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Dotarizine prevent electroconvulsive shock- and pentylenetetrazol-induced amnesia in rats
405 1993a). Phenyl-ethyl-amine (PEA), the preferred substrate of MAO-B, exerts amphetamine-like stimulatory effects, however, due to its rapid metabolism only in high doses. ( - ) D e p r e n y l may potentiate its effects by inhibiting the metabolism. However, while the stereotypy-inducing effect of PEA, a behavior related to the nigrostriatal dopaminergic system, is potentiated by ( - ) d e p r e n y l pretreatment, its effect on locomotion, a behavior related to the mesolimbic dopaminergic system, failed to change following the same pretreatment (Timfir et al., 1993b). In the experiments presented here the effect of ( - ) d e p r e n y l on the PEA-induced PPC, which behavior is also related to the mesolimbic dopaminergic system, was checked. Results are summarized in Table 1.
Table 1. Difference in time spent in the drug-paired compartment during pre- and postconditioning sessions (in percentage of the difference presented by the simultaneously tested controls); (-)deprenyl was given I h prior to PEA Drug
Dose (mg/kg)
%
PEA
40
113 + 54
PEA
80
1363 ± 404*
(-)Deprenyl + PEA
0.25 + 40
144 _+ 28
(-)Deprenyl + PEA
2.0 + 40
129 + 52
( - ) D e p r e n y l pretreatment either at its selective MAO-B inhibitory dose or at a higher one failed to potentiate the PEAinduced PPC. The results give further proof that ( - ) d e p r e n y l leaves the mesolimbic dopaminergic neurons unaffected and speaks against its possible abuse potential. References
Timfir, J., Gyarmati, Zs., Knoll, B., Barna, L. and Knoll, J. (1993a) ( - ) D e p r e n y l
lack of inducing place preference conditioning in rats. Eur. Neuropsychopharmacol. 3, 412. Timer, J., Gyarmati, Zs., Tekes, K., Hfirsing, G.L. and Knoll, J. (1993b) Further proof that ( - ) d e p r e n y l fails to facilitate mesolimbic dopaminergic activity. Pharmacol. Biochem. Behav. 46, 709 714.
Dotarizine prevents electroconvulsive shock- and pentylenetetrazol-induced amnesia in rats
M.B. Lazarova-Bakarova, B. Petkova and V.D. Petkov Institute of Physiology, Bulgarian Academy of Sciences, Acad. G. Bonchev St., bl. 23, 1113 Sofia, Bulgaria Key words. Amnesia; Electroconvulsive shock; Pentylenetrazol; Passive avoidance; Dotarizine; Rats The newly synthetized drug dotarizine (DOT) is a compound that acts both as a calcium antagonist and as a blocker of 5HT receptors (Braso et al., 1990). In recent years experimental data have demonstrated that 5-HT-selective antagonists have a memory-enhancing effect (McEntee and Crook, 1990). These data stimulated us to study DOT's ability to protect against electroconvulsive shock (ECS)- or pentylenetetrazol (PTZ)-induced amnesia in step-down trained rats. Passive avoidance 'step-down' was used to study the changes in learning and retention in male Wistar rats. Six consecutive training sessions were carried out. Immediately after reaching the learning criterion (remaining on the platform for at least 30 s) ECS (by corneal silver electrodes) or PTZ (45 mg/kg i.p.) was applied to provoke a performance deficit. A sham ECS (SECS) was given to the controls. DOT was administered orally at a dose of 50 mg/kg for 5 days prior to training. Retention tests were given 3 h, 24 h and 7 days after training. The number of rats reaching the learning criterion was calculated in percentage. The Z2 criterion was used for statistical analysis. ECS induced a pronounced retrograde amnesia. It significantly decreased the percentage of rats reaching the learning criterion upon retention testing at 3 h, 24 h and 7 days after training: from 80% in the controls to 33.3% in the ECS-treated group; from 70% in the controls to 22.2% in the ECS-treated rats; and from 70% in the controls to 33.3% in the ECS-treated rats. DOT completely abolished the amnestic effect of ECS. The percentage of rats reaching the learning criterion upon the
406 three retention tests in the group treated with both DOT and ECS was higher (80.0%, 70.0% and 70.0%, respectively) as compared to that in the group exposed to ECS only and was not significantly different from the controls (SECS). PTZ induced a pronounced retrograde amnesia. DOT prevented the amnestic effect of PTZ: it significantly increased the percentage of rats acquiring the learning task (from 0.0% to 33.3% upon retention testing at 3 h; from 11.1% to 50.0% upon retention testing at 24 h; and from 0.0% to 42.8% upon retention testing at 7 days). The observed antiamnestic effect of dotarizine suggests that it is promising for the treatment of cognitive disorders. References
Braso, A., Tejerina, T., Gonzales, P. and Lopez, J. (1990) Is dotarizine selective? Eur. J. Pharmacol. 183, 553. McEntee, W.P. and Crook, T.H. (1991) Serotonin, memory and the aging brain. Psychopharrnacology 103, 143 149.
Piracetam and fipexide abolish the amnesia provoked by PTZ kindling in rats
M. Genkova-Papazova and M. Lazarova-Bakarova Department qf Experimental Pharmacology, Institute of Physiology, 1113 Sofia, Bulgaria Key words: Kindling; Learning; Memory; Nootropic drugs Epilepsy is frequently accompanied by memory disturbances. It has been observed that antiepileptic drugs impair cognition (Thompson and Trimble, 1983). Memory deficit could be successfully treated with drugs with both anticonvulsant and memory-enhancing activity. Our earlier data have shown that nootropic drugs at doses known to exert an antiamnestic effect decrease the intensity of pentylenetetrazol (PTZ)-kindled seizures in rats (Genkova-Papazova and Lazarova-Bakarova, 1992). PTZ kindling impaired retention in shuttle-box and step-down trained rats and might be used as an experimental model of memory deficit, accompanying epilepsy (Genkova-Papazova, 1993). In the present work the effect of the nootropics piracetam and fipexide on amnesia induced by PTZ kindling is examined. Kindling was provoked in male Wistar rats by multiple injection of a subconvulsive dose (40 mg/kg) of PTZ. The changes in learning and memory were studied by the two-way punishment reinforced active avoidance method (shuttle-box) and the passive avoidance method (step-down). One group of kindled animals (16 rats) was trained for 5 days in the shuttle-box apparatus with 30 trials daily and the retention test was given 7 days after the last training session. By the step-down method 18 kindled rats were trained in six consecutive training sessions and retention was tested 3 h, 24 h and 7 days after training. Separate groups of kindled rats (10 rats per group) received piracetam 600 mg/kg or fipexide 10 mg/kg orally for 10 days (5 days prior to and 5 days during training in the shuttlebox and for 5 days before step-down training). The effect of nootropic drugs on PTZ-kindled rats in shuttle-box active avoidance was assessed using three-way ANOVA with repeated measures of the number of avoidances for each of the five training days and on the day of retention testing. The effect of nootropic drugs on retention in the step-down kindled rats was evaluated through the percentage of animals attaining the learning criterion. The results was assessed for statistical significance by Dunnett's test (shuttle-box) and by the 2 method (step-down). PTZ kindling significantly impaired retention in shuttle-box trained rats. The number of avoidances on the day of retention testing was markedly decreased as compared to controls (F1,36 = 34.7, P<0.001). Piracetam 600 mg/kg or fipexide 10 mg/kg completely abolished the memory deficit produced by kindling. In the piracetam- or fipexide-treated groups of kindled rats the number of avoidances significantly increased as compared to the kindled animals (A=2,52, and A=3.92 respectively, P<0.01). Kindling significantly decreased the percentage of step-down trained rats reaching the learning criterion. Compared with the group of unkindled controls in which 80% (3 h), 86.6% (24 h) and 66.6% (day 7) attained the learning criterion, in the PTZ-kindled group these percentages were 62.5, 31.2 (P<0.01) and 18.75 (P<0.01) respectively. Piracetam or fipexide abolished the memory-impairing effect of PTZ kindling: in the piracetam- and fipexide-treated groups of kindled animals the percentage of rats reaching the learning criterion was 80 (3 h), 73.3 (24 h, P<0.01) and 66.6 (7 days, P<0.01); and 73.3 (3 h), 80 (24 h, P<0.01) and 73.3 (7 days, P<0.01) respectively. Obviously, piracetam and fipexide completely abolish the retrograde amnesia induced by PTZ kindling in the active and passive avoidance situations. The favorable effects of piracetam and fipexide on amnesia provoked by PTZ kindling could contribute to the pharmacological characterization of these drugs and might be of interest in clinical practice.
Table 1. Difference in time spent in the drug-paired compartment during pre- and postconditioning sessions (in percentage of the difference presented by the simultaneously tested controls); (-)deprenyl was given I h prior to PEA Drug
Dose (mg/kg)
%
PEA
40
113 + 54
PEA
80
1363 ± 404*
(-)Deprenyl + PEA
0.25 + 40
144 _+ 28
(-)Deprenyl + PEA
2.0 + 40
129 + 52
( - ) D e p r e n y l pretreatment either at its selective MAO-B inhibitory dose or at a higher one failed to potentiate the PEAinduced PPC. The results give further proof that ( - ) d e p r e n y l leaves the mesolimbic dopaminergic neurons unaffected and speaks against its possible abuse potential. References
Timfir, J., Gyarmati, Zs., Knoll, B., Barna, L. and Knoll, J. (1993a) ( - ) D e p r e n y l
lack of inducing place preference conditioning in rats. Eur. Neuropsychopharmacol. 3, 412. Timer, J., Gyarmati, Zs., Tekes, K., Hfirsing, G.L. and Knoll, J. (1993b) Further proof that ( - ) d e p r e n y l fails to facilitate mesolimbic dopaminergic activity. Pharmacol. Biochem. Behav. 46, 709 714.
Dotarizine prevents electroconvulsive shock- and pentylenetetrazol-induced amnesia in rats
M.B. Lazarova-Bakarova, B. Petkova and V.D. Petkov Institute of Physiology, Bulgarian Academy of Sciences, Acad. G. Bonchev St., bl. 23, 1113 Sofia, Bulgaria Key words. Amnesia; Electroconvulsive shock; Pentylenetrazol; Passive avoidance; Dotarizine; Rats The newly synthetized drug dotarizine (DOT) is a compound that acts both as a calcium antagonist and as a blocker of 5HT receptors (Braso et al., 1990). In recent years experimental data have demonstrated that 5-HT-selective antagonists have a memory-enhancing effect (McEntee and Crook, 1990). These data stimulated us to study DOT's ability to protect against electroconvulsive shock (ECS)- or pentylenetetrazol (PTZ)-induced amnesia in step-down trained rats. Passive avoidance 'step-down' was used to study the changes in learning and retention in male Wistar rats. Six consecutive training sessions were carried out. Immediately after reaching the learning criterion (remaining on the platform for at least 30 s) ECS (by corneal silver electrodes) or PTZ (45 mg/kg i.p.) was applied to provoke a performance deficit. A sham ECS (SECS) was given to the controls. DOT was administered orally at a dose of 50 mg/kg for 5 days prior to training. Retention tests were given 3 h, 24 h and 7 days after training. The number of rats reaching the learning criterion was calculated in percentage. The Z2 criterion was used for statistical analysis. ECS induced a pronounced retrograde amnesia. It significantly decreased the percentage of rats reaching the learning criterion upon retention testing at 3 h, 24 h and 7 days after training: from 80% in the controls to 33.3% in the ECS-treated group; from 70% in the controls to 22.2% in the ECS-treated rats; and from 70% in the controls to 33.3% in the ECS-treated rats. DOT completely abolished the amnestic effect of ECS. The percentage of rats reaching the learning criterion upon the
406 three retention tests in the group treated with both DOT and ECS was higher (80.0%, 70.0% and 70.0%, respectively) as compared to that in the group exposed to ECS only and was not significantly different from the controls (SECS). PTZ induced a pronounced retrograde amnesia. DOT prevented the amnestic effect of PTZ: it significantly increased the percentage of rats acquiring the learning task (from 0.0% to 33.3% upon retention testing at 3 h; from 11.1% to 50.0% upon retention testing at 24 h; and from 0.0% to 42.8% upon retention testing at 7 days). The observed antiamnestic effect of dotarizine suggests that it is promising for the treatment of cognitive disorders. References
Braso, A., Tejerina, T., Gonzales, P. and Lopez, J. (1990) Is dotarizine selective? Eur. J. Pharmacol. 183, 553. McEntee, W.P. and Crook, T.H. (1991) Serotonin, memory and the aging brain. Psychopharrnacology 103, 143 149.
Piracetam and fipexide abolish the amnesia provoked by PTZ kindling in rats
M. Genkova-Papazova and M. Lazarova-Bakarova Department qf Experimental Pharmacology, Institute of Physiology, 1113 Sofia, Bulgaria Key words: Kindling; Learning; Memory; Nootropic drugs Epilepsy is frequently accompanied by memory disturbances. It has been observed that antiepileptic drugs impair cognition (Thompson and Trimble, 1983). Memory deficit could be successfully treated with drugs with both anticonvulsant and memory-enhancing activity. Our earlier data have shown that nootropic drugs at doses known to exert an antiamnestic effect decrease the intensity of pentylenetetrazol (PTZ)-kindled seizures in rats (Genkova-Papazova and Lazarova-Bakarova, 1992). PTZ kindling impaired retention in shuttle-box and step-down trained rats and might be used as an experimental model of memory deficit, accompanying epilepsy (Genkova-Papazova, 1993). In the present work the effect of the nootropics piracetam and fipexide on amnesia induced by PTZ kindling is examined. Kindling was provoked in male Wistar rats by multiple injection of a subconvulsive dose (40 mg/kg) of PTZ. The changes in learning and memory were studied by the two-way punishment reinforced active avoidance method (shuttle-box) and the passive avoidance method (step-down). One group of kindled animals (16 rats) was trained for 5 days in the shuttle-box apparatus with 30 trials daily and the retention test was given 7 days after the last training session. By the step-down method 18 kindled rats were trained in six consecutive training sessions and retention was tested 3 h, 24 h and 7 days after training. Separate groups of kindled rats (10 rats per group) received piracetam 600 mg/kg or fipexide 10 mg/kg orally for 10 days (5 days prior to and 5 days during training in the shuttlebox and for 5 days before step-down training). The effect of nootropic drugs on PTZ-kindled rats in shuttle-box active avoidance was assessed using three-way ANOVA with repeated measures of the number of avoidances for each of the five training days and on the day of retention testing. The effect of nootropic drugs on retention in the step-down kindled rats was evaluated through the percentage of animals attaining the learning criterion. The results was assessed for statistical significance by Dunnett's test (shuttle-box) and by the 2 method (step-down). PTZ kindling significantly impaired retention in shuttle-box trained rats. The number of avoidances on the day of retention testing was markedly decreased as compared to controls (F1,36 = 34.7, P<0.001). Piracetam 600 mg/kg or fipexide 10 mg/kg completely abolished the memory deficit produced by kindling. In the piracetam- or fipexide-treated groups of kindled rats the number of avoidances significantly increased as compared to the kindled animals (A=2,52, and A=3.92 respectively, P<0.01). Kindling significantly decreased the percentage of step-down trained rats reaching the learning criterion. Compared with the group of unkindled controls in which 80% (3 h), 86.6% (24 h) and 66.6% (day 7) attained the learning criterion, in the PTZ-kindled group these percentages were 62.5, 31.2 (P<0.01) and 18.75 (P<0.01) respectively. Piracetam or fipexide abolished the memory-impairing effect of PTZ kindling: in the piracetam- and fipexide-treated groups of kindled animals the percentage of rats reaching the learning criterion was 80 (3 h), 73.3 (24 h, P<0.01) and 66.6 (7 days, P<0.01); and 73.3 (3 h), 80 (24 h, P<0.01) and 73.3 (7 days, P<0.01) respectively. Obviously, piracetam and fipexide completely abolish the retrograde amnesia induced by PTZ kindling in the active and passive avoidance situations. The favorable effects of piracetam and fipexide on amnesia provoked by PTZ kindling could contribute to the pharmacological characterization of these drugs and might be of interest in clinical practice.