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Pharmacological Reports : PR 2012Contact hypersensitivity (CS) reaction in the skin is T-cell mediated immune reaction which plays a major role in the pathogenesis and chronicity of various inflammatory... (Comparative Study)
Comparative Study
BACKGROUND
Contact hypersensitivity (CS) reaction in the skin is T-cell mediated immune reaction which plays a major role in the pathogenesis and chronicity of various inflammatory skin disorders and, like other delayed-type hypersensitivity (DTH) reactions, affords immunity against tumor cells and microbes. CS response is a self-limiting reaction, and interleukin (IL)-10 is considered to be a natural suppressant of cutaneous inflammatory response. Recently, it has been demonstrated that major depression is related to activation of the inflammatory response and elevation of some parameters of cell-mediated immunity. It has been suggested that such activation of the immune system may play a role in etiology of depression. If this immunoactivation is involved in etiology of depression, one would expect that antidepressant agents may have negative immunoregulatory effects. To the best of our knowledge, the effect of antidepressants on contact hypersensitivity has not been studied.
METHODS
The aim of the present study was to establish the effect of prolonged desipramine or fluoxetine treatment on CS reaction to picryl chloride.
RESULTS
Antidepressants significantly suppressed CS reaction, fluoxetine by 53% whereas desipramine by 47% compared to positive control. Moreover, desipramine and fluoxetine decreased relative weight of auxillary lymph nodes. Desipramine decreased also relative weight of inguinal lymph nodes and spleens whereas desipramine and fluoxetine increased production of IL-10 in comparison to positive control.
CONCLUSION
The observed effect of antidepressant drugs on CS reaction is consistent with the hypothesis that T-cell mediated immunity is targeted by antidepressants.
Topics: Animals; Antidepressive Agents, Second-Generation; Antidepressive Agents, Tricyclic; Dermatitis, Contact; Desipramine; Fluoxetine; Interleukin-10; Lymph Nodes; Mice; Mice, Inbred CBA; Organ Size; Picryl Chloride; Spleen; T-Lymphocytes
PubMed: 22814024
DOI: 10.1016/s1734-1140(12)70866-6 -
Neuropharmacology May 2015Our recent study indicates that the lesions of the prefrontal cortex in rats result in depressive-like behavior in forced swim test and REM sleep alterations, two...
Our recent study indicates that the lesions of the prefrontal cortex in rats result in depressive-like behavior in forced swim test and REM sleep alterations, two well-established biomarkers of depression disorder. We hypothesized that antidepressants may target the PFC to reverse depression. Systemic injections of antidepressants: the tricyclic antidepressant desipramine (DMI), the selective serotonin reuptake inhibitor fluoxetine, and the NMDA-antagonist ketamine selectively increased cFos expression (a marker of neuronal activity) in the deep layers of the ventromedial PFC (vmPFC) in rats. Of the vmPFC's limbic system targets, only the nucleus accumbens (NAc) was also activated by DMI. Using a retrograde tracer and a neuronal toxin, we also found that DMI-activated vmPFC neurons project to the NAc and that NAc activation by DMI was lost following vmPFC lesion. These results suggest that the vmPFC may be an essential target of antidepressant drugs, its projections to the NAc may be a key circuit regulating antidepressant action, and dysfunction of this pathway may contribute to depression.
Topics: Analysis of Variance; Animals; Antidepressive Agents; Brain Injuries; Cell Count; Depression; Desipramine; Disease Models, Animal; Dose-Response Relationship, Drug; Electroencephalography; Electromyography; Gene Expression Regulation; Limbic System; Male; Neural Pathways; Prefrontal Cortex; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Sleep, REM
PubMed: 25637091
DOI: 10.1016/j.neuropharm.2015.01.010 -
Behavioural Pharmacology Dec 2008Reinforcement magnitude modulates the effects of the antidepressants fluvoxamine and desipramine in the pigeon. Increasing reinforcement magnitude diminishes the...
Reinforcement magnitude modulates the effects of the antidepressants fluvoxamine and desipramine in the pigeon. Increasing reinforcement magnitude diminishes the rate-dependent effects of these drugs. Whether this is also the case in other species is unknown. Rats were trained to respond under a multiple fixed-interval (FI 300 s) schedule of reinforcement. In one FI component, rats earned two food pellets, and in the other component they earned 10 food pellets when they completed the FI requirement. The effects of fluvoxamine (3, 5.6, 10, and 17.8 mg/kg) or desipramine (1, 3, 5.6, 10, 30 mg/kg) given 30 min presession (intraperitoneally) on overall response rate were examined. Local rates of responding (during each 10th of the component) increased throughout the FI as is typical, and were higher during the component reinforced with 10 pellets. Fluvoxamine and desipramine decreased overall response rates similarly in both components. Both drugs exerted limited rate-dependent effects, shown by a negative slope for the regression of log (drug rate/control rate) on log (control rate) using data from each 10th of the FI. The slope for the two-pellet condition was, however, significantly steeper than the slope for the 10-pellet condition after 3 and 10 mg/kg fluvoxamine and after 30 mg/kg desipramine. This result is consistent with those obtained in pigeons and shows that reinforcement magnitude can modulate rate-dependent effects of fluvoxamine and perhaps desipramine in rats.
Topics: Animals; Antidepressive Agents; Conditioning, Operant; Desipramine; Feeding Behavior; Fluvoxamine; Male; Rats; Rats, Inbred Lew; Regression Analysis; Reinforcement Schedule; Reinforcement, Psychology
PubMed: 19020418
DOI: 10.1097/FBP.0b013e32831d9667 -
Polish Journal of Pharmacology 2003Caffeine undergoes 3-N-demethylation via CYP1A2, as well as 1-N-demethylation, 7-N-demethylation and 8-hydroxylation, which may involve other CYP isoenzymes. The aim of... (Comparative Study)
Comparative Study
Caffeine undergoes 3-N-demethylation via CYP1A2, as well as 1-N-demethylation, 7-N-demethylation and 8-hydroxylation, which may involve other CYP isoenzymes. The aim of the present study was to investigate the influence of clomipramine, desipramine, sertraline, nefazodone and mirtazapine on cytochrome P-450 activity measured by caffeine oxidation in rat liver microsomes. The obtained results showed that all the investigated antidepressants, with an exception of mirtazapine, added in vitro to liver microsomes had an inhibitory effect on caffeine metabolism (via competitive or mixed mechanism), though their potency towards particular metabolic pathways was different. Dixon analysis of caffeine metabolism carried out in the control liver microsomes, in the absence and presence of the antidepressant drugs showed that desipramine and clomipramine exerted the most potent inhibitory effect on caffeine metabolism. Desipramine decreased the rates of 1-N-, 3-N- and 7-N-demethylations, and 8-hydroxylation of caffeine (Ki = 23.3, 36.6, 23.3 and 63.3 microM, respectively), the effect on 1-N- and 7-N-demethylation being the most pronounced. Clomipramine showed distinct inibition of 1-N- and 3-N-demethylation and 8-hydroxylation of caffeine, the effects on N-demethylations being the most pronounced (Ki = 38.6, 34.8, 45.6 microM, respectively). Its effect on 7-N-demethylation was rather weak (Ki = 97.8 microM). Sertraline decreased significantly the rate of 1-N- and 3-N-demethylation and 8-hydroxylation (Ki = 37.3, 69.3 and 64 microM, respectively), while its effect on 7-N-demethylation of caffeine was less pronounced (Ki = 92.1 microM). Nefazodone displayed clear effect on 3-N- and 7-N-demethylation (Ki = 68.8 and 66.4 microM, respectively), but was weak in inhibiting 1-N-demethylation and 8-hydroxylation of caffeine (Ki = 110 and 186 microM, respectively). In contrast to the above-tested antidepressants, mirtazapine did not decrease significantly the oxidation rates of 3-N-demethylation or 8-hydroxylation (Ki = 264 and 455 microM, respectively) and had no effect on other oxidation pathways of caffeine. In summary, we have observed intra- and inter-drug differences in the inhibitory effects of the antidepressants on the four oxidation pathways of caffeine in rat liver microsomes. The tested antidepressants (with an exception of mirtazapine) may lead to drug-drug metabolic interactions at a level of a few CYP isoforms. The obtained results provide further indirect evidence that apart from CYP1A2, other CYP isoforms are also important for the metabolism of caffeine.
Topics: Animals; Antidepressive Agents; Caffeine; Clomipramine; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Desipramine; Hydroxylation; In Vitro Techniques; Isoenzymes; Male; Mianserin; Microsomes, Liver; Mirtazapine; Piperazines; Rats; Rats, Wistar; Sertraline; Triazoles
PubMed: 14730100
DOI: No ID Found -
British Journal of Pharmacology Jul 19751 The sensitivity of single neurones to microelectrophoretically applied dopamine, noradrenaline (NA), 5-hydroxytryptamine (5-HT) and acetylcholing (ACh) was...
1 The sensitivity of single neurones to microelectrophoretically applied dopamine, noradrenaline (NA), 5-hydroxytryptamine (5-HT) and acetylcholing (ACh) was investigated in the caudate nucleus of the rat, anaesthetized with halothane. Both excitatory and depressant responses could be observed to each of the agonists. There was a high correlation between the direction of responses to dopamine and noradrenaline, whereas there was no significant correlation between the direction of responses to dopamine and ACh. 2 The effect of desipramine was studied on both excitatory and depressant responses to dopamine, NA and 5-HT, and on excitatory responses to ACh. Both potentiation and antagonism of neuronal responses to monoamines and ACh could be observed after a brief application of desipramine. 3 Excitatory responses to glutamate were not affected by desipramine. 4 The observation that responses to dopamine and NA can be potentiated by desipramine in the caudate nucleus suggests that uptake blockade is not a prerequisite for potentiation. 5 It is suggested that the potentiation of neuronal responses to dopamine by desipramine may be responsible for the therapeutic efficacy of desipramine in Parkinson's disease.
Topics: Acetylcholine; Action Potentials; Animals; Caudate Nucleus; Desipramine; Dopamine; Drug Synergism; Glutamates; Iontophoresis; Male; Neurons; Norepinephrine; Rats; Serotonin; Time Factors
PubMed: 1164588
DOI: 10.1111/j.1476-5381.1975.tb07567.x -
American Journal of Respiratory and... Oct 2016Obstructive sleep apnea is a state-dependent disease. One of the key factors that triggers upper airway collapse is decreased pharyngeal dilator muscle activity during... (Randomized Controlled Trial)
Randomized Controlled Trial
RATIONALE
Obstructive sleep apnea is a state-dependent disease. One of the key factors that triggers upper airway collapse is decreased pharyngeal dilator muscle activity during sleep. To date, there have not been effective methods to reverse pharyngeal hypotonia pharmacologically in sleeping humans.
OBJECTIVES
We tested the hypothesis that administration of desipramine 200 mg prevents the state-related reduction in genioglossus activity that occurs during sleep and thereby decreases pharyngeal collapsibility.
METHODS
We conducted a placebo-controlled, double-blind, crossover trial with 10 healthy participants. Participants received active treatment or placebo in randomized order 2 hours before sleep in the physiology laboratory.
MEASUREMENTS AND MAIN RESULTS
Genioglossus activity during wakefulness and sleep, genioglossus muscle responsiveness to negative epiglottic pressure, and upper airway collapsibility during passive and active conditions were compared between on- and off-drug states. Desipramine abolished the normal reduction of genioglossus activity from wakefulness to non-REM sleep that occurred on the placebo night. Specifically, tonic (median, 96% [86-120] vs. 75% [50-92] wakefulness; P = 0.01) but not phasic genioglossus activity was higher with desipramine compared with placebo. Upper airway collapsibility was also reduced with desipramine compared with placebo (-10.0 cm HO [-15.2 to -5.8] vs. -8.1 cm HO [-10.4 to -6.3]; P = 0.037).
CONCLUSIONS
Desipramine reduces the state-related drop in tonic genioglossus muscle activity that occurs from wakefulness to non-REM sleep and reduces airway collapsibility. These data provide a rationale for a new pharmacologic therapy for obstructive sleep apnea. Clinical trial registered with www.clinicaltrials.gov (NCT02428478).
Topics: Adrenergic Uptake Inhibitors; Adult; Continuous Positive Airway Pressure; Cross-Over Studies; Desipramine; Electromyography; Female; Healthy Volunteers; Humans; Male; Pharyngeal Muscles; Sleep; Sleep Apnea, Obstructive; Young Adult
PubMed: 26967681
DOI: 10.1164/rccm.201511-2172OC -
Magnetic Resonance in Chemistry : MRC Feb 2004The effect of tricyclic antidepressants (TCA) on phospholipid bilayer structure and dynamics was studied to provide insight into the mechanism of TCA-induced...
The effect of tricyclic antidepressants (TCA) on phospholipid bilayer structure and dynamics was studied to provide insight into the mechanism of TCA-induced intracellular accumulation of lipids (known as lipidosis). Specifically we asked if the lipid-TCA interaction was TCA or lipid specific and if such physical interactions could contribute to lipidosis. These interactions were probed in multilamellar vesicles and mechanically oriented bilayers of mixed phosphatidylcholine-phosphatidylglycerol (PC-PG) phospholipids using (31)P and (14)N solid-state NMR techniques. Changes in bilayer architecture in the presence of TCAs were observed to be dependent on the TCA's effective charge and steric constraints. The results further show that desipramine and imipramine evoke distinguishable changes on the membrane surface, particularly on the headgroup order, conformation and dynamics of phospholipids. Desipramine increases the disorder of the choline site at the phosphatidylcholine headgroup while leaving the conformation and dynamics of the phosphate region largely unchanged. Incorporation of imipramine changes both lipid headgroup conformation and dynamics. Our results suggest that a correlation between TCA-induced changes in bilayer architecture and the ability of these compounds to induce lipidosis is, however, not straightforward as imipramine was shown to induce more dramatic changes in bilayer conformation and dynamics than desipramine. The use of (14)N as a probe was instrumental in arriving at the presented conclusions.
Topics: Antidepressive Agents, Tricyclic; Benzylamines; Desipramine; Imipramine; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Phospholipids
PubMed: 14745789
DOI: 10.1002/mrc.1327 -
British Journal of Clinical Pharmacology May 1985Twenty-nine healthy volunteers participated in an experiment lasting for 8 weeks: Phase I (2 weeks)--pre-treatment control period; Phase II (4 weeks)--medication with... (Clinical Trial)
Clinical Trial Comparative Study
Twenty-nine healthy volunteers participated in an experiment lasting for 8 weeks: Phase I (2 weeks)--pre-treatment control period; Phase II (4 weeks)--medication with either ciclazindol hydrochloride (50 mg twice daily), or desipramine hydrochloride (50 mg twice daily) or lactose placebo (twice daily) administered in a single-blind fashion; Phase II (2 weeks)--recovery. Experimental sessions took place twice weekly for the photographic assessment of resting pupil diameter, and for the assessment of one of the following pupillary responses: mydriatic response to methoxamine, mydriatic response to tyramine, miotic response to pilocarpine. Resting pupil diameter increased during medication with either ciclazindol or desipramine. Methoxamine-evoked mydriasis and tyramine-evoked mydriasis were antagonized by both ciclazindol and desipramine. Pilocarpine-evoked miosis was potentiated by both ciclazindol and desipramine. The steady-state plasma levels (mean +/- s.e. mean) of the antidepressants were: ciclazindol: 5.90 +/- 0.74 microM; desipramine: 0.60 +/- 0.17 microM. The antagonism of methoxamine-evoked mydriasis is likely to reflect the blockade of postsynaptic alpha 1-adrenoceptors in the iris by the antidepressants, whereas the antagonism of tyramine-evoked mydriasis may reflect both the blockade of uptake of tyramine into presynaptic adrenergic terminals and the blockade of postsynaptic alpha-adrenoceptors. There is no immediate explanation for the potentiation of pilocarpine-evoked miosis by the two antidepressants.
Topics: Adolescent; Adult; Antidepressive Agents, Tricyclic; Desipramine; Female; Humans; Indoles; Male; Methoxamine; Pilocarpine; Pupil; Tyramine
PubMed: 4005103
DOI: 10.1111/j.1365-2125.1985.tb02691.x -
American Journal of Physiology. Heart... Mar 2006Cardiac sympathetic transmitter stores are reduced in the failing heart. In this study, we proposed to investigate whether the reduction of cardiac sympathetic...
Cardiac sympathetic transmitter stores are reduced in the failing heart. In this study, we proposed to investigate whether the reduction of cardiac sympathetic neurotransmitters was associated with increased interstitial norepinephrine (NE) and reactive oxygen species in congestive heart failure (CHF), using a microdialysis technique and salicylate to detect .OH generation. Rabbits with and without rapid ventricular pacing (340 beats/min) were randomized to receive desipramine (10 mg/day) or placebo for 8 wk. Rapid pacing produced left ventricular dilation and systolic dysfunction. The failing myocardium also showed reduced tissue contents of NE and tyrosine hydroxylase protein and activity. In contrast, myocardial interstitial NE was increased in CHF (0.89 +/- 0.11 ng/ml) compared with the sham-operated animals (0.26 +/- 0.03 ng/ml). In addition, cardiac oxidative stress was increased in CHF animals as measured by myocardial interstitial .OH radical, tissue oxidized glutathione, and oxidized mitochondrial DNA. Desipramine treatment produced significant NE uptake inhibition as evidence by an exaggerated pressor response and a greater increase of myocardial interstitial NE in response to intravenous NE infusion but no significant effects on cardiac function or hemodynamics in sham-operated or CHF animals. However, desipramine treatment attenuated the reductions of tissue NE and tyrosine hydroxylase protein and activity in CHF. Desipramine also prevented the reduction of tyrosine hydroxylase produced by NE in PC12 cells. Thus the reduction of cardiac sympathetic neurotransmitters is related to the increased interstitial NE and tissue oxidative stress in CHF. Also, normal neuronal uptake of NE is required for NE or its oxidized metabolites to exert their neurotoxic effects.
Topics: Animals; Cardiac Pacing, Artificial; Cardiomyopathies; Desipramine; Heart; Neuroprotective Agents; Norepinephrine; Rabbits; Reactive Oxygen Species; Sympathetic Nervous System; Tachycardia; Treatment Outcome
PubMed: 16214845
DOI: 10.1152/ajpheart.00569.2005 -
British Journal of Pharmacology Oct 19981. Venlafaxine is an antidepressant agent which blocks in vitro the reuptake of both 5-HT and NA. The present in vivo electrophysiological studies were undertaken, in... (Comparative Study)
Comparative Study
1. Venlafaxine is an antidepressant agent which blocks in vitro the reuptake of both 5-HT and NA. The present in vivo electrophysiological studies were undertaken, in the rat, to compare the effects of venlafaxine on 5-HT and NA reuptake to those of the selective 5-HT reuptake inhibitor paroxetine and the selective NA reuptake inhibitor desipramine. 2. Administered acutely, venlafaxine dose-dependently prolonged the time required for a 50% recovery (RT50) of the firing activity of dorsal hippocampus CA3 pyramidal neurons from the suppression induced by microiontophoretic applications of 5-HT and NA. Venlafaxine and paroxetine increased with a similar potency the RT50 values for 5-HT, while desipramine was more potent than venlafaxine at increasing the RT50 values for NA. Moreover, venlafaxine demonstrated a greater potency at increasing the RT50 values for 5-HT compared to that of NA. 3. A two-day treatment with venlafaxine (delivered s.c. by osmotic minipumps) increased the RT50 values for both 5-HT and NA applications. The RT50 values for 5-HT were significantly increased at a dose of 10 mg kg(-1) day(-1), whereas those for NA were increased at a dose of 20 mg kg(-1) day(-1), consistent with the data obtained following the acute administration of venlafaxine. 4. Taken together, these results indicate that, in vivo, venlafaxine blocks both reuptake processes, with a potency greater for the 5-HT than for the NA reuptake process. This dual action, combined with the differential potency of venlafaxine, might constitute the biological substratum responsible for its apparent unique clinical efficacy in major depression.
Topics: Adrenergic Uptake Inhibitors; Animals; Cyclohexanols; Depression; Desipramine; Hippocampus; Injections, Intravenous; Iontophoresis; Male; Norepinephrine; Paroxetine; Rats; Rats, Sprague-Dawley; Serotonin; Selective Serotonin Reuptake Inhibitors; Venlafaxine Hydrochloride
PubMed: 9806336
DOI: 10.1038/sj.bjp.0702074