Urszula Doboszewska

Chronic treatment with caffeine and its withdrawal modify the antidepressant-like activity of selective serotonin reuptake inhibitors in the forced swim and tail suspension tests in mice. Effects on Comt, Slc6a15 and Adora1 gene expression

&NA; Recent preclinical and clinical data suggest that low dose of caffeine enhances the effects of common antidepressants. Here we investigated the effects of chronic administration of caffeine (5 mg/kg, twice daily for 14 days) and its withdrawal on day 15th on the activity of per se ineffective doses of fluoxetine (5 mg/kg) and escitalopram (2 mg/kg) given on day 15th. We found decreased immobility time in the forced swim and tail suspension tests in mice in which caffeine was administered simultaneously with antidepressants on day 15th following a 14‐day caffeine treatment and no alterations in the spontaneous locomotor activity. A decrease in the level of escitalopram and an increase in the level of caffeine in serum were observed after concomitant administration of these compounds, while the joint administration of caffeine and fluoxetine was not associated with changes in their levels in serum or brain. Caffeine withdrawal caused a decrease in Adora1 mRNA level in the cerebral cortex (Cx). Administration of escitalopram or fluoxetine followed by caffeine withdrawal caused an increase in this gene expression, whereas administration of escitalopram, but not fluoxetine, on day 15th together with caffeine caused a decrease in Adora1 mRNA level in the Cx. Furthermore, antidepressant‐like activity observed after joint administration of the tested drugs with caffeine was associated with decreased Slc6a15 mRNA level in the Cx. The results show that withdrawal of caffeine after its chronic intake may change activity of antidepressants with concomitant alterations within monoamine, adenosine and glutamate systems. HighlightsCaffeine was administered for 14 days and on day 15th it was withdrawn.Ineffective doses of fluoxetine or escitalopram (FLX/ESC) were administered on day 15th.FLX/ESC given together with caffeine displayed antidepressant‐like activity.Caffeine and FLX/ESC modified Adora1 and Slc6a15 mRNA level in the cerebral cortex.Caffeine withdrawal after its chronic intake may change activity of FLX/ESC.

Rho kinase inhibition ameliorates cyclophosphamide-induced cystitis in rats

Hemorrhagic cystitis often develops in patients treated with cyclophosphamide (CYP). Studies have indicated that Rho kinase (ROCK) inhibitors may suppress detrusor overactivity symptoms and possess anti-inflammatory properties. The aim of the present study was to investigate whether inhibition of ROCK reduces cystometric and histopathological changes associated with CYP-induced cystitis. The rats received GSK 269962, a ROCK inhibitor, at a dose of 30xa0mg/kg daily, or vehicle for 7xa0days. Then, acute chemical cystitis leading to bladder overactivity was induced by CYP injection (200xa0mg/kg i.p.). Following CYP injection, cystometric studies with physiological saline were performed. Moreover, bladder edema (by the Evans Blue dye leakage technique) and urothelium thickness were measured. CYP injection resulted in a significant increase in cystometric parameters: basal pressure, threshold pressure, bladder contraction duration, relaxation time, detrusor overactivity index, non-voiding contractions amplitude, and non-voiding contractions frequency as well as increased Evans Blue extravasation into bladder tissue, whereas micturition voiding pressure, voided volume, post-void residual, volume threshold, intercontraction interval, bladder compliance, and volume threshold to elicit non-voiding contractions as well as urothelium thickness were significantly decreased in CYP-injected rats. Administration of GSK 269962 normalized the abovementioned CYP injection-induced changes. Inhibition of ROCK was found to ameliorate CYP-induced detrusor overactivity and bladder inflammation. Our data indicate uroprotective effects following ROCK inhibition, which further suggests that this strategy may become an interesting pharmacological tool to prevent urinary adverse effects in patients treated with chemotherapy using CYP.

SN003, a CRF1 receptor antagonist, attenuates depressive-like behavior and detrusor overactivity symptoms induced by 13-cis-retinoic acid in rats.

&NA; Overactive bladder (OAB) often co‐exists with depression in women. The corticotropin‐releasing factor (CRF) system participates in the pathophysiology of both disorders. Therefore, we tested the effects of acute treatment with a reversible CRF receptor type‐1 (CRF1) antagonist, SN003 (1 mg/kg, i.v.), representatives of first (solifenacin, 0.03 mg/kg, i.v.) and second (mirabegron, 1 mg/kg, i.v.) line treatments for OAB as well as an antidepressant imipramine (30 mg/kg, i.p.) on changes in depressive‐like behavior and detrusor overactivity (DO) symptoms induced by a 6‐week administration of 13‐cis‐retinoic acid (13‐cis‐RA, 1 mg/kg/day, i.p.) in female Wistar rats, using in vivo cystometric investigations, forced swim test (FST) and spontaneous locomotor activity test. Following cystometric and behavioral studies, tissue was harvested and CRF level was assessed in the hypothalamus, amygdala and plasma. 13‐cis‐RA‐induced depressive‐like behavior and DO symptoms were associated with increased CRF levels in the hypothalamus, amygdala and plasma. Solifenacin and mirabegron attenuated DO symptoms induced by 13‐cis‐RA, did not display antidepressant‐like activity and did not influence CRF levels in brain tissues or plasma. Imipramine and SN003 displayed antidepressant‐like activity and lowered increased levels of CRF in brain tissues and plasma. Imipramine attenuated changes in some of the cystometric parameters, which are associated with OAB dry (without urge incontinence), whereas SN003 attenuated changes in almost all cystometric parameters that were induced by 13‐cis‐RA. CRF1 antagonist may be beneficial in case of OAB wet (with urge incontinence) or dry co‐existing with depression. The possible mechanism may be related to the effects on central/peripheral CRF system.

Withdrawal of caffeine after its chronic administration modifies the antidepressant-like activity of atypical antidepressants in mice. Changes in cortical expression of Comt, Slc6a15 and Adora1 genes

RationaleDepressed patients often present increased consumption of caffeine.ObjectivesWe aimed to investigate the effects of chronic treatment with caffeine (5xa0mg/kg, twice daily for 14xa0days) on the activity of single, ineffective doses of agomelatine (20xa0mg/kg) or mianserin (10xa0mg/kg) given on dayxa015 alone or simultaneously with caffeine.MethodsWe used the forced swim test (FST), tail suspension test (TST), and locomotor activity test in mice and quantitative real-time PCR analysis of the selected genes in the cerebral cortex (Cx).ResultsThere were no changes in the immobility time between mice that received saline and caffeine for 14xa0days. Administration of agomelatine or mianserin on dayxa015 did not produce an antidepressant-like effect, but such effect was observed after administration of agomelatine or mianserin simultaneously with caffeine on dayxa015, in both mice that received saline and caffeine for 14xa0days. In mice treated with caffeine for 14xa0days, joint administration of agomelatine or mianserin and caffeine on dayxa015 decreased solute carrier family 6, member 15 (Slc6a15), messenger RNA (mRNA) level in the Cx, compared to the group which received only the respective antidepressant on this day. Moreover, in mice treated with caffeine for 14xa0days, joint administration of mianserin and caffeine on dayxa015 decreased adenosine A1 receptor (Adora1) and catechol-O-methyltransferase (Comt) mRNA level in the Cx, compared to the group which received mianserin without caffeine on this day.ConclusionsWithdrawal of caffeine after its chronic intake can modify the activity of antidepressants. Adora1, Slc6a15, and Comt may be involved in the antidepressant-like effect observed after joint administration of caffeine and mianserin or agomelatine, following chronic treatment with caffeine.

Zinc signaling and epilepsy

&NA; Evidence from both preclinical and clinical studies suggest the importance of zinc homeostasis in seizures/epilepsy. Undoubtedly, zinc, via modulation of a variety of targets, is necessary for maintaining the balance between neuronal excitation and inhibition, while an imbalance between excitation and inhibition underlies seizures. However, the relationship between zinc signaling and seizures/epilepsy is complex as both extracellular and intracellular zinc may produce either protective or detrimental effects. This review provides an overview of preclinical/behavioral, functional and molecular studies, as well as clinical data on the involvement of zinc in the pathophysiology and treatment of seizures/epilepsy. Furthermore, the potential of targeting elements associated with zinc signaling or homeostasis and zinc levels as a therapeutic strategy for epilepsy is discussed.

Antidepressant-Like Activity of Typical Antidepressant Drugs in the Forced Swim Test and Tail Suspension Test in Mice Is Augmented by DMPX, an Adenosine A 2A Receptor Antagonist

Unsatisfactory therapeutic effects of currently used antidepressants force to search for new pharmacological treatment strategies. Recent research points to the relationship between depressive disorders and the adenosinergic system. Therefore, the main goal of our studies was to evaluate the effects of DMPX (3xa0mg/kg, i.p.), which possesses selectivity for adenosine A2A receptors versusxa0A1 receptors, on the activity of imipramine (15xa0mg/kg, i.p.), escitalopram (2.5xa0mg/kg, i.p.), and reboxetine (2xa0mg/kg, i.p.) given in subtherapeutic doses. The studies carried out using thexa0forced swim and tail suspension tests in mice showed that DMPX at a dose of 6 and 12xa0mg/kg exerts antidepressant-like effect and does not affect the locomotor activity. Co-administration of DMPX at a dose of 3xa0mg/kg with the studied antidepressant drugs caused the reduction of immobility time in both behavioral tests. The observed effect was not associated with an increase in the locomotor activity. To evaluate whether the observed effects were due to a pharmacokinetic/pharmacodynamic interaction, the levels of the antidepressants in blood and brain were measured using high-performance liquid chromatography. It can be assumed that the interaction between DMPX and imipramine was exclusively pharmacodynamic in nature, whereas an increased antidepressant activity of escitalopram and reboxetine was at least partly related to its pharmacokinetic interaction with DMPX.

Effect of Tadalafil on Seizure Threshold and Activity of Antiepileptic Drugs in Three Acute Seizure Tests in Mice

Tadalafil, a selective phosphodiesterase type 5 inhibitor, is a long-acting oral agent for the treatment of erectile dysfunction of multiple etiologies. Although generalized tonic-clonic seizures were reported in a healthy man after taking tadalafil, the influence of tadalafil on seizure susceptibility has not been studied so far. Therefore, the aim of the present study was to investigate the effect of tadalafil on seizure threshold as well as on the activity of some first- and second-generation antiepileptic drugs in three acute seizure tests in mice. The obtained results showed that tadalafil, at the highest dose tested (20xa0mg/kg), significantly decreased the threshold for the first myoclonic twitch in the intravenous pentylenetetrazole (i.v. PTZ) seizure test. It did not affect the threshold for generalized clonic seizure and forelimb tonus in the i.v. PTZ, for tonic hindlimb extension in the maximal electroshock seizure threshold test, and for psychomotor seizure in the 6-Hz-induced seizure threshold test. Tadalafil did not alter the anticonvulsant activity of any of the studied antiepileptic drugs in electrically induced seizure tests. Interestingly, tadalafil potentiated the anticonvulsant activity of clonazepam and decreased the anticonvulsant activity of oxcarbazepine in the i.v. PTZ test. These interactions were pharmacodynamic in nature, as tadalafil did not alter clonazepam and oxcarbazepine concentrations both in serum and brain tissue. Furthermore, neither tadalafil alone nor its combinations with the studied antiepileptic drugs produced any significant impairment of motor coordination (assessed in the chimney test), muscular strength (investigated in the grip-strength test), and long-term memory (assessed in the passive avoidance task). In conclusion, tadalafil may increase the risk of myoclonic seizure and decrease the anticonvulsant efficacy of oxcarbazepine. Further studies are warranted to evaluate the safety of tadalafil usage in patients with epilepsy.

Blebbistatin, a Myosin II Inhibitor, Exerts Antidepressant-Like Activity and Suppresses Detrusor Overactivity in an Animal Model of Depression Coexisting with Overactive Bladder

Overactive bladder (OAB) coexists with depression in women. Here, we assessed the effects of a 1-week treatment with blebbistatin, a myosin II inhibitor, on changes in behavior and detrusor overactivity (DO) symptoms induced by a 6-week administration of 13-cis-retinoic acid (13-cis-RA), with the aid of the forced swim test (FST), spontaneous locomotor activity test, and in vivo cystometric investigations in female Wistar rats. 13-cis-RA-induced depressive-like behavior and DO symptoms were associated with increased corticotropin-releasing factor (CRF) level in the plasma, prefrontal cortex (PFC), hippocampus (Hp), Barrington’s nucleus (BN), and urinary bladder. Moreover, 13-cis-RA decreased brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in plasma, PFC, Hp, and BN, while it increased BDNF and NGF levels in urinary bladder. Blebbistatin exerted antidepressant-like effect and attenuated changes in the cystometric parameters as well as the central and peripheral levels of CRF, BDNF, and NGF that were induced by 13-cis-RA, while it did not affect urine production, mean, systolic or diastolic blood pressure, or heart rate. The results point to blebbistatin as a potential treatment option for OAB coexisting with depression.

DPCPX, a selective adenosine A1 receptor antagonist, enhances the antidepressant-like effects of imipramine, escitalopram, and reboxetine in mice behavioral tests

The main goal of the present study was to evaluate the influence of the adenosine A1 receptor (A1R) antagonistxa0—xa0DPCPXxa0—xa0on depressive-like behavior in mice, as well as the effect of DPCPX on the activity of imipramine, escitalopram, and reboxetine, each at non-effective doses. The influence of DPCPX on behavior and its influence on the activity of selected antidepressants was evaluated in the forced swim test (FST) and the tail suspension test (TST) in mice. Locomotor activity was measured to verify and exclude false-positive data obtained in the FST and TST. Moreover, serum and brain concentrations of tested antidepressants were determined using HPLC. DPCPX, at doses of 2 and 4xa0mg/kg, exhibited antidepressant activity in the FST and TST, which was not related to changes in the spontaneous locomotor activity. Co-administration of DPCPX with imipramine, escitalopram, or reboxetine, each at non-active doses, significantly reduced the immobilization period in the FST and TST in mice, which was not due to the increase in locomotor activity. Both antagonists of 5-HT receptors (WAY 100635 and ritanserin) completely antagonized the effect elicited by DPCPX in the behavioral tests. Results of assessment of the nature of the interaction between DPCPX and test drugs show that in the case of DPCPX and imipramine or reboxetine, there were pharmacodynamic interactions, whereas the DPCPX-escitalopram interaction is at least partially pharmacokinetic in nature. Presented outcomes indicate that an inhibition of A1Rs andxa0an increase of monoaminergic transduction in the CNS may offer a novel strategy for the development of antidepressant drugs.

The influence of selective A1 and A2A receptor antagonists on the antidepressant-like activity of moclobemide, venlafaxine and bupropion in mice

The main goal of our study was to investigate whether a selective antagonism of the adenosine A1 or A2A receptors is able to enhance the antidepressant activity of commonly prescribed drugs.