats with desipramine (10 mg/kg i.p. twice daily for 10 days) to that caused by central infusion of l-isoproterenol (5 micrograms/hr for 7 days). Beta adrenoceptors were measured by quantitative autoradiography of the binding of [125I]iodopindolol ([125I]IPIN) to coronal sections of rat brain as well as the binding of this radioligand to homogenates of certain areas of brain. Administration of desipramine caused significant reductions in the total specific binding of [125I]IPIN in many areas of the brain, including regions of the amygdala, cerebral cortex, hippocampus, hypothalamus and thalamus." [Abstract]

Ko HC, Lu RB, Shiah IS, Hwang CC.
Plasma free 3-methoxy-4-hydroxyphenylglycol predicts response to fluoxetine.
Biol Psychiatry 1997 Apr 1;41(7):774-81
"This study was designed to investigate the relationship between platelet serotonin (5-HT) and plasma free 3-methoxy-4-hydroxyphenylglycol (MHPG) measures in depressed outpatients obtained from the same patient with unipolar depression during the pretreatment period and subsequent response to 6 weeks of treatment with either fluoxetine or maprotiline. Compared to the nonresponder group, the fluoxetine responders showed significantly higher pretreatment levels of MHPG, but no difference in pretreatment 5-HT levels. There were no significant differences in either 5-HT or MHPG levels between maprotiline responders and nonresponders. As to posttreatment levels, there were no between-group differences in 5-HT or MHPG between responders and nonresponders to either fluoxetine or maprotiline. When the relationships between changes in 5-HT or MHPG levels and treatment response were examined, 5-HT values showed a marked decrease in both fluoxetine responders and nonresponders, but no significant changes were found in the maprotiline treatment groups. On the other hand, MHPG levels in the fluoxetine nonresponders tended to increase (borderline significance), whereas the MHPG levels for fluoxetine responders and maprotiline responders and nonresponders were unaffected from pre- to posttreatment. Pretreatment levels of plasma free MHPG appear to predict response to fluoxetine." [Abstract]

De Bellis MD, Geracioti TD Jr, Altemus M, Kling MA.
Cerebrospinal fluid monoamine metabolites in fluoxetine-treated patients with major depression and in healthy volunteers.
Biol Psychiatry 1993 Apr 15-May 1;33(8-9):636-41
"Cerebrospinal fluid (CSF) levels of the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and homovanillic acid (HVA) were measured in three groups: 46 healthy volunteers; 9 medication-free patients with DSM III-R major depressive disorder, recurrent; and these same 9 patients following at least 4 weeks of fluoxetine treatment at 20 mg/day. CSF monoamine metabolite levels in medication-free patients did not differ from healthy volunteers; however, CSF 5-HIAA and MHPG decreased significantly from 95.9 +/- 24.6 (all values +/- SD) to 64.2 +/- 26.1 pmol/ml and from 46.7 +/- 14.2 to 42.6 +/- 11.6 pmol/ml, respectively, following fluoxetine treatment. Fluoxetine also significantly decreased mean Hamilton Depression Rating Scale scores from 23.2 +/- 6.5 to 17.4 +/- 5.0 and significantly increased the CSF HVA/5-HIAA ratio." [Abstract]

Sheline Y, Bardgett ME, Csernansky JG.
Correlated reductions in cerebrospinal fluid 5-HIAA and MHPG concentrations after treatment with selective serotonin reuptake inhibitors.
J Clin Psychopharmacol 1997 Feb;17(1):11-4
"We sought to determine whether fluvoxamine and fluoxetine, two different antidepressants with in vitro selectivity for the serotonin uptake transporter also demonstrated similar selectivity in vivo. To accomplish this, we measured cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and homovanillic acid (HVA) before and after 6 weeks of treatment with these two drugs. Twenty-four subjects who had major depression according to DSM-III-R criteria gave written, informed consent for the collection of CSF during a double-blind comparative treatment trial of fluvoxamine (50-150 mg/day) and fluoxetine (20-80 mg/day). The symptoms of subjects were assessed clinically on a weekly basis throughout the treatment trial. CSF samples were obtained after a 7- to 14-day washout period before treatment and again at the end of treatment. CSF samples were analyzed for 5-HIAA, HVA, and MHPG using high-pressure liquid chromatography coupled to electrochemical detection. Fluvoxamine- and fluoxetine-treated patients did n