On the role of noradrenergic neurotransmission in the action of desipramine and amitriptyline in animal models of depression

Three weeks of treatment with desipramine (DMI) and amitriptyline (AMI) reduced the hypothermic action of clonidine in rats. Both electrolytic and 6-hydroxydopamine lesions of the locus coeruleus (LC) and administration of DSP-4 counteracted the reduction of clonidine hypothermia produced by antidepressants. Lesions of the LC and DSP-4 administration also antagonized the anti-immobility action of single doses of DMI but failed to modulate the action of AMI in the forced swim test. Chronic DMI action on the rat immobility was reduced by 6-hydroxydopamine lesions of the LC: other lesions (electrolytic, DSP-4) were ineffective. Electrical stimulation of the LC increased the rat activity in the forced swim paradigm, producing an effect similar to that of antidepressants. The anti-immobility effect of DMI as well as LC stimulation were antagonized by drugs blocking alpha-adrenoceptors (phenoxybenzamine, prazosin) but not by propranolol, a non-selective antagonist of beta-adrenoceptors. On the other hand, the anti-immobility action of AMI was unchanged by all adrenolytics used in that study. The results indicate that the LC system and alpha 1-adrenoceptors play an important role in the antidepressive action of DMI, but not AMI, in the forced swim test.     

Reserpine augmentation of desipramine in refractory depression: clinical and neurobiological effects

Early studies showed dramatic improvement in some depressed patients when a brief course of parenteral reserpine was added to ineffective tricyclic antidepressant (TCA) treatment. We treated eight patients with DSM-III melancholic major depression with desipramine (DMI)2.5 mg/kg/day (plasma levels>125 ng/ml) for at least 4 weeks. All patients failed to respond and received reserpine 5 mg IM b.i.d. over 2 days, in seven cases as a placebo-controlled, double-blind trial. One patient had dramatic resolution of depressive and psychotic symptoms within 48 h, but relapsed within 2 weeks; two other patients had transient hypomanic symptoms. Depression ratings did not significantly change for the sample as a whole, but plasma and cerebrospinal fluid (CSF) levels of 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) decreased and CSF levels of homovanillic acid (HVA) and 5-hydroxy-indoleacetic acid (5-HIAA) increased. Despite robust effects on central monoamine metabolism, reserpine augmentation appears insufficiently effective for routine use in managing refractory depression.     

Acute and chronic effects of desipramine administration to rhesus monkeys

Rhesus monkeys were studied for changes in noradrenergic functioning before and after chronic oral administration (28 days) of the tricyclic antidepressant desipramine (DMI). Decreases in cerebrospinal fluid concentration of the norepinephrine metabolite MHPG were evident following the first dose (5.0 mg/kg) of DMI, but not after chronic administration of the drug. The alpha 2-adrenoceptor agonist clonidine reduced plasma norepinephrine prior to DMI treatment, but not after 28 days of treatment with DMI. These adaptive changes in noradrenergic function were evident in spite of very low plasma levels of DMI due to rapid metabolism of the drug in the rhesus monkey. The development of changes compatible with alpha 2-adrenoceptor subsensitivity in the presence of plasma levels of the drug that are well below those considered therapeutic in the treatment of depression suggests that such a receptor change may be dissociated from the drug's antidepressant effect.     

Acute and chronic effects of desipramine and clorgyline on alpha(2)-adrenoceptors regulating noradrenergic transmission in the rat brain: a dual-probe microdialysis study

1. The effects of desipramine (3 mg kg(-1) i.p.) and clorgyline (1 mg kg(-1) i.p.) on extracellular noradrenaline (NA) in the locus coeruleus (LC) and cingulate cortex were assessed in freely-moving rats by dual-probe microdialysis. Functional activities of alpha(2)-adrenoceptors regulating NA release in the LC and cingulate cortex were determined by systemic (0.3 mg kg(-1) i.p.) or local (0.1 - 100 microM) clonidine administration. 2. Extracellular NA was increased in the LC and cingulate cortex following acute desipramine but not clorgyline treatment. Systemic clonidine decreased NA similarly in desipramine-, clorgyline-, and saline-treated animals, in both brain areas. 3. Long-term (twice daily, 14 days) but not short-term (twice daily, 7 days) desipramine, and long-term clorgyline (once daily, 21 days) treatments increased NA (3 fold) in cingulate cortex but not in the LC. Following long-term treatments, responses of NA to systemic clonidine were attenuated in the LC and cingulate cortex. 4. Clonidine perfusion by reverse dialysis into the cingulate cortex decreased local NA (-55 +/- 9%). The effect was attenuated by long-term desipramine (-31 +/- 9%) and clorgyline (-10 +/- 2%) treatments. 5. Clonidine perfusion by reverse dialysis into the LC decreased NA in the LC (-89 +/- 2%) and in cingulate cortex (-52 +/- 12%). This effect was attenuated in the LC following long-term desipramine (-72 +/- 4%) and clorgyline (-62 +/- 12%) treatments but it was not modified in the cingulate cortex (-57 +/- 10% and -68 +/- 6%, respectively). 6. These findings demonstrate that chronic desipramine or clorgyline treatments increase NA in noradrenergic terminal areas and desensitize alpha(2)-adrenoceptors modulating local NA release at somatodendritic and terminal levels. However, somatodendritic alpha(2)-adrenoceptors that control LC firing activity are not desensitized.     

Response to desipramine treatment in adolescent major depression

Thirty adolescents (ages 15-20) who met DSM-III-R criteria for major depressive disorder completed a double-blind, placebo-controlled, 6-week, fixed-dose (200 mg daily) study of desipramine (DMI). Thirty-three percent of the placebo group and 50 percent of the DMI group improved (greater than or equal to 50% change on the Hamilton Rating Scale for Depression). Subjective reports of adverse effects did not significantly differentiate the two groups. Major adverse effects, necessitating study discontinuation, occurred solely in the DMI group.     

Acute effects of lithium chloride on noradrenergic neurons from rat cerebral cortex

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1. 1.1. Acute effects of lithium chloride upon the parameters of central noradrenergic function were assessed at either a therapeutic dose (2 m-equiv/kg) or a toxic one (10 m-equiv/kg) on rats.
2. 2.2. Lithium chloride lacked a direct effect on tyrosine hydroxylase (TH), monoamine oxidase (MAO), or catechol-O-methyltransferase (COMT) in concentrations up to 2 mM.
3. 3.3. A single i.p. injection of both studied doses inhibited MAO 1 hr later.
4. 4.4. Endogenous NA levels in frontal cerebral cortex were increased by a therapeutic dose and slightly increased by a toxic dose.
5. 5.5. Uptake of [³H]NA was increased in pretreated tissues at a therapeutic level but decreased by a toxic dose.
6. 6.6. The unmetabolized [³H]NA was always increased over controls.

     

Brainstem noradrenergic system depression by cyclobenzaprine

A possible mechanism for CBZ's depressant action on the brainstem noradrenergic system was investigated in precollicularly decerebrated cats immobilized with Flaxedil (2 mg/kg, i.V.). Phenoxybenzamine (2 mg/kg, i.v.) was consistently observed to antagonize CBZ's suppression of both the flexor and extensor MSRs. Subsequent evidence for the brainstem noradrenergic system mediating the CBZ effect was established by extracellular recordings. Unitary discharges of LC neurons identified histologically were demonstrated to be inhibited chiefly by CBZ (1 mg/kg, i.V.). In some instances, the inhibition of spontaneous coerulear activity was found to parallel temporally the MSR response following CBZ administration. Coerulospinal neurons characterized by physiological criteria also revealed diminished activities following CBZ (0.5 mg/kg, i.V.). A decreased neuronal somatic excitability was also observed by the antidromically driven coerulospinal neurons following CBZ. It is concluded that CBZ's depressant action is mediated, at least in part, by the noradrenergic coerulospinal system. Other possible mechanisms of CBZ action are also discussed.     

Effects of chronic desipramine treatment on rat brain noradrenergic responses to alpha-adrenergic drugs

It has been previously reported that long-term tricyclic antidepressant treatment in the rat causes a subsensitivity of central beta-receptor-stimulated adenylate cyclase along with alterations of brain norepinephrine (NE) content and metabolism. We have confirmed earlier findings that after one week of desipramine treatment (5.0 mg/kg b.i.d.) brain NE levels decline while NE metabolism is similar to control animals, but is above control after 12 days of treatment. Single cell recordings from noradrenergic neurons of the locus coeruleus (LC) show that after one week of desipramine treatment, neuronal firing rate is lower than in control rats but greater than that seen in response to acutely administered drug. Furthermore, desipramine injection in a dose which profoundly altered LC impulse flow in control rats produced little or no effect on impulse flow in chronically treated rats. Of 25 or 250 microgram/kg doses of clonidine, which are equieffective for decreasing brain NE metabolism in control animals, only the larger dose decreased NE metabolism in 12 day desipramine-treated rats. The postsynaptic alpha-antagonist prazosin (5.0 mg/kg) increased NE metabolism in both groups. These results suggest that presynaptic (alpha 2) adrenoreceptors become subsensitive during long-term desipramine treatment, thus allowing recovery of noradrenergic impulse flow in the presence of NE uptake inhibition.     

A controlled trial of adinazolam versus desipramine in geriatric depression

Thirty outpatients between the ages of 60 and 85 with DSM-III Major Depression entered an 8 week randomized, double-blind comparison of desipramine and adinazolam mesylate, a triazolobenzodiazepine derivative. Outcome was assessed on several measures including the Hamilton Depression Rating Scale (HDRS), Montgomery-Asberg Rating Scale, Clinical Global Impressions (CGI), the 35-item Self-Rating Symptom Scale, and Carroll Depression Scale. Patients in both groups demonstrated a highly significant decrease in average HDRS scores (p less than 0.001) over the course of the study. Adinazolam was associated with significantly greater reduction in average HDRS scores by the third day. Repeated measures analysis of variance showed a significantly greater reduction in HDRS scores for adinazolam over the course of the study. The study medications were associated with distinct patterns of adverse reactions. Desipramine more often produced dry mouth, constipation and nervousness, while adinazolam was more likely to cause drowsiness and lightheadedness. Three of these elderly patients, all of whom were taking desipramine reported at least one fall during the study. Adinazolam may be a promising agent in the treatment of depression in the elderly.     

Acute and chronic desipramine treatment effects on rewarding electrical stimulation of the lateral hypothalamus

Two weeks of chronic desipramine HCl (DMI) (10 mg/kg, IP) treatment did not alter reward or motor/performance components of intracranial self-stimulation (ICSS) as assessed with the rate-frequency method. Acute DMI treatment produced an ICSS reward decrement relative to saline control treatment, which was similar in size on Day 1 and Day 15 of chronic testing. The failure to find a chronic DMI effect on ICSS reward suggests that ICSS in normal rats may not be a valid animal model of depression. A better paradigm may be to test the ability of antidepressants to reverse a chronic reduction in ICSS reward function that is first produced by some other method.     

Effect of desipramine and amphetamine on noradrenergic neurotransmission: electrophysiological studies in the rat brain.

The present electrophysiological experiments were undertaken to investigate the effect of desipramine and d-amphetamine on noradrenergic neurotransmission in the rat central nervous system. The effectiveness of electrical stimulation of the locus coeruleus and of microiontophoretic application of norepinephrine (NE) in suppressing the firing activity of CA3 pyramidal neurons was studied in the dorsal hippocampus. Desipramine (0.5 and 5 mg/kg i.v.) and d-amphetamine (0.25 and 5 mg/kg i.v.) decreased the effectiveness of locus coeruleus stimulation and prolonged the effect of microiontophoretically applied NE on the same pyramidal neurons. Subsequent i.v. administration of idazoxan, an alpha 2-adrenoceptor antagonist, reversed the effects of desipramine and d-amphetamine on the effectiveness of locus coeruleus stimulation and decreased that of microiontophoretically applied NE. In addition, idazoxan prevented the effect of subsequent administration of desipramine (5 mg/kg i.v.) on the effectiveness of locus coeruleus stimulation. High doses of d-amphetamine (5 and 10 mg/kg i.v.) decreased the firing activity of hippocampus pyramidal neurons by 70 and 98%, respectively, whereas low doses of desipramine (0.5 mg/kg i.v.) or of d-amphetamine (0.25 mg/kg i.v.) were without effect. After lesioning of NE projections with 6-hydroxydopamine, the effect of the 5 mg/kg dose of d-amphetamine on the firing activity of hippocampus pyramidal neurons was markedly reduced, whereas the cumulative 10 mg/kg dose of d-amphetamine completely suppressed, as in control rats, the firing activity of these neurons. This effect of d-amphetamine in 6-hydroxydopamine-pretreated rats was reversed by the administration of the 5-HT1A receptor antagonist BMY 7378. These data provide evidence that acute administration of desipramine and d-amphetamine decreases the effectiveness of locus coeruleus stimulation by increasing the activation of terminal alpha 2-adrenoceptor autoreceptors. In addition, acute administration of high doses of d-amphetamine decreases the firing rate of hippocampus pyramidal neurons by increasing NE and serotonin release.     

Treatment of depression in chronic cocaine and phencyclidine abuse with desipramine

An open field trial was conducted comparing desipramine and an active placebo in separate populations of chronic cocaine and phencyclidine (PCP) abusers, who discontinued their abuse. Subjects who received desipramine showed a decrease in depressive symptoms after a 20-40 day period regardless of whether they abused PCP or cocaine.     

Acute and chronic effects of the atypical antidepressant,mianserin on brain noradrenergic neurons

Corticotropin-releasing factor (CRF), which may serve as a neurotransmitter in the noradrenergic nucleus, locus coeruleus (LC), has been postulated to be hypersecreted in depression. The present study was designed to test the hypothesis that antidepressants interfere with CRF putative neurotransmission in the LC. The acute and chronic effects of the atypical antidepressant mianserin on LC spontaneous discharge, LC sensory-evoked discharge, LC activation by a stressor which requires endogenous CRF, and LC activation by ICV CRF were characterized in halothane-anesthetized rats. Acute IV administration of mianserin (0.0001–1.0 mg/kg) increased LC spontaneous discharge and decreased LC discharge evoked by repeated sciatic nerve stimulation in a dose-dependent manner. Additionally, mianserin (0.1 mg/kg) inhibited LC activation by hemodynamic stress (IV infusion of nitroprusside) and by ICV administration of CRF (3.0 µg). In rats chronically administered mianserin LC spontaneous and sensory-evoked discharge rates, and LC activation by CRF were similar to those of untreated rats or rats chronically administered saline. Moreover, acute IV administration of mianserin (0.1 mg/kg) to rats chronically treated with mianserin was less effective in altering LC spontaneous and sensory-evoked discharge. In contrast, LC activation by hemodynamic stress was still greatly attenuated in rats chronically administered mianserin. This is similar to the previously reported effect produced by chronic administration of the antidepressant, desmethylimipramine. The present results demonstrate that acute administration of low doses of mianserin attenuates LC activation by a variety of stimuli and suggest that tolerance developes with chronic administration to some of the effects of mianserin on LC discharge characteristics. The finding that LC activation by hemodynamic stress, which requires endogenous CRF, is attenuated after chronic mianserin administration suggests that interference with putative CRF neurotransmission in the LC may be an important common mode of antidepressant action.This work was supported by U.S.P.H.S. Grants MH42796, MH40008, MH00840, and a NARSAD award to A.L.C.     

Brain noradrenergic receptors in major depression and schizophrenia.

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

A comparison of adinazolam and desipramine in the treatment of major depression

Thirty-one patients with a DSM-III (R) diagnosis of Major Depression received adinazolam (n = 16) or desipramine (n = 15) during a 6 week double-blind randomized controlled trial. Both groups showed a significant decline in Hamilton Rating Scale for Depression scores (21.8 +/- 4.5 to 10.7 +/- 8.5 for adinazolam and 23.5 +/- 5.5 to 12.9 +/- 8.6) for desipramine. Melancholic and anxiety symptoms were reduced equally by both drugs. Initial sedation was the most common side-effect with adinazolam. Plasma levels of desipramine and hydroxy-desipramine correlated highly with oral dose after 3 weeks of treatment.     

Do noradrenergic reuptake inhibitors affect serotonergic function in depression?

  d-Fenfluramine, a specific 5-HT releasing agent without the catecholamine effects of d,l-fenfluramine, was used as a serotonergic neuroendocrine challenge in subjects with unipolar major depression. Prolactin and cortisol responses to 30 mg d-fenfluramine were measured in patients at baseline. Patients were then randomly assigned to treatment for 6 weeks with a specific noradrenergic reuptake inhibitor, a tricyclic antidepressant, or placebo. Response to antidepressant treatment was assessed, and patients underwent further testing with d-fenfluramine. Prolactin responses were increased by treatment, but this was independent of whether or not patients’ depression responded to treatment. Seven patients were treated with a specific noradrenergic reuptake inhibitor. These patients showed a significant rise in 5-HT-mediated cortisol responses after treatment, independent of whether their depression improved. We conclude that antidepressants which selectively modify noradrenergic function also have effects on 5-HT function as measured by neuroendocrine testing. Received: 21 March 1997 / Final version: 3 July 1997