Dose Of Desipramine Research Articles

Protective effects of curcumin on desipramine-induced islet β-cell damage via AKAP150/PKA/PP2B complex.

Tricyclic antidepressants (TCAs) are widely used to treat depression and anxiety-related mood disorders. But evidence shows that TCAs elevate blood glucose levels and inhibit insulin secretion, suggesting that TCAs are a risk factor, particularly for individuals with diabetes. Curcumin is a bioactive molecule from the rhizome of the Curcuma longa plant, which has shown both antidepressant and anti-diabetic activities. In the present study, we investigated the protective effect of curcumin against desipramine-induced apoptosis in β cells and the underlying molecular mechanisms. In the mouse forced swimming test (FST), we found that lower doses of desipramine (5 and 10 mg/kg) or curcumin (2.5 mg/kg) alone did not affect the immobility time, whereas combined treatment with curcumin (2.5 mg/kg) and desipramine (5, 10 mg/kg) significantly decreased the immobility time. Furthermore, desipramine dose-dependently inhibited insulin secretion and elevated blood glucose levels, whereas the combined treatment normalized insulin secretion and blood glucose levels. In RIN-m5F pancreatic β-cells, desipramine (10 μM) significantly reduced the cell viability, whereas desipramine combined with curcumin dose-dependently prevented the desipramine-induced impairment in glucose-induced insulin release, most effectively with curcumin (1 and 10 μM). We demonstrated that desipramine treatment promoted the cleavage and activation of Caspase 3 in RIN-m5F cells. Curcumin treatment inhibited desipramine-induced apoptosis, increased mitochondrial membrane potential and Bcl-2/Bax ratio. Desipramine increased the generation of reactive oxygen species, which was reversed by curcumin treatment. Curcumin also inhibited the translocation of forkhead box protein O1 (FOXO1) from the cytoplasm to the nucleus and suppressed the binding of A-kinase anchor protein 150 (AKAP150) to protein phosphatase 2B (PP2B, known as calcineurin) that was induced by desipramine. These results suggest that curcumin protects RIN-m5F pancreatic β-cells against desipramine-induced apoptosis by inhibiting the phosphoinositide 3-kinase/AKT/FOXO1 pathway and the AKAP150/PKA/PP2B interaction. This study suggests that curcumin may have therapeutic potential as an adjunct to antidepressant treatment.

Revisiting the antidepressant-like effects of desipramine in male and female adult rats: sex disparities in neurochemical correlates

BackgroundThe preclinical antidepressant-like characterization of desipramine relied almost exclusively in male rodents, with only a few contradictory reports done in females. Given that most experiments assessed a single dose and/or timepoint of analysis after-treatment, this study evaluated potential sex-differences in the length of the antidepressant-like response induced by different doses of desipramine as well as the molecular underpinnings driving the different responses by sex.MethodsMale and female Sprague–Dawley rats were treated (i.p.) with 3 pulses of desipramine (5, 10 or 20 mg/kg) or vehicle (0.9% NaCl) within 24 h. The antidepressant-like effects were evaluated in the forced-swim test 1-h, 1- and 3-day post-treatment. The rate of cell proliferation and the regulation of key neuroplasticity markers (FADD, Cdk5, p35, p25) involved in antidepressant-like responses in the hippocampus were evaluated 1-h, 1-day and 5-day post-treatment.ResultsDesipramine induced similar antidepressant-like effects in male and female rats (effective doses of 10 and 20 mg/kg, with effects that lasted up to 1-day post-treatment), without altering the rate of cell proliferation. However, some sex-differences emerged when evaluating neuroplasticity markers in the hippocampus, while no changes were observed for female rats, desipramine regulated FADD, Cdk-5 and p25 in males in a way that suggested neuroprotective actions.ConclusionsOur findings imply that while desipramine induced similar antidepressant-like responses for male and female rats, some differences emerged in the regulation of certain neuroplasticity markers, suggesting that distinctive molecular mechanisms might be participating in the therapeutic response of desipramine for both sexes.

The role of sphingolipid metabolism disruption on lipopolysaccharide-induced lung injury in mice

AimThis study assessed pulmonary outcomes generated by inhibiting key enzymes of sphingolipid metabolism pathways related to ceramide synthesis in a murine model of lung injury induced by lipopolysaccharide (LPS). MethodsC57BL/6 male adult mice received LPS intratracheally and the expressions of acid sphingomyelinase (ASM), neutral sphingomyelinase (NSM), serine palmitoyl transferase (SPT) and dihydroceramide synthase (DS) were assessed at 2, 4, 6, 12 and 24 h after LPS instillation in lung homogenate (n = 30). The pharmacological inhibition of ASM, NSM, SPT and DS were assayed in other mice groups by three different doses of desipramine, GW4869, myriocin and fumonisin, respectively (n = 90). Their most effective doses were administered intraperitoneally 1 or 2 h before LPS to different animal groups (n = 120). Mice underwent determination of pulmonary mechanics, lung histopathological aspects and apoptosis. ResultsThe expression levels of the enzymes reached their peak at 2–4 h after LPS administration. ASM inhibition attenuated alveolar collapse and GW4869 decreased lung elastance, proinflammatory cytokines' levels and was more effective to improve alveolar collapse than desipramine. On the other hand, SPT blockage aggravated lung lesion and no effects it was observed with fumonisin. Moreover, simultaneous administration of inhibitors (desipramine + GW4869, myriocin + fumonisin and all inhibitors together) resulted in no changes. ConclusionBlockage of sphingomyelinases and the de novo pathways improved and aggravated lung injury, respectively, putatively suggesting specific targets to therapeutic strategies in LPS-induced lung injury.

Interaction of Different Antidepressants with Acute and Chronic Methadone in Mice, and Possible Clinical Implications

We studied the interaction of a single dose of different antidepressant medications with a single (acute) dose or implanted mini-pump (chronic) methadone administration in mice, using the hotplate assay. For the acute experiment, subthreshold doses of six antidepressant drugs were administered separately with a single dose of methadone. The addition of a subthreshold dose of desipramine or clomipramine to methadone produced significant augmentation of the methadone effect with each drug (p < 0.05). Fluvoxamine given at a fixed subthreshold dose induced a synergistic effect only with a low methadone dose. Escitalopram, reboxetine and venlafaxine given separately, each at a fixed subthreshold dose, induced no interaction. Possible clinical implications of these findings are that while escitalopram, reboxetine and venlafaxine do not affect methadone's antinociception in mice and are safe to be given together with methadone when indicated, fluvoxamine, clomipramine and desipramine considerably augment methadone-induced effects and should be avoided in this population due to the risk of inducing opiate overdose. For the chromic experiment, when a subthreshold dose of either escitalopram, desipramine or clomipramine was injected to mice following 2 weeks of methadone administration with the mini-pump, none of the antidepressant drugs strengthened methadone's analgesic effect. Further studies are needed before possible clinical implications can be drawn.

4-[18F]Fluoro-m-hydroxyphenethylguanidine: a radiopharmaceutical for quantifying regional cardiac sympathetic nerve density with positron emission tomography.

4-[(18)F]Fluoro-m-hydroxyphenethylguanidine ([(18)F]4F-MHPG, [(18)F]1) is a new cardiac sympathetic nerve radiotracer with kinetic properties favorable for quantifying regional nerve density with PET and tracer kinetic analysis. An automated synthesis of [(18)F]1 was developed in which the intermediate 4-[(18)F]fluoro-m-tyramine ([(18)F]16) was prepared using a diaryliodonium salt precursor for nucleophilic aromatic [(18)F]fluorination. In PET imaging studies in rhesus macaque monkeys, [(18)F]1 demonstrated high quality cardiac images with low uptake in lungs and the liver. Compartmental modeling of [(18)F]1 kinetics provided net uptake rate constants Ki (mL/min/g wet), and Patlak graphical analysis of [(18)F]1 kinetics provided Patlak slopes Kp (mL/min/g). In pharmacological blocking studies with the norepinephrine transporter inhibitor desipramine (DMI), each of these quantitative measures declined in a dose-dependent manner with increasing DMI doses. These initial results strongly suggest that [(18)F]1 can provide quantitative measures of regional cardiac sympathetic nerve density in human hearts using PET.

Effects of chronic antidepressant treatments in a putative genetic model of vulnerability (Roman low-avoidance rats) and resistance (Roman high-avoidance rats) to stress-induced depression

The Roman low- (RLA) and high-avoidance (RHA) rats were selectively bred for, respectively, poor versus rapid acquisition of active avoidance in a shuttle box and, under aversive conditions, display reactive (RLA) versus proactive (RHA) coping behaviors. In the forced swim test (FST), RLA rats exhibit a depression-like behavior characterized by greater immobility and fewer climbing counts when compared with their RHA counterparts. Furthermore, subacute treatments with clinically effective antidepressant drugs decrease immobility and increase climbing or swimming in RLA rats but do not modify the performance of RHA rats. Because chronic treatment with antidepressants is usually required to produce clinical effects, the present study was designed to compare the behaviors of RLA and RHA rats in the FST after subacute (1day) and chronic (15days) administration of desipramine, fluoxetine, and chlorimipramine. In RLA rats, subacute treatments with low doses of desipramine, fluoxetine, and chlorimipramine (2.5-5mg/kg) were ineffective whereas chronic treatments with the same doses of all three antidepressants decreased immobility and also increased climbing (desipramine) or swimming (fluoxetine). By contrast, neither subacute nor chronic treatments with these antidepressants induced significant changes in the behavior of RHA rats in the FST. RLA and RHA rats represent two divergent phenotypes, respectively susceptible and resistant to develop depression-like behavior under aversive environmental conditions that may be used to identify genetically determined neural substrates and mechanisms underlying vulnerability and resistance to stress-induced depression.

Quantification of Cardiac Sympathetic Nerve Density with N-11C-Guanyl-meta-Octopamine and Tracer Kinetic Analysis

Most cardiac sympathetic nerve radiotracers are substrates of the norepinephrine transporter (NET). Existing tracers such as (123)I-metaiodobenzylguanidine ((123)I-MIBG) and (11)C-(-)-meta-hydroxyephedrine ((11)C-HED) are flow-limited tracers because of their rapid NET transport rates. This prevents successful application of kinetic analysis techniques and causes semiquantitative measures of tracer retention to be insensitive to mild-to-moderate nerve losses. N-(11)C-guanyl-(-)-meta-octopamine ((11)C-GMO) has a much slower NET transport rate and is trapped in storage vesicles. The goal of this study was to determine whether analyses of (11)C-GMO kinetics could provide robust and sensitive measures of regional cardiac sympathetic nerve densities. PET studies were performed in a rhesus macaque monkey under control conditions or after intravenous infusion of the NET inhibitor desipramine (DMI). Five desipramine dose levels were used to establish a range of available cardiac NET levels. Compartmental modeling of (11)C-GMO kinetics yielded estimates of the rate constants K1 (mL/min/g), k2 (min(-1)), and k3 (min(-1)). These values were used to calculate a net uptake rate constant K(i) (mL/min/g) = (K1k3)/(k2 + k3). In addition, Patlak graphical analyses of (11)C-GMO kinetics yielded Patlak slopes K(p) (mL/min/g), which represent alternative measurements of the net uptake rate constant K(i). (11)C-GMO kinetics in isolated rat hearts were also measured for comparison with other tracers. In isolated rat hearts, the neuronal uptake rate of (11)C-GMO was 8 times slower than (11)C-HED and 12 times slower than (11)C-MIBG. (11)C-GMO also had a long neuronal retention time (>200 h). Compartmental modeling of (11)C-GMO kinetics in the monkey heart proved stable under all conditions. Calculated net uptake rate constants K(i) tracked desipramine-induced reductions of available NET in a dose-dependent manner, with a half maximal inhibitory concentration (IC50) of 0.087 ± 0.012 mg of desipramine per kilogram. Patlak analysis provided highly linear Patlak plots, and the Patlak slopes Kp also declined in a dose-dependent manner (IC50 = 0.068 ± 0.010 mg of desipramine per kilogram). Compartmental modeling and Patlak analysis of (11)C-GMO kinetics each provided quantitative parameters that accurately tracked changes in cardiac NET levels. These results strongly suggest that PET studies with (11)C-GMO can provide robust and sensitive quantitative measures of regional cardiac sympathetic nerve densities in human hearts.

The effects of isolated and enriched housing conditions on baseline and drug-induced behavioural responses in the male rat

Environmental enrichment (EE) involves enhancing an animal's environment, with the goal of improving animal welfare. Though a well-established discipline, the consequences of EE on behavioural pharmacological tests have not been extensively examined. The purpose of this study was to examine the consequences of EE (or isolation) housing on a range of behavioural pharmacological tests in the rat. Male Sprague-Dawley rats were randomly assigned to the 3 housing conditions; IC (isolation) and SC (standard group-housed, 4/cage) were housed in standard cages (42cm×25.5cm×20cm), while the EE group was housed in groups of 4 in larger cages (54cm×38cm×19cm) enriched with a variety of wooden, cardboard and plastic toys/objects. After 4 weeks, housing effects were examined in the following pharmacological tests: diazepam (DZP) effects on anxiolytic behaviour in the elevated plus maze (EPM); desipramine (DMI) effects on immobility time in the forced swim test (FST) and amphetamine (AMP) effects on homecage activity. Dose–response assessments demonstrated that rats housed in EE showed reduced sensitivity to the behavioural effects of DZP and DMI but increased sensitivity to the locomotor-enhancing effects of AMP compared to SC and IC; while IC animals exhibited the clearest dose–response effects to increasing doses of DMI. It may be concluded that environmental manipulation can vary along a continuum and its intensity may be crucial to observable effects. Nonetheless, environmental factors can influence sensitivity to psychotropic drugs and should be considered when implementing EE protocols in such evaluations.

Increased antidepressant-like effect of desipramine combined with central stimulants (caffeine and amphetamine) in mice

Abstract Desipramine is a widely used antidepressive agent that inhibits the reuptake of noradrenaline and serotonin, and central stimulants such as caffeine and amphetamine help to release noradrenaline and serotonin. This work aimed to evaluate whether the combination of these agents could produce a stronger antidepressant-like effect than either of the drugs alone. To this end, male mice were treated with different doses of desipramine, caffeine, amphetamine, desipramine-caffeine and desipramine-amphetamine. The results showed that all drugs produced decreased immobility time in the forced swimming model. The combined treatment of desipramine (0.31, 1.0 or 3.1 mg/kg i.p.) with caffeine or amphetamine (0.31 or 1 mg/kg i.p.) reduced immobility time greater than either of those drugs alone. The combined treatment of desipramine (0.31, 1 and 3.1 mg/kg i.p.) with amphetamine or caffeine (0.1 and 1 mg/kg i.p.) did not increase the motor activity significantly compared to the control. These results also suggested that drugs which promote the release of noradrenaline and serotonin could increase antidepressant-like effect of desipramine.

Effects of desipramine on the antioxidant status in rat tissues at carrageenan‐induced paw inflammation

The pathogenesis of many diseases and different pathological conditions, including inflammation, is associated with excess production of reactive oxygen species (ROS). The present study aimed to investigate the effects of the antidepressant desipramine (DES) on carrageenan (CG)-induced inflammation, as well as on the endogenous levels of cell enzyme and non-enzyme antioxidants in rat liver and spleen, 4 and 24 h after CG injection. The intra-plantar CG injection into the right hind paw resulted in a time-dependent increase in the paw volume; the maximum of CG-induced edema peak was in 2-4 h. A single DES dose of 20 mg · kg(-1) , administered 30 min before CG, had no effect on paw edema, whereas the higher drug dose used (50 mg · kg(-1) ) suppressed the edematous response to CG. The latter drug dose protected CG-induced decrease of glutathione (non-enzyme antioxidant) in the liver; it did not affect CG-unchanged activities of superoxide dismutase, glutathione peroxidase (enzyme antioxidants) and glucose-6-phosphate dehydrogenase (enzyme, important for the activity of glutathione-conjugated antioxidant enzymes) in both liver and spleen. The drug showed an efficient antioxidant capacity in ROS-generating chemical systems; it was higher than that of fluoxetine (another type of antidepressant). The present results suggest that the good antioxidant activity of DES might contribute to its beneficial effects in liver injuries.

Augmentation of the behavioural effects of desipramine by repeated immobilization stress

The present report provides evidence that repeated immobilization stress (RIS) induced a noradrenergic-dependent depressive-like behaviour and an augmented behavioural response to desipramine (DMI), a noradrenaline reuptake inhibitor (NRI), in the forced swimming test (FST). The present results show that RIS decreased the baseline of climbing behaviour in the FST. Whereas subchronic administration of DMI (10 mg/kg, three times in a 24 h period) induced a significantly higher increase in climbing behaviour on repeatedly stressed rats compared to controls. The results also show that the concomitant administration of the low dose of DMI (3 mg/Kg) during the RIS fully prevented the decrease of climbing behaviour induced by RIS, without exerting behavioural effects in control rats, further supporting an augmented response to the DMI antidepressant effects in the repeatedly stressed rats. In conclusion, our data indicate that RIS not only changes the behavioural responses in the FST but also increases the antidepressant effects of DMI.

Increase of the antidepressant action of desipramine caused by caffeine and amphetamine

Desipramine is an antidepressive agent widely used which acts through the inhibition of the recapture of noradrenaline and serotonin, on the other hand, central stimulants such as caffeine and amphetamine help to release noradrenaline and serotonin, for this reason the combination of these agents with desipramine could increase the antidepressant response to desipramine, The aim of this work was to evaluate the antidepressive response of desipramine when its combine with caffeine and amphetamine in the forced swimming model. Male mice were used they received different doses of desipramine, caffeine, amphetamine, desipramine‐caffeine and desipramine‐amphetamine. The results showed that all agents produce immobility time decreased. When performing dose combinations without antidepressant effect of caffeine and amphetamine with desipramine was observed an increase in antidepressant response to desipramine, presenting only the combination of desipramine‐amphetamine on motor activity changes. These results suggest that drugs that promote the release of noradrenaline and serotonin could be used in combination with antidepressants to increase its effect, especially caffeine.

Simultaneous ST-segment elevation in inferior and precordial leads following ingestion of a lethal dose of desipramine: a novel Brugada-like EKG pattern

The typical Brugada electrocardiographic (EKG) pattern includes ST-segment elevation in the right precordial leads (V1-V3) associated with right bundle branch block (rSR') like morphology. Recently, a Brugada-like EKG pattern with ST-segment elevation in inferior leads called the "Brugada variant" has been reported. We report a case of simultaneous typical and variant Brugada EKG patterns with ST-segment elevation in the inferior as well as the precordial leads following ingestion of a lethal dose of desipramine.

Identification of discrete sites of action of chronic treatment with desipramine in a model of neuropathic pain

Tricyclic antidepressants (TCAs) are an important analgesic treatment for neuropathic pain, though the neural substrates mediating these effects are poorly understood. We have used an integrative approach combining behavioural pharmacology with functional magnetic resonance imaging (fMRI) to investigate the effects of chronic treatment with the TCA desipramine, on touch-evoked pain (mechanical allodynia) and brain regional activity in the selective spinal nerve ligation (SNL) model of neuropathic pain. SNL and sham-operated rats received once daily i.p. administration of 10 mg/kg DMI, or saline, for 14 days. Withdrawal responses to the application of a normally non-noxious (10 g) stimulus were recorded in SNL and sham-operated rats over this period. On the final day of the study, SNL and sham-operated rats received a final challenge dose of DMI (10 mg/kg i.p.) during fMRI scanning. Chronic administration of desipramine (DMI) significantly attenuated mechancial allodynia in SNL rats. DMI challenge in chronic DMI-treated neuropathic rats produced significantly greater activation of the deep mesencephalic nucleus, primary somatosensory cortex, insular cortex, medial globus pallidus, inferior colliculus, perirhinal cortex and cerebellum compared to sham-operated rats and saline controls. By contrast, the spatial pattern of brain regional activation by chronic DMI treatment in sham controls encompassed a number of other areas including those associated with learning and memory processes. These novel findings identify key brain regions implicated in the analgesic and mood altering effects associated with chronic treatment with DMI.

Alpha-2 adrenergic-induced changes in rectal temperature in adult and 13-day old rats following acute and repeated desipramine administration

BackgroundThe effects of acute and repeated treatment with desipramine on the functional response of α2-adrenoceptors were tested in adult and 13-day old rats. The functional response measured was hypothermia that was induced by brimonidine, an α2-adrenoceptor agonist. The change in the extent of the brimonidine-induced hypothermia following pretreatment with either single or 4 twice-daily injections of desipramine was compared in 13-day old and adult (65–75 days old) male rats.ResultsBrimonidine, alone, lowered rectal temperature to a greater extent in juvenile than in adult rats, and this response was dose-dependently blocked by the selective α2-adrenoceptor antagonist, RX821002, in both groups of rats. Single desipramine administration lowered rectal temperature in the absence of brimonidine in adult but not in juvenile rats. The adult rats developed tolerance to this hypothermic effect after 4 days of desipramine treatment (10 mg/kg twice daily). Repeated desipramine treatment of adult rats also resulted in an enhancement in the brimonidine-induced hypothermic effect 24 h after the last dose, a time when above 90% of desipramine and its metabolite, desmethyldesipramine, had cleared the brain, but not at 14, 48 or 96 h after the last dose. In juvenile rats repeated injections of desipramine (3 mg/kg twice daily for 4 days) had no effect on the α2-agonist-induced hypothermia when brimonidine was given 14, 24, 63 and 96 h after the last dose of desipramine.ConclusionThe results suggest that juvenile rats response differently than adult rats to agonist stimulation of α2-adrenoceptors with and without pretreatment with the antidepressant desipramine. In the absence of desipramine pretreatment, the α2-adrenoceptor-induced hypothermic effect in juvenile rats is greater than in adult rats. Acute injections of desipramine, in the absence of agonist produced a hypothermic effect in adult but not juvenile rats. In addition, the increased α2-agonist-induced hypothermic effect following repeated injections of desipramine that is seen in adult rats is not seen in juvenile rats.

An Assessment of Drug-Drug Interactions: The Effect of Desvenlafaxine and Duloxetine on the Pharmacokinetics of the CYP2D6 Probe Desipramine in Healthy Subjects

A number of antidepressants inhibit the activity of the cytochrome P450 2D6 enzyme system, which can lead to drug-drug interactions. Based on its metabolic profile, desvenlafaxine, administered as desvenlafaxine succinate, a new serotonin-norepinephrine reuptake inhibitor, is not expected to have an impact on activity of CYP2D6. This single-center, randomized, open-label, four-period, crossover study was undertaken to evaluate the effect of multiple doses of desvenlafaxine (100 mg/day, twice the recommended therapeutic dose for major depressive disorder in the United States) and duloxetine (30 mg b.i.d.) on the pharmacokinetics (PK) of a single dose of desipramine (50 mg). A single dose of desipramine was given first to assess its PK. Desvenlafaxine or duloxetine was then administered, in a crossover design, so that steady-state levels were achieved; a single dose of desipramine was then coadministered. The geometric least-square mean ratios (coadministration versus desipramine alone) for area under the plasma concentration versus time curve (AUC) and peak plasma concentrations (C(max)) of desipramine and 2-hydroxydesipramine were compared using analysis of variance. Relative to desipramine alone, increases in AUC and C(max) of desipramine associated with duloxetine administration (122 and 63%, respectively) were significantly greater than those associated with desvenlafaxine (22 and 19%, respectively; P < 0.001). Duloxetine coadministered with desipramine was also associated with a decrease in 2-hydroxydesipramine C(max) that was significant compared with the small increase seen with desvenlafaxine and desipramine (-24 versus 9%; P < 0.001); the difference between changes in 2-hydroxydesipramine AUC did not reach statistical significance (P = 0.054). Overall, desvenlafaxine had a minimal impact on the PK of desipramine compared with duloxetine, suggesting a lower risk for CYP2D6-mediated drug interactions.

Desipramine or glutamate antagonists synergized the antidepressant-like actions of intra-nucleus accumbens infusions of minocycline in male Wistar rats

Minocycline produces antidepressant-like actions in male rats tested in the forced swimming test (FST) and synergizes with several glutamate receptor antagonists. However, the limbic regions implicated in the antidepressant-like actions of minocycline are unknown. The objective of the present study was to test the potential antidepressant activity of nucleus accumbens infusions of minocycline alone or combined with antidepressant drugs or with several glutamate receptor antagonists, using the time-sampling method in the FST. The results show that intra-NAcc infusions of minocycline reduced immobility (1.0 µg, P < 0.05; 1.5 µg, P < 0.05) by increasing climbing (1.0 µg, P < 0.05; 1.5 µg, P < 0.05) in the FST. Likewise, systemic injections of desipramine ( P < 0.05), fluoxetine ( P < 0.05) or several glutamate receptor antagonists: EMQMCM ( P < 0.05), MTEP ( P < 0.05) or dizocilpine ( P < 0.05) combined with intra-nucleus accumbens infusions of vehicle produced antidepressant-like actions. The subthreshold dose of intra-nucleus accumbens infusions of minocycline combined with systemic injections of subthreshold doses of desipramine ( P < 0.05) or EMQMCM ( P < 0.05) or MTEP ( P < 0.05) or dizocilpine ( P < 0.05) produced antidepressant-like actions. It is concluded that intra-NAcc infusions of minocycline alone or combined with systemic injections of desipramine or with systemic injections of several glutamate receptor antagonists produced antidepressant-like actions in the FST.

Reinforcement magnitude modulates the rate-dependent effects of fluvoxamine and desipramine on fixed-interval responding in the pigeon

Some doses of fluvoxamine can decrease ethanol-maintained behavior more than food-maintained behavior. This might be explained by differences in reinforcement magnitude. In a previous study, the effects of fluvoxamine on fixed-ratio responding did not depend upon reinforcement magnitude. Response rates, however, differed with reinforcement magnitude. These differences in response rates might explain the failure to observe differences in the potency of fluvoxamine with changes in reinforcement magnitude. In this study, we examined whether the effects of fluvoxamine and desipramine depended on the reinforcement magnitude and response rate, by administering these drugs to pigeons responding under a multiple fixed-interval schedule, in which responding in three components was maintained by differing durations of food presentation (2, 4, and 8 s). The effects of fluvoxamine and desipramine depended jointly on control rate, reinforcement magnitude, and dose. Low fluvoxamine doses had rate-dependent effects in all three components, increasing lower rates more than higher rates: as dose increased, these rate-dependent effects became greater in the components maintained by the 2-s or 4-s food presentation; whereas, in the component maintained by the 8-s presentations, they declined. Low desipramine doses had rate-dependent effects only in the component maintained by the 2-s presentations, whereas higher doses had rate-dependent effects in components maintained by 2-s or 4-s presentations. Still higher doses had rate-dependent effects in all the three components. Although the effects of fluvoxamine and desipramine might not depend on reinforcement magnitude when studied under fixed-ratio schedules, reinforcement magnitude can modulate their effects when they are studied over a wider range of control response rates.

Antidepressant-like actions of minocycline combined with several glutamate antagonists

This study tested the potential antidepressant activity of minocycline alone or combined with two traditional antidepressant drugs or several glutamate receptor antagonists, using the time sampling method in the forced swimming test. Results showed that: desipramine (10.0 mg/kg, P < 0.05; 15.0 mg/kg, P < 0.05), minocycline (60.0 mg/kg, P < 0.05; 80.0 mg/kg, P < 0.05) and EMQMCM (1.5 mg/kg, P < 0.05; 2.0 mg/kg, P < 0.05), reduced immobility by increasing climbing. Fluoxetine (20.0 mg/kg, P < 0.05; 25.0 mg/kg, P < 0.05) reduced immobility by increasing swimming. MTEP (5.0 mg/kg, P < 0.05; 10.0 mg/kg, P < 0.05) and dizolcipine (1.0 mg/kg, P < 0.05; 1.5 mg/kg, P < 0.05) reduced immobility by increasing swimming and climbing. Combination experiments showed that a subthreshold dose of minocycline (50.0 mg/kg) synergized the antidepressant-like actions of subthreshold doses of: desipramine (5.0 mg/kg; P < 0.05), EMQMCM (0.6 mg/kg; P < 0.05), MTEP (2.5 mg/kg; P < 0.05) and dizolcipine (0.5 mg/kg; P < 0.05). In conclusion, minocycline produced antidepressant-like actions in the FST and subthreshold dose of minocycline combined with subthreshold dose of desipramine and several glutamate receptor antagonists and produced antidepressant-like actions.

Estrogens participate in the antidepressant-like effect of desipramine and fluoxetine in male rats

In male rats, the antidepressant-like effect of fluoxetine (FLX) and desipramine (DMI) in the forced swimming test (FST) is reduced by orchidectomy and partially restored by testosterone (T). It is unknown if this modulation of T is produced by its estrogenic metabolites. The objectives of this study were to evaluate if the aromatase inhibitor, formestane, interferes with the antidepressant-like effect of DMI and FLX in intact male rats, and to analyze if 17β-estradiol (E 2) modifies the FST and interacts with the antidepressants in orchidectomized (Orx) males. Intact males received DMI (1.25–5.0 mg/kg) and FLX (2.5–10 mg/kg) alone or in combination with formestane (17.5 mg/kg). Orx rats received E 2 (5, 10, 20 and 40 μg/rat) or the combination of E 2 [at sub-threshold (5 μg/rat) and optimal (10 μg/rat) doses] plus sub-effective doses of DMI (2.5 mg/kg) or FLX (10 mg/kg). Serum testosterone and estradiol levels were measured in intact-control and -formestane treated animals as well as in castrated males replaced with various doses of E 2. Formestane in intact males lacked of an action in the FST, but cancelled the antidepressant-like effect of DMI and FLX. E 2 at the supra-physiological doses of 10 and 20 μg/rat produced antidepressant-like effects. E 2 at 5 μg/rat (that re-established the levels of this hormone to physiological levels) and at 10 μg/rat restored the antidepressant-like action of DMI and FLX in Orx rats. It was concluded that estrogens participate in the antidepressant-like effect of DMI and FLX in the FST.