The atypical anxiolytic drug, tofisopam, selectively blocks phosphodiesterase isoenzymes and is active in the mouse model of negative symptoms of psychosis

Tofisopam is a member of the 2,3-benzodiazepine compound family which is marketed for the treatment of anxiety in some European countries. In contrast to classical 1,4-benzodiazepines, the compound does not bind to the benzodiazepine binding site of the γ-aminobutyric acid receptor and its psychopharmacological profile differs from such compounds. In addition to anxiolytic properties, antipsychotic effects are reported. We now show that tofisopam, 50 mg/kg intraperitoneally (i.p.), administered in parallel to repeated doses of dizocilpine 0.2 mg/kg i.p. can ameliorate dizocilpine-induced prolongation of immobility, which is considered to be a model of negative symptoms of psychosis. We further show that tofisopam acts as an isoenzyme-selective inhibitor of phosphodiesterases (PDEs) with highest affinity to PDE-4A1 (0.42 μM) followed by PDE-10A1 (0.92 μM), PDE-3 (1.98 μM) and PDE-2A3 (2.11 μM). The data indicate that tofisopam is an interesting candidate for the adjuvant treatment of psychosis with focus on negative symptoms. Combined partial inhibition of PDE-4 and PDE-10 as well as PDE-2 may be the underlying mechanism to this activity. Due to the good safety profile of tofisopam as evident from long-term use of this agent in patients, it may be concluded that dual or triple inhibition of PDE isoenzymes with additive or synergistic effects may be an interesting approach to pharmacological activity, resulting in active compounds with beneficial safety profile. Dose-limiting side effects such as emesis induced by selective inhibition of PDE-4 may be prevented by such strategies

A complex interaction between glycine/NMDA receptors and serotonergic/noradrenergic antidepressants in the forced swim test in mice

Both clinical and preclinical studies demonstrate the antidepressant activity of the functional NMDA receptor antagonists. In this study, we assessed the effects of two glycine/NMDA receptor ligands, namely L-701,324 (antagonist) and d-cycloserine (a partial agonist) on the action of antidepressant drugs with different pharmacological profiles in the forced swim test in mice. Swim sessions were conducted by placing mice individually in glass cylinders filled with warmed water for 6 min. The duration of behavioral immobility during the last 4 min of the test was evaluated. The locomotor activity of mice was measured with photoresistor actimeters. L-701,324 and d-cycloserine given with reboxetine (administered in subeffective doses) did not change the behavior of animals in the forced swim test. A potentiating effect was seen when both tested glycine site ligands were given concomitantly with imipramine or fluoxetine in this test. The lesion of noradrenaline nerve terminals produced by DSP-4 neither altered the baseline activity nor influenced the antidepressant-like action of L-701,324 or d-cycloserine. The depletion of serotonin by p-CPA did not alter baseline activity in the forced swim test. However, it completely antagonized the antidepressant-like action produced by L-701,324 and d-cycloserine. Moreover, the antidepressant-like effects of imipramine, fluoxetine and reboxetine were abolished by d-serine, a full agonist of glycine/NMDA receptors. The present study demonstrates that glycine/NMDA receptor functional antagonists enhance the antidepressant-like action of serotonin, but not noradrenaline-based antidepressants and such their activity seems to depend on serotonin rather than noradrenaline pathway

Involvement of NMDA receptor complex in the anxiolytic-like effects of chlordiazepoxide in mice

In the present study, we demonstrated that low, ineffective doses of N-methyl-d-aspartic acid (NMDA) receptor antagonists [competitive NMDA antagonist, CGP 37849, at 0.312 mg/kg intraperitoneally (i.p.), antagonist of the glycineB sites, L-701,324, at 2 mg/kg i.p., partial agonist of glycineB sites, d-cycloserine, at 2.5 mg/kg i.p.] administered jointly with an ineffective dose of the benzodiazepine, chlordiazepoxide (CDP, 2.5 mg/kg i.p.), significantly increased the percentage of time spent in the open arms of the elevated plus-maze (index of anxiolytic effect). Furthermore, CDP-induced anxiolytic-like activity (5 mg/kg i.p.) was antagonized by NMDA (75 mg/kg i.p.) and by an agonist of glycineB sites of the NMDA receptor complex, d-serine [100 nmol/mouse intracerebroventricularly (i.c.v.)]. The present study showed a positive interaction between γ-aminobutyric acid (GABA) and glutamate neurotransmission in the anxiolytic-like activity in the elevated plus-maze test in mice and this activity seems to particularly involve the NMDA receptors

Sildenafil, a phosphodiesterase type 5 inhibitor, enhances the antidepressant activity of amitriptyline but not desipramine, in the forced swim test in mice

The cholinergic theory of depression highlights the involvement of muscarinic acetylcholine receptors in the neurobiology of mood disorders. The present study was designed to investigate the effect of sildenafil, a phosphodiesterase type 5 inhibitor which exhibits cholinomimetic properties, alone and in combination with scopolamine in the forced swim test in mice. Moreover, we assessed the ability of sildenafil to modify the antidepressant activity of two tricyclic antidepressants with distinct cholinolytic activity, amitriptyline and desipramine. Swim sessions were conducted by placing mice in glass cylinders filled with water for 6 min and the duration of behavioral immobility during the last 4 min of the test was evaluated. Locomotor activity was measured with photoresistor actimeters. To evaluate the potential pharmacokinetic interaction between amitriptyline and sildenafil, brain and serum concentrations of amitriptyline were determined by HPLC. Sildenafil (1.25–20 mg/kg) as well as scopolamine (0.5 mg/kg) and its combination with sildenafil (1.25 mg/kg) did not affect the total immobility time duration. However, joint administration of scopolamine with sildenafil at doses of 2.5 and 5 mg/kg significantly reduced immobility time as compared to control group. Moreover, co-administration of scopolamine with sildenafil at the highest dose (5 mg/kg) significantly decreased immobility time as compared to scopolamine-treated group. Sildenafil (1.25, 2.5 and 5 mg/kg) significantly enhanced the antidepressant activity of amitriptyline (5 mg/kg). No changes in anti-immobility action of desipramine (20 mg/kg) in combination with sildenafil (5, 10 and 20 mg/kg) were observed. Sildenafil did not affect amitriptyline level in both brain and serum. In conclusion, the present study suggests that sildenafil may enhance the activity of antidepressant drugs which exhibit cholinolytic activity

Przeciwdrgawkowe działanie 10 różnych pochodnych p-izopropoksyfenylobursztynimidów w modelu progu maksymalnego wstrząsu elektrycznego u myszy

Background. To compare the anticonvulsant potency of 10 various p-isopropoxyphenylsuccinimide (IPPS) derivatives [i.e., IPPS (IPPS); N-(morpholinomethyl)-IPPS (MM-IPPS); N-(anilinomethyl)-IPPS (AM-IPPS); N-hydroxymethyl-IPPS (HM-IPPS); N-(p-acetylphenyl)-IPPS (AP-IPPS); N-(p-ethoxycarbonylphenylmethyl)-IPPS (ECPM-IPPS); N-(m-bromoanilinomethyl)-IPPS (BAM-IPPS); N-(o-carboxyanilinomethyl)-IPPS (o-CAMIPPS); N-(m-carboxyanilinomethyl)-IPPS (m-CAM-IPPS); N-(p-carboxyanilinomethyl)-IPPS (p-CAM-IPPS)] in the maximal electroshock-induced seizure threshold (MEST) test in mice. Material and methods. Linear regression analysis of doses of IPPS derivatives and their threshold increases in the MEST test in mice allowed to calculate TID20 values i.e., doses of the tested IPPS derivatives that elevate by 20% the seizure threshold in IPPS-treated mice over the threshold in control animals. Results. A ll t he studied IPPS derivatives (i.e., IPPS, MMIPPS, HM-IPPS, AP-IPPS, AM-IPPS, ECPM-IPPS, o-CAM-IPPS, m-CAM-IPPS, p-CAM-IPPS and BAM-IPPS) increased in a dose dependent manner the threshold for maximal electroshockinduced seizures in mice. The TID20 values in the MEST test for IPPS, AP-IPPS, AM-IPPS, BAMIPPS, o-CAM-IPPS, m-CAM-IPPS, p-CAM-IPPS, ECPM-IPPS, HM-IPPS, and MM-IPPS were 60.44 mg/kg, 86.30 mg/kg, 44.69 mg/kg, 103.34 mg/kg, 22.43 mg/kg, 52.84 mg/kg, 80.85 mg/kg, 109.75 mg/kg, 32.62 mg/kg and 53.50 mg/kg, respectively. Conclusions. The studied IPPS derivatives with respect to their anticonvulsant potency in the MEST test can be arranged as follows: o-CAM-IPPS > HM-IPPS > AM-IPPS > m-CAM-IPPS > MM-IPPS > IPPS > p-CAM-IPPS >AP-IPPS > BAM-IPPS > ECPM-IPPS.Wprowadzenie. Porównać siłę przeciwdrgawkowego działania 10 różnych pochodnych p-izopropoksyfenylobursztynimidów (IPPS) [tj. (IPPS); N-(morfolinometylo)-IPPS (MM-IPPS); N-(anilinometylo)-IPPS (AM-IPPS); N-hydroksymetylo-IPPS (HM-IPPS); N-(p-acetylofenylo)-IPPS (AP-IPPS); N-(p-etoksykarbonylofenylometylo)-IPPS (ECPM-IPPS); N-(m-bromoanilinometylo)-IPPS (BAM-IPPS); N-(o-karboksyanilinometylo)-IPPS (o-CAM-IPPS); N-(m-karboksyanilinometylo)-IPPS (m-CAM-IPPS); N-(p-karboksyanilinometylo)-IPPS (p-CAM-IPPS)] w teście progu maksymalnego wstrząsu elektrycznego (MEST) u myszy. Materiał i metody. Analiza regresji liniowej dawek pochodnych IPPS i ich wzrostów progu w teście MEST u myszy pozwoliła policzyć wartości TID20 tj. dawki badanych pochodnych IPPS, które podnoszą o 20% próg drgawkowy u myszy, którym podano IPPS, ponad próg u zwierząt kontrolnych. Wyniki. Wszystkie badane pochodne IPPS (tj. IPPS, MM-IPPS, HM-IPPS, AP-IPPS, AM-IPPS, ECPM-IPPS, o-CAM-IPPS, m-CAM-IPPS, p-CAM-IPPS and BAM-IPPS) zwiększały w sposób zależny od dawki próg maksymalnego wstrząsu elektrycznego u myszy. Wartości TID20 w teście MEST dla IPPS, AP-IPPS, AM-IPPS, BAM-IPPS, o-CAM-IPPS, m-CAM-IPPS, p-CAM-IPPS, ECPM-IPPS, HM-IPPS i MM-IPPS wynosiły odpowiednio: 60,44 mg/kg, 86,30 mg/kg, 44,69 mg/kg, 103,34 mg/kg, 22,43 mg/kg, 52,84 mg/kg, 80,85 mg/kg, 109,75 mg/kg, 32,62 mg/kg i 53,50 mg/kg. Wnioski. Badane pochodne IPPS w odniesieniu do ich siły przeciwdrgawkowego działania można uporządkować następująco: o-CAM-IPPS > HM-IPPS > AM-IPPS > m-CAM-IPPS > MM-IPPS > IPPS > p-CAM-IPPS > AP-IPPS > BAM-IPPS > ECPM-IPPS