Systematic review and meta-analysis of the effects of treatment modalities for vestibulodynia in women.

Objective: To quantify the effects of available treatments of vestibulodynia. Methods: Systematic review of randomised controlled trials (RCTs) in six search engines until December 2018, comparing any intervention vs. placebo or sham in women with vestibulodynia. Primary outcome was dyspareunia assessed with visual analogue (VAS) or numeric rating (NRS) scales. Secondary outcomes were daily vestibular symptoms (DVS), McGill Pain Questionnaire (MPQ) and Index of Sexual Satisfaction (ISS). Effects were described as mean differences (MDs) with their 95% confidence intervals (CIs). Traditional and frequentist network meta-analyses (NMA) were performed using random effect models. Results: Four RCTs (n = 275) were included evaluating vaginal cream of conjugated oestrogens, oral desipramine with or without topical lidocaine, topical lidocaine, laser therapy and transcranial direct current. In traditional MA, interventions did not reduce dyspareunia (MD = 0.08; 95%CI = -0.49 to 0.64), DVS (MD = -0.04; 95%CI = -0.31 to 0.24; 4 interventions), or MPQ (MD = -0.17; 95%CI = -2.16 to 1.81; 4 interventions). ISS was significantly improved (MD = -5.14; 95%CI = -9.52 to -0.75). In NMA, oral desipramine with or without lidocaine significantly improved ISS vs. other treatments. Conclusions: Several existing interventions were not associated with improvements in vestibulodynia. There only was improvement of sexual function with oral desipramine with or without lidocaine.

Failure to detect the action of antidepressants in the forced swim test in Swiss mice.

OBJECTIVE: The aims of this study were to replicate previously published experiments and to modify the protocol to detect the effects of chronic antidepressant treatment in mice. METHODS: Male Swiss mice (n=6-8/group) housed in reversed light/dark cycle were randomly assigned into receive vehicle (10% sucrose), sub-effective doses (1 and 3 mg/kg) or effective doses (10 and 30 mg/kg) of bupropion, desipramine, and fluoxetine and a candidate antidepressant, sodium butyrate (1-30 mg/kg) per gavage (p.o.) 1 h before the forced swim test (FST). Treatments continued daily for 7 and 14 days during retests 1 and 2, respectively. In an additional experiment, mice received fluoxetine (20 mg/kg) or vehicle (10% sucrose or 0.9% saline) p.o. or i.p. before the FST. Mice housed in reversed or standard light/dark cycles received fluoxetine (20 mg/kg) prior FST. Video recordings of behavioural testing were used for blind assessment of the outcomes. RESULTS: According to the expected, doses of antidepressants considered sub-effective failed to affect the immobility time of mice in the FST. Surprisingly, acute and chronic treatment with the high doses of bupropion, desipramine, and fluoxetine or sodium butyrate also failed to reduce the immobility time of mice in the FST. Fluoxetine 20 mg/kg was also ineffective in the FST when injected i.p. or in mice housed in normal light/dark cycle. CONCLUSION: Data suggest the lack of efficacy of orally administered bupropion, desipramine, fluoxetine in the FST in Swiss mice. High variability, due to high and low immobility mice, may explain the limited effects of the treatments.

Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis.

BACKGROUND: Major depressive disorder is one of the most common mental disorders in children and adolescents. However, whether to use pharmacological interventions in this population and which drug should be preferred are still matters of controversy. Consequently, we aimed to compare and rank antidepressants and placebo for major depressive disorder in young people. METHODS: We did a network meta-analysis to identify both direct and indirect evidence from relevant trials. We searched PubMed, the Cochrane Library, Web of Science, Embase, CINAHL, PsycINFO, LiLACS, regulatory agencies' websites, and international registers for published and unpublished, double-blind randomised controlled trials up to May 31, 2015, for the acute treatment of major depressive disorder in children and adolescents. We included trials of amitriptyline, citalopram, clomipramine, desipramine, duloxetine, escitalopram, fluoxetine, imipramine, mirtazapine, nefazodone, nortriptyline, paroxetine, sertraline, and venlafaxine. Trials recruiting participants with treatment-resistant depression, treatment duration of less than 4 weeks, or an overall sample size of less than ten patients were excluded. We extracted the relevant information from the published reports with a predefined data extraction sheet, and assessed the risk of bias with the Cochrane risk of bias tool. The primary outcomes were efficacy (change in depressive symptoms) and tolerability (discontinuations due to adverse events). We did pair-wise meta-analyses using the random-effects model and then did a random-effects network meta-analysis within a Bayesian framework. We assessed the quality of evidence contributing to each network estimate using the GRADE framework. This study is registered with PROSPERO, number CRD42015016023. FINDINGS: We deemed 34 trials eligible, including 5260 participants and 14 antidepressant treatments. The quality of evidence was rated as very low in most comparisons. For efficacy, only fluoxetine was statistically significantly more effective than placebo (standardised mean difference -0·51, 95% credible interval [CrI] -0·99 to -0·03). In terms of tolerability, fluoxetine was also better than duloxetine (odds ratio [OR] 0·31, 95% CrI 0·13 to 0·95) and imipramine (0·23, 0·04 to 0·78). Patients given imipramine, venlafaxine, and duloxetine had more discontinuations due to adverse events than did those given placebo (5·49, 1·96 to 20·86; 3·19, 1·01 to 18·70; and 2·80, 1·20 to 9·42, respectively). In terms of heterogeneity, the global I(2) values were 33·21% for efficacy and 0% for tolerability. INTERPRETATION: When considering the risk-benefit profile of antidepressants in the acute treatment of major depressive disorder, these drugs do not seem to offer a clear advantage for children and adolescents. Fluoxetine is probably the best option to consider when a pharmacological treatment is indicated. FUNDING: National Basic Research Program of China (973 Program).

Stimulation of adrenergic activity by desipramine enhances hematopoietic stem and progenitor cell mobilization along with G-CSF in multiple myeloma: A pilot study.

Hematopoietic stem cell (HSC) release is positively regulated by the sympathetic nervous system through the ß3 adrenergic receptor. Preclinical studies have demonstrated that the combination of desipramine and G-CSF resulted in improved HSC mobilization. Here, we present the results of an open-label single-arm pilot study in patients with multiple myeloma undergoing autologous stem cell transplantation (ASCT) to assess the safety and efficacy of desipramine combined with G-SCF to induce HSC mobilization. The primary endpoint was safety of the combination including engraftment kinetics. The secondary endpoint was the proportion of patients who collected ≥5 × 106 CD34+ cells/kg. Outcomes were compared with historical matched controls during the same time period with multiple myeloma mobilized with G-CSF. All study patients received desipramine 100 mg daily for 7 days, starting 4 days prior to G-CSF administration (D-3) and continued taking it along with G-CSF for a total of 7 days. Six of ten patients enrolled completed the protocol with minimal side effects. All of them achieved the target collection of 5 × 106 CD34 cells/kg in a median of 1.5 apheresis session with two patients needing additional plerixafor (16%), while 11 out of 13 patients (85%) achieved the target of 5 × 106 CD34 cells/kg in the historical control group in a median of 2 apheresis procedures and seven patients needed plerixafor (54%). The combination of desipramine and G-CSF is safe and signals improved mobilization over G-CSF alone, providing a possible alternative means of mobilization that needs further investigation.

Desipramine Increases Genioglossus Activity and Reduces Upper Airway Collapsibility during Non-REM Sleep in Healthy Subjects.

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 H2O [-15.2 to -5.8] vs. -8.1 cm H2O [-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).

Desipramine administered chronically inhibits lipopolysaccharide-stimulated production of IL-1ß in the brain and plasma of rats.

Nowadays, it is assumed that therapeutic efficacy of antidepressants depends, at least partly, on their anti-inflammatory properties. The present study investigated for the first time the effect of 21-day oral administration of desipramine on the lipopolysaccharide (LPS)-stimulated IL-1ß concentration in the olfactory bulb, hypothalamus, frontal cortex, hippocampus and plasma of rats, and on the LPS-induced IL-1ß mRNA level in the olfactory bulb. Desipramine (15mg/kg/day) reduced significantly the LPS (250 µg/kg i.p.)-induced IL-1ß concentration in the olfactory bulb, hypothalamus and in plasma, and diminished the LPS effect on IL-1ß mRNA in the olfactory bulb. Plasma concentration of desipramine was comparable to its therapeutic range. By using the α1/α2-adrenoceptor antagonist prazosin and the unspecific ß-adrenoceptor antagonist propranolol given prior to LPS, we found that the effect of desipramine on LPS-induced IL-1ß production was partially mediated by both adrenoceptors in the olfactory bulb and plasma, and that ß-adrenoceptors contributed also to its effect on the stimulated IL-1ß concentration in the hypothalamus. The effect of LPS on the cerebral IL-1ß levels was, in part, mediated by ß-adrenoceptors and, in a region-specific manner, by α1/α2-adrenoceptors. The findings provide evidence for central and peripheral anti-inflammatory activity of desipramine and confirm the impact of the noradrenergic system on IL-1ß production induced by an immunostimulatory challenge.

The effects of prolonged administration of norepinephrine reuptake inhibitors on long-term potentiation in dentate gyrus, and on tests of spatial and object recognition memory in rats.

Phasic norepinephrine (NE) release events are involved in arousal, novelty detection and in plasticity processes underlying learning and memory in mammalian systems. Although the effects of phasic NE release events on plasticity and memory are prevalently documented, it is less understood what effects chronic NE reuptake inhibition and sustained increases in noradrenergic tone, might have on plasticity and cognitive processes in rodent models of learning and memory. This study investigates the effects of chronic NE reuptake inhibition on hippocampal plasticity and memory in rats. Rats were administered NE reuptake inhibitors (NRIs) desipramine (DMI; 0, 3, or 7.5mg/kg/day) or nortriptyline (NTP; 0, 10 or 20mg/kg/day) in drinking water. Long-term potentiation (LTP; 200 Hz) of the perforant path-dentate gyrus evoked potential was examined in urethane anesthetized rats after 30-32 days of DMI treatment. Short- (4-h) and long-term (24-h) spatial memory was tested in separate rats administered 0 or 7.5mg/kg/day DMI (25-30 days) using a two-trial spatial memory test. Additionally, the effects of chronically administered DMI and NTP were tested in rats using a two-trial, Object Recognition Test (ORT) at 2- and 24-h after 45 and 60 days of drug administration. Rats administered 3 or 7.5mg/kg/day DMI had attenuated LTP of the EPSP slope but not the population spike at the perforant path-dentate gyrus synapse. Short- and long-term memory for objects is differentially disrupted in rats after prolonged administration of DMI and NTP. Rats that were administered 7.5mg/kg/day DMI showed decreased memory for a two-trial spatial task when tested at 4-h. In the novel ORT, rats receiving 0 or 7.5mg/kg/day DMI showed a preference for the arm containing a Novel object when tested at both 2- and 24-h demonstrating both short- and long-term memory retention of the Familiar object. Rats that received either dose of NTP or 3mg/kg/day DMI showed impaired memory at 2-h, however this impairment was largely reversed at 24-h. Animals in the high-dose NTP (20mg/kg/day) group were impaired at both short- and long-term intervals. Activity levels, used as an index of location memory during the ORT, demonstrated that rats receiving DMI were again impaired at retaining memory for location. DMI dose-dependently disrupts LTP in the dentate gyrus of anesthetized rats and also disrupts memory for tests of spatial memory when administered for long periods.

Tricyclic antidepressants for the treatment of tenesmus associated with rectal prolapse.

AIM: Tenesmus in rectal prolapse leads to a vicious circle of straining with deterioration of prolapse. The primary phenomenon triggering this may be rectal hypersensitivity. We aimed to assess whether treatment with tricyclic antidepressants (TCAs) may break the vicious circle and improve tenesmus. METHOD: A retrospective review was carried out of patients with rectal prolapse and severe tenesmus who were poor surgical candidates or had refused surgery. They were treated at our tertiary centre with low dose tricyclic antidepressants. RESULTS: Twenty-three (18 female) patients were included, with mean age 75.3 (±SD 14.6) years. The mean duration of symptoms was 10.8 (± 8.6) months. Full-thickness rectal prolapse was diagnosed in 16 (70%) patients while seven (30%) had mucosal or incomplete prolapse. Ten (43%), eight (35%) and five (22%) patients were treated with nortriptyline (25 mg daily), amitriptyline (10 mg daily) and desipramine (25 mg daily). After a mean follow-up of 9.05 (± 8.2) months, 14 (61%) patients reported significant improvement in symptoms, five (22%) had a partial response, three (13%) were lost to follow-up and one (4%) failed to respond. The response rates for nortriptyline, desipramine and amitriptyline were 90%, 100% and 62.5%. CONCLUSION: To the best of our knowledge this is the first report to address the symptomatic, conservative treatment of tenesmus in patients with rectal prolapse. TCAs may be an acceptable option for poor surgical candidates or patients refusing surgery.

Desipramine ameliorates Cr(VI)-induced hepatocellular apoptosis via the inhibition of ceramide channel formation and mitochondrial PTP opening.

BACKGROUND: Hexavalent chromium (Cr(VI)) is a common environmental pollutant. Cr(VI) exposure can lead to severe damage in the liver, but the preventive measures to diminish Cr(VI)-induced hepatotoxicity need further study. Acid sphingomyelinase (ASMase) is responsible for the production of ceramide via the hydrolysis of sphingomyelin. The present study was designed to investigate effects of desipramine (DES), as an ASMase inhibitor, on Cr(VI)-induced hepatotoxicity. METHODS: L-02 hepatocytes were incubated with different concentrations of Cr(VI) for 24h, and ASMase activities and ceramide levels were measured. Moreover, the study investigated the role of DES played in ASMase activities and ceramide levels. Finally, effects of DES on mRNA and protein expressions of the components of mitochondrial permeability transition pore (PTP) and PTP opening were detected. RESULTS: The ASMase activities and ceramide contents increased in L-02 hepatocytes treated with Cr(VI). The results demonstrated that apoptosis rates, ASMase activities and ceramide content decreased in groups treated with the combination of DES and Cr(VI) compared to Cr(VI) groups. Furthermore, DES inhibited Cr(VI)-induced mitochondrial PTP opening by intervening the mRNA and protein expressions of the components of mitochondrial PTP. CONCLUSIONS: DES may exert protective effects on Cr(VI)-induced hepatocellular apoptosis probably by inhibiting ceramide channel formation and mitochondrial PTP opening.

The effect of mirabegron, a potent and selective ß3-adrenoceptor agonist, on the pharmacokinetics of CYP2D6 substrates desipramine and metoprolol.

Mirabegron is a potent and selective ß3-adrenoceptor agonist developed for the treatment of overactive bladder. In vitro studies demonstrated that mirabegron partly acts as a (quasi-) irreversible, metabolism-dependent inhibitor of CYP2D6. The effect of steady-state mirabegron on single doses of the sensitive CYP2D6 substrates metoprolol (100 mg) and desipramine (50 mg) was assessed in two open-label, one-sequence crossover studies in healthy subjects (CYP2D6 extensive metabolizers). Mirabegron 160 mg/day increased metoprolol maximum plasma concentration (C max) 1.90-fold (90 % confidence interval [CI] 1.54; 2.33) and total exposure (AUC0-∞) 3.29-fold (90 % CI 2.70; 4.00) in 12 males (study 1). Mean metoprolol half-life increased from 2.96 to 4.11 h. α-Hydroxymetoprolol C max and AUC to last measurable concentration decreased 2.6-fold and 2.2-fold, respectively. In study 2, mirabegron 100 mg/day increased desipramine C max 1.79-fold (90 % CI 1.69; 1.90) and AUC0-∞ 3.41-fold (90 % CI 3.07; 3.80) in 14 males and 14 females. Mean desipramine half-life increased from 19.5 to 35.8 h. C max of 2-hydroxydesipramine decreased ~twofold, while AUC increased ~1.3-fold. Desipramine was administered again 2 weeks after the last mirabegron dose. Desipramine C max and AUC0-∞ were still ~1.13-fold increased; the 90 % CIs fell within the 0.80-1.25 interval. All treatments were well tolerated. In conclusion, mirabegron is a moderate CYP2D6 inhibitor (ratio and 90 % CI <5.0).

Desipramine pretreatment improves sympathetic remodeling and ventricular fibrillation threshold after myocardial ischemia.

Abnormal increase in sympathetic nerve sprouting was responsible for the ventricular arrhythmogenesis after myocardial infarction. This study investigated whether the norepinephrine transporter inhibitor, desipramine, can modulate sympathetic remodeling and ventricular fibrillation threshold (VFT) after myocardial ischemia-reperfusion. Rats were administered desipramine (0.8 mg/kg, i.v.) before or after myocardial ischemia. VFT, infarct size, tyrosine hydroxylase (TH) and growth-associated protein 43 (GAP43)-positive nerve fibers were measured after one week. The VFT of preischemic treatment group was 11.0 ± 2.65 V and significantly higher than that of control ischemic group (7.2 ± 1.30 V, P < 0.05). Infarct size in the preischemic treatment group (23.3 ± 2.4%) was significantly lower than that in the control ischemic group (30.8 ± 1.3%, P < 0.05) and the delayed application group (27.1 ± 2.6%, P < 0.05). The density of TH and GAP43-positive nerve fibers in the control ischemic group was significantly higher than that in the other three groups (P < 0.05). The density of nerve fibers improved after desipramine treatment. Moreover, there was a negative correlation between the VFT and both TH and GAP43-positive nerve fiber density in the infarct border zone (P < 0.05). Desipramine treatment before acute myocardial ischemia can decrease infarct size, improve sympathetic remodeling, and increase VFT and electrical stability of ischemic hearts. Desipramine appears to cause myocardial ischemic preconditioning.

"Pre-cebo": an unrecognized issue in the interpretation of adequate relief during irritable bowel syndrome drug trials.

OBJECTIVES: In drug trials involving subjects with irritable bowel syndrome (IBS), the placebo effect seems to be very important. However, events even before starting the study may also impact patient expectations. In this study, we utilized consent language from prior studies of diarrhea predominant IBS (D-IBS) drug trials to determine whether the knowledge imparted during this process affects the response to different therapies. METHODS: Consecutive IBS subjects who met the Rome III criteria for IBS were enrolled. Patients were presented with a mock trial and randomized to 1 of 3 questionnaires with consent using similar language from consent forms of 3 drugs used in D-IBS: desipramine, alosetron, and rifaximin. Demographics, IBS symptoms using visual analog scale, and percent improvement needed for patients to report adequate relief of IBS from theoretically taking their assigned drug was asked. Data were expressed as mean ± SE. RESULTS: Subjects who were anticipating rifaximin had the highest expectation of improvement to determine adequate relief of 87.3 ± 10.9% compared with 73.4 ± 18.0% for desipramine (P<0.01) and 76.8 ± 20% for alosetron (P=0.049). There was no major difference in expectation of response from any medication to satisfy adequate relief on the basis of a belief that IBS is psychologic or organic in origin. In addition, sex and previous use of a drug did not influence the expectation of adequate relief. CONCLUSIONS: Benefits of drugs in D-IBS drug trials have the potential to be influenced by preconceived notions derived from familiarity of drug class and the consent process even before the study begins which we refer to as the "pre-cebo" effect. The higher pre-cebo effect for rifaximin may be an obstacle to successful treatment effect during drug trials compared with drugs such as desipramine. The pre-cebo effect may need to be taken into account when formulating consent forms for IBS study.

Further evidence for an immediate antidepressant action of intracerebral drug administration in a model of chronic depression.

This study was designed to replicate an earlier finding of a rapid acute therapeutic action of intracerebrally administered antidepressant in chronically depressed rodents. The effects of acute fourth ventricular (ivt.) injections were compared to those of acute peripheral (i.p.) injections of desipramine (DMI) in mice subjected to repeated open-space forced swim. In confirmation, it was found that a single ivt. injection of a low (3 nmol) but not high (30 nmol) dose immediately reversed the immobility and inactivity of the model whereas acute i.p. administration was without effect up to 30 mg/kg. The repeated forced swim stress was also found to significantly reduce the net accumulation of DMI in the brain but not liver after a single i.p. injection of a moderate dose (10 mg/kg). The results suggest that stress-induced alterations of regional drug uptake or metabolism in the CNS may contribute to the therapeutic lag for antidepressants and other compounds in disorders with high distress.

Chronic desipramine treatment alters tyrosine hydroxylase but not norepinephrine transporter immunoreactivity in norepinephrine axons in the rat prefrontal cortex.

Pharmacological blockade of norepinephrine (NE) reuptake is clinically effective in treating several mental disorders. Drugs that bind to the NE transporter (NET) alter both protein levels and activity of NET and also the catecholamine synthetic enzyme tyrosine hydroxylase (TH). We examined the rat prefrontal cortex (PFC) by electron microscopy to determine whether the density and subcellular distribution of immunolabelling for NET and co-localization of NET with TH within individual NE axons were altered by chronic treatment with the selective NE uptake inhibitor desipramine (DMI). Following DMI treatment (21 d, 15 mg/kg.d), NET-immunoreactive (ir) axons were significantly less likely to co-localize TH. This finding is consistent with reports of reduced TH levels and activity in the locus coeruleus after chronic DMI and indicates a reduction of NE synthetic capacity in the PFC. Measures of NET expression and membrane localization, including the number of NET-ir profiles per tissue area sampled, the number of gold particles per NET-ir profile area, and the proportion of gold particles associated with the plasma membrane, were similar in DMI- and vehicle-treated rats. These findings were verified using two different antibodies directed against distinct epitopes of the NET protein. The results suggest that chronic DMI treatment does not reduce NET expression within individual NE axons in vivo or induce an overall translocation of NET protein away from the plasma membrane in the PFC as measured by ultrastructural immunogold labelling. Our findings encourage consideration of possible post-translational mechanisms for regulating NET activity in antidepressant-induced modulation of NE clearance.

Effect of antidepressant drugs on the brain sphingolipid system.

BACKGROUND: Major depression is a common mood disorder and the central sphingolipid system has been identified as a possible drug target of this condition. Here we investigated the action of antidepressant drugs on sphingolipid levels in rat brain regions, plasma and in cultured mouse macrophages. METHODS: Two antidepressant drugs were tested: the serotonin reuptake inhibitor paroxetine and the noradrenaline reuptake inhibitor desipramine, either following acute or chronic treatments. Content of sphingosine and ceramide were analysed using LC-MS or HPLC-UV, respectively. This was from samples of brain, plasma and cultured mouse macrophages. Antidepressant-induced effects on mRNA expression for two key genes of the sphingolipid pathway, SMPD1 and ASAH1, were also measured by using quantitative real-time PCR. RESULTS: Chronic but not acute administration of paroxetine or desipramine reduced sphingosine levels in the prefrontal cortex and hippocampus (only paroxetine) but not in the striatum. Ceramide levels were also measured in the hippocampus following chronic paroxetine and likewise to sphingosine this treatment reduced its levels. The corresponding collected plasma samples from chronically treated animals did not show any decrease of sphingosine compared to the corresponding controls. Both drugs failed to reduce sphingosine levels from cultured mouse macrophages. The drug-induced decrease of sphingolipids coincided with reduced mRNA expression of two enzymes of the central sphingolipid pathway, i.e. acid sphingomyelinase (SMPD1) and acid ceramidase (ASAH1). CONCLUSIONS: This study supports the involvement of brain sphingolipids in the mechanism of action by antidepressant drugs and for the first time highlights their differential effects on brain versus plasma levels.

Prefrontal cortical D1 dopamine receptors modulate subcortical D2 dopamine receptor-mediated stress responsiveness.

Increased responsiveness to stress plays an important role in the manifestation of schizophrenia symptoms. Evidence indicates that the prefrontal cortex (PFC), and dopamine neurotransmission in the PFC in particular, is involved in the modulation of stress responsiveness. Decreased dopaminergic activity and loss of dopamine fibres have been reported in PFC in schizophrenia patients. Consequently, it was hypothesized that depletion of dopamine in PFC may facilitate increased stress responsiveness. Adult Sprague-Dawley rats received injections of 6-hydroxydopamine or saline bilaterally into the medial PFC (mPFC) following desipramine pretreatment to selectively deplete dopaminergic fibres. Following a 3-wk recovery period, the lesioned and control rats received injections of a D1 or D2 dopamine receptor agonist or vehicle into the mPFC and were immediately subjected to forced swimming as a stressor. Results showed that frequency of locomotion and rearing, behavioural measures indicative of increased dopaminergic activity in the nucleus accumbens (NAc), were significantly increased following stress in prefrontal cortical dopamine-depleted rats. This effect was significantly ameliorated by infusions of a D1 dopamine receptor agonist directly into the mPFC in a dose-dependent manner but not by infusion of a D2 dopamine receptor agonist. In addition, stress-induced behavioural changes in prefrontal cortical dopamine-depleted rats were significantly reduced following selective discrete infusions of a D2 dopamine receptor antagonist into the NAc shell. The results suggest that dopaminergic transmission via D1 receptors in the mPFC modulates D2 dopamine receptor-mediated stress responsiveness in the NAc, a feature that may be disrupted in schizophrenia patients.

Increased intracranial self-stimulation in rats after long-term administration of desipramine.

The effects of long- and short-term administration of the tricyclic antidepressant desipramine on intracranial self-stimulation in rats were studied with electrodes in the A10 region of the dopamine-containing cell bodies of the ventromedial tegmentum. Long-term desipramine administration resulted in a significant shift to the left in the ascending portion of the rate--current intensity function, indicating that the activity of the mesolimbic dopamine system was enhanced. These findings point to a possible dopaminergic mechanism of action of antidepressants and support speculations concerning the role of dopamine-containing neurons in the pathophysiology of depression.

Reversal of chloroquine resistance in malaria parasite Plasmodium falciparum by desipramine.

Desipramine and several other tricyclic antidepressant drugs reverse chloroquine resistance in Plasmodium falciparum in vitro at concentrations observed in the plasma of human patients treated for depression. Reversal of resistance is associated with increased chloroquine accumulation in the parasite, probably because of inhibition of a putative chloroquine efflux pump. When owl monkeys (Aotus lemurinus lemurinus) infected with chloroquine-resistant Plasmodium falciparum were treated with chloroquine plus desipramine, their parasitemias were rapidly suppressed. Desipramine was found to be one of the most effective compounds yet described for the reversal of chloroquine resistance both in vitro and in vivo.

Serotoninergic and non-serotoninergic effects of two tricyclic antidepressants on visceral nociception in a rat model.

OBJECTIVE: Tricyclic antidepressants (TCAs) are well established in the treatment of patients with irritable bowel syndrome (IBS). The effects are believed to be linked to serotoninergic antinociceptive properties, but data on the antinociceptive effects of various TCAs with variable serotoninergic and non-serotoninergic properties have not been investigated. The aim of this study was to compare the antinociceptive effects of different TCAs. MATERIAL AND METHODS: Colorectal distension (CRD) using a barostat device was carried out in rats and the visceromotor response (VMR) to CRD was quantified by abdominal wall electromyography. Prior to CRD, saline (control), amitriptyline (AM), desipramine (DES), reserpine (RES) or a combination of TCAs and RES (AM + RES or DES + RES) was applied intraperitoneally. Serum 5-HT levels were determined using high-performance liquid chromatography (HPLC). RES was used to antagonize the serotoninergic actions of TCAs in order to discriminate between these effects and others. RESULTS: Both TCAs decreased the VMR compared to placebo. After RES application without TCAs, the VMR was increased compared to controls (6403 microV+/-1772 microV). Co-administration of AM and RES resulted in a modest decrease in VMR (5774 microV+/-1953 microV), while in rats treated with RES and DES the VMR again was significantly lower (3446 microV (+/-1347 microV; p <0.05)). 5-HT levels were higher in TCA pretreated rats than those in controls and significantly lower 5-HT levels were found in all rats pretreated with RES. CONCLUSIONS: AM and DES have antinociceptive properties while RES is pro-nociceptive. The antinociceptive effects of DES are not abolished by RES pretreatment, while AM only attenuates the pro-nociceptive effects of RES. The non-serotoninergic properties of TCAs substantially contribute to the differences in the antinococeptive effects of various TCAs.

d-Amphetamine and methylmercury exposure during adolescence alters sensitivity to monoamine uptake inhibitors in adult mice.

Gestational exposure to methylmercury (MeHg), an environmental neurotoxicant, and adolescent administration of d-amphetamine (d-AMP) disrupt dopamine neurotransmission and alter voluntary behavior in adult rodents. We determined the impact of adolescent exposure to MeHg and d-AMP on monoamine neurotransmission in mice by assessing sensitivity to acute d-AMP, desipramine, and clomipramine, drugs that target dopamine, norepinephrine, and serotonin reuptake, respectively. Male C57Bl/6n mice were given 0 (control) or 3 ppm MeHg via drinking water from postnatal day 21 to 60 (murine adolescence). Within each group, mice were given once-daily injections of d-AMP or saline (i.p.) from postnatal day 28 to 42. This exposure regimen produced four treatment groups (n = 10-12/group): control, d-AMP, MeHg, and d-AMP + MeHg. As adults, the mice lever pressed under fixed-ratio schedules of reinforcement (FR 1, 5, 15, 30, 60, and 120). Acute i.p. injections of d-AMP (.3-1.7 mg/kg), desipramine (5.6-30 mg/kg), and clomipramine (5.6-30 mg/kg) were administered in adulthood after a stable behavioral baseline was established. Adolescent MeHg exposure increased saturation rate and minimum response time, an effect that was mitigated by chronic administration of d-AMP in adolescence. In unexposed mice, the three monoamine reuptake inhibitors had separable behavioral effects. Adolescent d-AMP increased sensitivity to acute d-AMP, desipramine, and clomipramine. Adolescent MeHg exposure alone did not alter drug sensitivity. Combined adolescent d-AMP + MeHg exposure enhanced sensitivity to acute d-AMP's and desipramine's effects on minimum response time. Adolescence is a vulnerable developmental period during which exposure to chemicals can have lasting effects on monoamine function and behavior.