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British Journal of Pharmacology Feb 19801 The cardiovascular effects of intravenous desipramine (0.03 and 0.1 mg/kg), maprotiline (0.5 mg/kg), mianserin (1.0 and 3.0 mg/kg) and phentolamine (0.25 mg/kg) were... (Comparative Study)
Comparative Study
Comparison of mianserin with desipramine, maprotiline and phentolamine on cardiac presynaptic and vascular postsynaptic alpha-adrenoceptors and noradrenaline reuptake in pithed normotensive rats.
1 The cardiovascular effects of intravenous desipramine (0.03 and 0.1 mg/kg), maprotiline (0.5 mg/kg), mianserin (1.0 and 3.0 mg/kg) and phentolamine (0.25 mg/kg) were examined and compared in pithed rats. Several experimental procedures were used in order to distinguish between the effects of the compounds on cardiac presynaptic alpha-adrenoceptors and on neuronal noradrenaline reuptake, as inhibition of either mechanism produces an increase of neurotransmitter concentration within the sympathetic synapse and therefore results in a greater end organ response.2 Pressor responses elicited by noradrenaline were potentiated by desipramine and maprotiline, reduced by phentolamine and not significantly modified by mianserin. However, all four compounds inhibited the pressor action of tyramine. Furthermore, mianserin reduced the pressor response to adrenaline.3 Desipramine, maprotiline and mianserin, but not phentolamine enhanced the positive chronotropic effects of noradrenaline, without affecting those of isoprenaline.4 All four compounds abolished the clonidine-induced inhibition of heart rate responses to short term electrical stimulation of the spinal cord. Moreover, in rats with a persistent tachycardia (induced by continuous stimulation of the thoracic spinal cord) desipramine, maprotiline and mianserin further increased heart rate. This effect was also observed in animals pretreated with phentolamine, administered in order to inhibit cardiac presynaptic alpha-adrenoceptors.5 In rats with a sustained tachycardia (100 beats/min produced by electrical stimulation of the spinal cord) both mianserin and phentolamine, in contrast to desipramine, shifted the clonidine heart rate dose-response curve to the right. Phentolamine was about 34 times more potent than mianserin in this respect.6 In pithed, reserpine-treated rats, the pressor responses to clonidine were not significantly modified by desipramine. The dose-response curves were shifted to the right by phentolamine (0.25 mg/kg) and mianserin (3.0 mg/kg).7 These results indicate that mianserin is an antagonist of both cardiac presynaptic and vascular postsynaptic alpha-adrenoceptors and also inhibits the neuronal reuptake of noradrenaline.
Topics: Animals; Anthracenes; Blood Vessels; Cardiovascular System; Clonidine; Desipramine; Dibenzazepines; Drug Interactions; Heart; Male; Maprotiline; Mianserin; Norepinephrine; Phentolamine; Rats; Receptors, Adrenergic; Receptors, Adrenergic, alpha; Spinal Cord
PubMed: 6244040
DOI: 10.1111/j.1476-5381.1980.tb10421.x -
Journal of Psychiatry & Neuroscience :... Jan 1994In neurochemistry there are advantages in determining how patients are likely to react to psychoactive drugs prior to the commencement of drug therapy. Explanations of a... (Review)
Review
In neurochemistry there are advantages in determining how patients are likely to react to psychoactive drugs prior to the commencement of drug therapy. Explanations of a patient's nonresponse, or unexpected adverse reactions to drugs are required. In many instances, a knowledge of the drug metabolism status of a patient can be helpful in the selection of a drug and its dosage regimen, and in the prediction of possible drug/drug interactions when two or more drugs have to be administered concomitantly. Important information on these topics may be obtained by phenotyping patients prior to drug therapy. The metabolism of various antidepressant and neuroleptic drugs is catalyzed by CYP2D6, a cytochrome P450 isozyme (also named P450IID6), whereas the metabolism of other drugs may involve different cytochromes P450. The properties of CYP2D6 and four other isozymes (CYP1A1, CYP1A2, CYP2C8/9 and CYP3A4) are described, and substrates identified. Phenotyping of patients for CYP2D6 activity and mephenytoin hydroxylase activity is described.
Topics: Clomipramine; Cytochromes; Dealkylation; Depressive Disorder; Desipramine; Dextromethorphan; Drug Interactions; Female; Humans; Hydroxylation; Imipramine; Isoenzymes; Male; Mephenytoin; Nortriptyline; Phenotype; Polymorphism, Genetic
PubMed: 8148364
DOI: No ID Found -
The Psychiatric Clinics of North America Dec 1996The patient presenting with binge-eating disorder requires a detailed clinical assessment that takes into account behavioral, somatic, and psychological aspects of the... (Review)
Review
The patient presenting with binge-eating disorder requires a detailed clinical assessment that takes into account behavioral, somatic, and psychological aspects of the disorder. Treatment selection depends on the patient's particular goals. Antidepressant medications and CBT are effective, at least in the short term, in suppressing binge eating and reducing depressive symptoms. Fluoxetine may, in addition, promote short-term weight loss, which is more likely to be maintained if medication is administered in the context of behavior therapy. Preliminary study suggests that behavior therapy may be designed to promote weight loss, even in the absence of medication treatment, without undermining binge cessation. Appetite suppressant medications clearly promote weight loss, but their use in suppressing binge eating has yet to be studied specifically. Further study is needed in several areas including the feasibility and efficacy of treatment approaches that combine medication and psychotherapy, the efficacy of individual versus group psychotherapy, the long-term outcome of various forms of treatment, and the clinical features that predict favorable response to different treatment modalities.
Topics: Adult; Anorexia Nervosa; Antidepressive Agents; Bulimia; Cognitive Behavioral Therapy; Combined Modality Therapy; Desipramine; Female; Humans; Psychiatric Status Rating Scales
PubMed: 8933607
DOI: 10.1016/s0193-953x(05)70380-4 -
International Journal of... 2013Allergic rhinitis (AR) is characterized by IgE-mediated immediate hypersensitivity and usually progresses to chronic nasal inflammation, with depression as one of its...
Allergic rhinitis (AR) is characterized by IgE-mediated immediate hypersensitivity and usually progresses to chronic nasal inflammation, with depression as one of its comorbidities. The importance of treating the depression in AR patients has been increasingly recognized. Desipramine is a representative of tricyclic-antidepressant agents. In the present study we investigate whether desipramine has therapeutic effects on AR inflammation. BALB/C mice were sensitized by intraperitoneal injection of ovalbumin (OVA), followed by repeated challenge with OVA intranasally. Desipramine was administered orally to treat the mice. The nasal symptoms (sneezing, nasal scratching etc.) of AR were evaluated to determine the severity of AR. Cytokines in the nasal lavage fluid (NALF), including interferon-gamma (IFN-gamma), interleukin 4 (IL-4) and serum OVA-specific immunoglobulin E (IgE) antibody were measured by ELISA. The regulatory T cells (Treg) and T helper cells 17 (Th17) were quantified by flow cytometric analysis. As a result, the repeated oral administration of desipramine attenuated the nasal symptoms (sneezing and nasal rubbing) in AR mice. Desipramine also suppressed the serum OVA-specific IgE and IL-4 levels, but had no effect on IFN-gamma level. Moreover, desipramine treatment up regulated CD4+CD25+Foxp3+ Treg cells, which were found down-regulated in established AR mice. Meanwhile, desipramine administration attenuated CD4+IL-17+ Th17 cells, which were significantly increased in AR mice. These results suggest that the antidepressant drug, desipramine, also has anti-allergic action, which was possibly achieved by reducing allergen-specific IgE and Th2 cytokine production and maintaining a balance between Treg and Th17 cells. Thus, this study provide the first evidence that desipramine may be utilized to treat allergic diseases, especially for those allergic patients with depression or depression patients with allergy.
Topics: Allergens; Animals; Anti-Allergic Agents; Antidepressive Agents; Desipramine; Immunoglobulin E; Interferon-gamma; Interleukin-4; Male; Mice; Mice, Inbred BALB C; Nasal Lavage Fluid; Ovalbumin; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; Spleen; T-Lymphocytes, Regulatory; Th17 Cells
PubMed: 23527713
DOI: 10.1177/039463201302600110 -
Cellular Physiology and Biochemistry :... 2010Acid sphingomyelinase (ASM) is an important lipid-metabolizing enzyme cleaving sphingomyelin to ceramide, mainly within lysosomes. Acid ceramidase (AC) further degrades... (Review)
Review
Acid sphingomyelinase (ASM) is an important lipid-metabolizing enzyme cleaving sphingomyelin to ceramide, mainly within lysosomes. Acid ceramidase (AC) further degrades ceramide to sphingosine which can then be phosphorylated to sphingosine-1-phosphate. Ceramide and its metabolite sphingosine-1-phosphate have been shown to antagonistically regulate apoptosis, cellular differentiation, proliferation and cell migration. Inhibitors of ASM or AC therefore hold promise for a number of new clinical therapies, e.g. for Alzheimer's disease and major depression on the one hand and cancer on the other. Inhibitors of ASM have been known for a long time. Cationic amphiphilic substances induce the detachment of ASM protein from inner lysosomal membranes with its consecutive inactivation, thereby working as functional inhibitors of ASM. We recently experimentally identified a large number of hitherto unknown functional inhibitors of ASM and determined specific physicochemical properties of such cationic amphiphilic substances that functionally inhibit ASM. We propose the acronym "FIASMA" (Functional Inhibitor of Acid SphingoMyelinAse) for members of this large group of compounds with a broad range of new clinical indications. FIASMAs differ markedly with respect to molecular structure and current clinical indication. Most of the available FIASMAs are licensed for medical use in humans, are minimally toxic and may therefore be applied for disease states associated with increased activity of ASM.
Topics: Acid Ceramidase; Alzheimer Disease; Clinical Trials as Topic; Desipramine; Humans; Phosphodiesterase Inhibitors; Sphingomyelin Phosphodiesterase
PubMed: 20502000
DOI: 10.1159/000315101 -
Science (New York, N.Y.) Sep 2007Tricyclic antidepressants exert their pharmacological effect-inhibiting the reuptake of serotonin, norepinephrine, and dopamine-by directly blocking neurotransmitter...
Tricyclic antidepressants exert their pharmacological effect-inhibiting the reuptake of serotonin, norepinephrine, and dopamine-by directly blocking neurotransmitter transporters (SERT, NET, and DAT, respectively) in the presynaptic membrane. The drug-binding site and the mechanism of this inhibition are poorly understood. We determined the crystal structure at 2.9 angstroms of the bacterial leucine transporter (LeuT), a homolog of SERT, NET, and DAT, in complex with leucine and the antidepressant desipramine. Desipramine binds at the inner end of the extracellular cavity of the transporter and is held in place by a hairpin loop and by a salt bridge. This binding site is separated from the leucine-binding site by the extracellular gate of the transporter. By directly locking the gate, desipramine prevents conformational changes and blocks substrate transport. Mutagenesis experiments on human SERT and DAT indicate that both the desipramine-binding site and its inhibition mechanism are probably conserved in the human neurotransmitter transporters.
Topics: Amino Acid Sequence; Animals; Antidepressive Agents, Tricyclic; Bacterial Proteins; Binding Sites; Caenorhabditis elegans Proteins; Cell Line; Conserved Sequence; Crystallography, X-Ray; Desipramine; Dopamine; Dopamine Uptake Inhibitors; Drosophila Proteins; Humans; Leucine; Models, Molecular; Molecular Sequence Data; Neurotransmitter Uptake Inhibitors; Norepinephrine; Norepinephrine Plasma Membrane Transport Proteins; Plasma Membrane Neurotransmitter Transport Proteins; Protein Binding; Protein Conformation; Sequence Homology, Amino Acid; Serotonin; Selective Serotonin Reuptake Inhibitors
PubMed: 17690258
DOI: 10.1126/science.1147614 -
Translational Psychiatry Sep 2019BTB/POZ domain-containing 3 (BTBD3) was identified as a potential risk gene in the first genome-wide association study of obsessive-compulsive disorder (OCD). BTBD3 is a...
BTB/POZ domain-containing 3 (BTBD3) was identified as a potential risk gene in the first genome-wide association study of obsessive-compulsive disorder (OCD). BTBD3 is a putative transcription factor implicated in dendritic pruning in developing primary sensory cortices. We assessed whether BTBD3 also regulates neural circuit formation within limbic cortico-striato-thalamo-cortical circuits and behaviors related to OCD in mice. Behavioral phenotypes associated with OCD that are measurable in animals include compulsive-like behaviors and reduced exploration. We tested Btbd3 wild-type, heterozygous, and knockout mice for compulsive-like behaviors including cage-mate barbering, excessive wheel-running, repetitive locomotor patterns, and reduced goal-directed behavior in the probabilistic learning task (PLT), and for exploratory behavior in the open field, digging, and marble-burying tests. Btbd3 heterozygous and knockout mice showed excessive barbering, wheel-running, impaired goal-directed behavior in the PLT, and reduced exploration. Further, chronic treatment with fluoxetine, but not desipramine, reduced barbering in Btbd3 wild-type and heterozygous, but not knockout mice. In contrast, Btbd3 expression did not alter anxiety-like, depression-like, or sensorimotor behaviors. We also quantified dendritic morphology within anterior cingulate cortex, mediodorsal thalamus, and hippocampus, regions of high Btbd3 expression. Surprisingly, Btbd3 knockout mice only showed modest increases in spine density in the anterior cingulate, while dendritic morphology was unaltered elsewhere. Finally, we virally knocked down Btbd3 expression in whole, or just dorsal, hippocampus during neonatal development and assessed behavior during adulthood. Whole, but not dorsal, hippocampal Btbd3 knockdown recapitulated Btbd3 knockout phenotypes. Our findings reveal that hippocampal Btbd3 expression selectively modulates compulsive-like and exploratory behavior.
Topics: Animals; Antidepressive Agents; Behavior, Animal; Brain; Compulsive Behavior; Desipramine; Disease Models, Animal; Exploratory Behavior; Fluoxetine; Mice; Mice, Knockout; Motor Activity; Nerve Net; Nerve Tissue Proteins; Obsessive-Compulsive Disorder
PubMed: 31501410
DOI: 10.1038/s41398-019-0558-7 -
Pharmacological Research Dec 2016Neuropathic pain impacts approximately 3-4.5% of the global population and remains an unresolved health problem. The management of neuropathic pain has two distinct...
Prophylactic treatment with the tricyclic antidepressant desipramine prevents development of paclitaxel-induced neuropathic pain through activation of endogenous analgesic systems.
Neuropathic pain impacts approximately 3-4.5% of the global population and remains an unresolved health problem. The management of neuropathic pain has two distinct goals-prevention of development and control of established neuropathic pain. We examined the impact of both prophylactic and therapeutic treatments with the tricyclic antidepressant desipramine on the development and maintenance of toxic neuropathic pain induced by the chemotherapeutic agent paclitaxel. We also investigated the involvement of endogenous analgesic (i.e., endogenous opioid and endocannabinoid) systems in the antinociceptive actions of desipramine in these two distinct phases of neuropathic pain. Chronic subcutaneous infusion of desipramine via osmotic pumps suppressed both the development and maintenance of paclitaxel-induced neuropathic pain. However, only prophylactic desipramine treatment blocked the development of neuropathic pain throughout the three month observation interval; neuropathic pain did not return. The opioid receptor antagonist naloxone blocked the antinociceptive effects of both prophylactic and therapeutic desipramine treatments throughout the entire timecourse of desipramine-induced antinociception. By contrast, cannabinoid CB and CB receptor antagonists partially attenuated the antinociceptive actions of desipramine in a manner that was restricted to the development phase of paclitaxel-induced neuropathic pain only. Paclitaxel decreased cell viability in TMD231 tumor cells in an MTT assay in vitro. Notably, desipramine (1nM-1μM) alone did not alter tumor cell viability and did not prevent the cytotoxic effects of paclitaxel under identical conditions. The highest concentration of desipramine (10μM) reduced tumor cell viability alone and enhanced the cytotoxic effects of paclitaxel. Our study identifies a previously unrecognized preemptive analgesic strategy that prevents development of paclitaxel-induced neuropathic pain, and also dissects receptor mechanisms underlying desipramine-induced antinociceptive effects. This information may be applied to improve current therapeutic strategies with the goal of preventing and managing neuropathic pain induced by chemotherapeutic treatment.
Topics: Animals; Antidepressive Agents, Tricyclic; Antineoplastic Agents, Phytogenic; Desipramine; Hyperalgesia; Male; Neuralgia; Paclitaxel; Rats, Sprague-Dawley; Receptors, Cannabinoid; Signal Transduction
PubMed: 27773824
DOI: 10.1016/j.phrs.2016.10.007 -
British Journal of Pharmacology Nov 19741 The technique of microelectrophoresis was used in order to study the effects of imipramine and desipramine on single neurones in the somatosensory cortex of the cat,...
1 The technique of microelectrophoresis was used in order to study the effects of imipramine and desipramine on single neurones in the somatosensory cortex of the cat, anaesthetized with halothane.2 Imipramine and desipramine, when applied for a brief period, did not affect the firing rate of the vast majority of the neurones tested.3 Both potentiation and antagonism of excitatory responses to noradrenaline could be observed after a brief application of either of the antidepressants. Four drug-interaction patterns could be distinguished: potentiation of immediate onset; potentiation reaching its maximum after a delay; antagonism followed by potentiation; antagonism followed by recovery.4 When different doses of the same antidepressant were applied, it was found that the drug-interaction patterns were related to the dose of antidepressant applied, a lower dose causing potentiation, and a higher dose antagonism of the response.5 Both potentiation and antagonism of depressant responses to noradrenaline could be observed.6 Both excitatory and depressant responses to 5-hydroxytryptamine were modified by imipramine and desipramine: a smaller dose of the antidepressant potentiated, and a higher dose antagonized the responses.7 Excitatory responses to glutamate were not affected by imipramine and desipramine.
Topics: Action Potentials; Animals; Cats; Cerebral Cortex; Desipramine; Drug Interactions; Female; Glutamates; Imipramine; Male; Neurons; Norepinephrine; Serotonin; Serotonin Antagonists
PubMed: 4458844
DOI: 10.1111/j.1476-5381.1974.tb08602.x -
Translational Psychiatry Dec 2014Depression is a complex, heterogeneous mental disorder. Currently available antidepressants are only effective in about one-third to one-half of all patients. The...
Depression is a complex, heterogeneous mental disorder. Currently available antidepressants are only effective in about one-third to one-half of all patients. The mechanisms underlying antidepressant response and treatment resistance are poorly understood. Recent clinical evidence implicates the involvement of leptin in treatment response to antidepressants. In this study, we determined the functional role of the leptin receptor (LepRb) in behavioral responses to the selective serotonergic antidepressant fluoxetine and the noradrenergic antidepressant desipramine. While acute and chronic treatment with fluoxetine or desipramine in wild-type mice elicited antidepressant-like effects in the forced swim test, mice null for LepRb (db/db) displayed resistance to treatment with either fluoxetine or desipramine. Fluoxetine stimulated phosphorylation of Akt(Thr308) and GSK-3β(Ser9) in the hippocampus and prefrontal cortex (PFC) of wild-type mice but not in db/db mice. Desipramine failed to induce measurable changes in Akt, GSK-3β or ERK1/2 phosphorylation in the hippocampus and PFC, as well as hypothalamus of either genotype of mice. Deletion of LepRb specifically from hippocampal and cortical neurons resulted in fluoxetine insensitivity in the forced swim test and tail suspension test while leaving the response to desipramine intact. These results suggest that functional LepRb is critically involved in regulating the antidepressant-like behavioral effects of both fluoxetine and desipramine. The antidepressant effects of fluoxetine but not desipramine are dependent on the presence of functional LepRb in the hippocampus and cortex.
Topics: Adrenergic Uptake Inhibitors; Animals; Behavior, Animal; Depressive Disorder, Treatment-Resistant; Desipramine; Fluoxetine; Hippocampus; Hypothalamus; Mice; Mice, Knockout; Prefrontal Cortex; Receptors, Leptin; Selective Serotonin Reuptake Inhibitors; Signal Transduction
PubMed: 25463972
DOI: 10.1038/tp.2014.126