- Email: [email protected]
Effect of peripheral administration of cinnarizine and verapamil on diazepam withdrawal hyperactivity in rats
1985 On the 5th day of continuous treatment, in case of diazepam, significantly increased activity of GAD (p < 0.05) with simultaneous decrease in GABA-T activity (p < 0.02) was obtained. With oxazepam, GAD activity remaining unaffected, GABA-T activity was decreased significantly (p < 0.001). The ratio of the rate of synthesis to breakdown of G A B A i.e. G A D / G A B A - T values was increased (p < 0.001) in both cases. Following discontinuation from 6th day, in case of diazepam group, the increased GAD (p < 0.05) and decreased GABA-T activity (p < 0.025) persisted for longer period (12-15th day) and thereafter normalised. In case of oxazepam, under similar condition, GAD activity remaining unaltered the decreased activity of GABA-T attained control range much earlier (8th day). As a result the observed increased value of G A D / G A B A - T ratio attained control range much earlier in oxazepam group than diazepam group. When Ro15-1788 was adn~nistc[ed after 5 days of diazepam and oxazepam treatment respectively, the increased activity of GAD a n d / o r decreased GABA-T activities attained control range very rapidly (on the 6th day) in case of both diazepam and oxazepam. Similarly the increased value of G A D / G A B A - T rapidly reduced tocontrol range. Conclusion: The enzyme GAD and GABA-T regulate in an overall manner the dynamic equilibrium of GABA at the synapse and hence the 'GABAergic activity' ((Tapia et al., 1975; Kihara et al., 1988). In addition, the ratio of rate of synthesis to breakdown of GABA (i.e. GAD/GABA-T) may also gives an indication of endogenous steady state level of GABA at synapse. Results obtained indicate that during discontinuation of diazepam "GABAergic activity' remained elevated for a longer period but reduced to control range much earlier in case of oxazepam. Furthermore, the observed rapid reduction of the elevated "GABAergic activity' in presence of the antagonist Ro15-1788 fur, her supports the idea of the involvement of GABAergic mechanism in BDZ withdrawal reactions. References Lucks, S.E. and R.R. Grfffiths, 1982, Science 217, ii61. Tapia, R., M.-E. Sandoval and P. Contreras, 1975, J. Neurochem. 24, 1283. Kihara, M., Y. Misu and T. Kubo, 1988, Life Sci. 42, 1817.
I P.th.382 1
Effect of peripheral administration of cinnarizine and verapamil on diazepam withdrawal hyperactivity in rats Chugh, Y., Saha, N., S a ~ a r a n a r a y a n a n , A. and Sharma, P.L. Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012. India
Benzodiazepines represent a class of compounds widely recognized and prescribed for their beneficial effects in a variety of neurological states including anxiety, sleep and seizure disorders (Haefely et al., 1985). However. the benzodiazepines and related structures acting through atleast two distinct receptor types, possess a number of activities whereby they influence the cellular function. One of these activities which is receiving renewed attention is the regulation of calcium mobilization. If benzodiazepines do exert any part of their activity on calcium mobilization process, including calcium channels there will be wide ranging pharmacological implications. Evidence has shown the potential role of calcium channel blockers in morphine (Baeyens et al., 1987) and alcohol dependance. The present study was designed to observe the effect of calcium channel blockers (verapamil and cinnarizine) on diazepam wihdrawal symptoms. Rats were made diazepam dependent by chronic treatment with daily injections of the drug (20 mg/kg, i.p., for 3 wks). The injections were made daily between 9 a.m. and 10 a.m. On abrupt termination of the drug, the animals showed withdrawal hyperactivity, that was assessed by various autonomic, behavioural and motor parameters. Autonomic parameters evaluated included: piloerection and blanching of ears. The behavioural parameters included: struggle response, irritability and startle response. Motor parameters tested were: ear twitches, tail erection, posture, movement and spontaneous locomotor activity. The parameters were graded from 0-3 with the grade of 3 indicating the maximum intensity. The peak withdrawal effect was seen on the 3rd day after withdrawal of diazepam. On i.p. administration, verapamil and cinnarizine (10, 20, and 40 mg/kg) given twice daily at an interval of 12 hrs reversed the different withdrawal signs to varying degrees. In suppressing the motor and autonomic signs,
cinnarizine was effecti"e at all the dose levels used. However among the behavioural signs only the highest dose of c/nn:u'/z/ne (40 mg/kg) was effective in suppressing the struggle response and startle response (tactile-evoked) On the other hand verapamil was not as effective as cinnarizine in preventing the withdrawal signs. Spontaneous motor activity wag significantly reduced only at 40 mg/kg dose level while tail ezection, posture and i~ov:.ment of the animal did not show any significant change as compared to control animals. Among the behavioural signs, only the starti~ t,esponse (auditory-evoked) was effected at 40 mg/kg dose level. These results sugg~t that modulation of calci~Lm influx in the CNS might influence the b,:nTx~diazepine-induced withdrawal phenomena. References Haefely, W., Kyburz, E., Gerecke, M. and Mohler, H., 1985, Adv. Drug. Res. 14, 165. Baeyens, J.M., Esposito, E., Ossowska, G. and Samanin, R., 1987, Eur. J. Pharmacol. 137, 9.
Effect of acute and trained exercise on time course of cholinesterase activity in RBC and tissues of rat after physostigmine administration Dube, S.N. and Somani, S.M. Department of PharmacoloD,. S~,utkc.,~ Illinois Uni,.,ersity, School of Medicine, P. 0. Box 19230, Springfiel~ IL 62794-9230, U.S.A.
Physostigmine (Phy) and its analogues have been shown to improve memory function in Alzheimer's patients, and also a potential pretreatment agent against organophosphates. We have recently reported that different levels of acute exercise modify the effect of Phy by increasing the ChE inhibition in RBC and brain without affecting other tissues (Dube et al., 1989)~ Somani and Khalique (1986, 1987) have previously reported the pharmacokinetics and pharmacodynamics of Phy in rat after i.v., i.m. and oral administration. This presentation describes the interactive effects of acute exercise (AE), endurance training (ET) and Phy on time course of ChE activity in RBC and tissues of rat. Male Sprague-Dawley rats were disC:led into six groups (each consisting of 4-8 rats): Gr31, sedentary control; Gr.ll, acute exercise (80% VO2 max), Gr.lU endurance training; Gr.IV, 3H-Phy (70 g/kg, i.m.); Gr.V, acute exercise + 3H-Phy and Gr.Vl, endurance training +3H-Phy. Rats from Gr.lll and Gr.VI were trained for 6 weeks (5 days per week) at progressive intensive levels on a 9 channel motor-driven treadmill (built in SIU-SM workshop). Rats from Gr. II, IIL V and VI weze given acute bouts of exercise and were sacrificed at various time points (2-60 rain). RBC and tissues (brain, heart, diaphragm and thigh muscle) were analyzed for ChE enzyme activity by radiometric method. The results are shown below as percent of control ChE activity and also the effect of acute and trained exercise on rate of decarbamylation (K d) of ChE af',er Phy administration in RBC and tissues. Groups
Times (n~n)
RBC
Brain
Heart
Diaphragm
Muscle
il. AE llI. ET IV. Phy K d (rain - ! ) V. AE + Phy K d (rain- i ) VL ET + Phy K d (rain- ~)
2-30 5-60 2-60
114-95 66-76 72-79 0.0207 78-93 0.0239 70-71
91-97 96-92 85-78 0.0139 99-100 0.0252 75-63 0.0092
90-96 85-75 86-89 0.0185 79-101
97-95 85-78 90-81 0.0103 93-102 0.0396 81-68 0.0083
99-105 89-79 86-83 0.0126 81-80 0.0083 81-76 0.0116
2-60 2-60
71-73 0.0082
The percent gain in body weight was sinfilar in sedentary control as well as endurance trained group. It seems that acute exercise + Phy increased, whereas endurance training-~-Phy decreased the ChE activity in RBC and various tissues as compared to Phy alone. The percent ChE in.hibition was plotted on semilog graph to obtain the rate of decarbamylation of the enzyme. Acute exercise + Phy (Gr.V) decreased me half time of ChE recovery in RBC (29
I P.th.382 1
Effect of peripheral administration of cinnarizine and verapamil on diazepam withdrawal hyperactivity in rats Chugh, Y., Saha, N., S a ~ a r a n a r a y a n a n , A. and Sharma, P.L. Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012. India
Benzodiazepines represent a class of compounds widely recognized and prescribed for their beneficial effects in a variety of neurological states including anxiety, sleep and seizure disorders (Haefely et al., 1985). However. the benzodiazepines and related structures acting through atleast two distinct receptor types, possess a number of activities whereby they influence the cellular function. One of these activities which is receiving renewed attention is the regulation of calcium mobilization. If benzodiazepines do exert any part of their activity on calcium mobilization process, including calcium channels there will be wide ranging pharmacological implications. Evidence has shown the potential role of calcium channel blockers in morphine (Baeyens et al., 1987) and alcohol dependance. The present study was designed to observe the effect of calcium channel blockers (verapamil and cinnarizine) on diazepam wihdrawal symptoms. Rats were made diazepam dependent by chronic treatment with daily injections of the drug (20 mg/kg, i.p., for 3 wks). The injections were made daily between 9 a.m. and 10 a.m. On abrupt termination of the drug, the animals showed withdrawal hyperactivity, that was assessed by various autonomic, behavioural and motor parameters. Autonomic parameters evaluated included: piloerection and blanching of ears. The behavioural parameters included: struggle response, irritability and startle response. Motor parameters tested were: ear twitches, tail erection, posture, movement and spontaneous locomotor activity. The parameters were graded from 0-3 with the grade of 3 indicating the maximum intensity. The peak withdrawal effect was seen on the 3rd day after withdrawal of diazepam. On i.p. administration, verapamil and cinnarizine (10, 20, and 40 mg/kg) given twice daily at an interval of 12 hrs reversed the different withdrawal signs to varying degrees. In suppressing the motor and autonomic signs,
cinnarizine was effecti"e at all the dose levels used. However among the behavioural signs only the highest dose of c/nn:u'/z/ne (40 mg/kg) was effective in suppressing the struggle response and startle response (tactile-evoked) On the other hand verapamil was not as effective as cinnarizine in preventing the withdrawal signs. Spontaneous motor activity wag significantly reduced only at 40 mg/kg dose level while tail ezection, posture and i~ov:.ment of the animal did not show any significant change as compared to control animals. Among the behavioural signs, only the starti~ t,esponse (auditory-evoked) was effected at 40 mg/kg dose level. These results sugg~t that modulation of calci~Lm influx in the CNS might influence the b,:nTx~diazepine-induced withdrawal phenomena. References Haefely, W., Kyburz, E., Gerecke, M. and Mohler, H., 1985, Adv. Drug. Res. 14, 165. Baeyens, J.M., Esposito, E., Ossowska, G. and Samanin, R., 1987, Eur. J. Pharmacol. 137, 9.
Effect of acute and trained exercise on time course of cholinesterase activity in RBC and tissues of rat after physostigmine administration Dube, S.N. and Somani, S.M. Department of PharmacoloD,. S~,utkc.,~ Illinois Uni,.,ersity, School of Medicine, P. 0. Box 19230, Springfiel~ IL 62794-9230, U.S.A.
Physostigmine (Phy) and its analogues have been shown to improve memory function in Alzheimer's patients, and also a potential pretreatment agent against organophosphates. We have recently reported that different levels of acute exercise modify the effect of Phy by increasing the ChE inhibition in RBC and brain without affecting other tissues (Dube et al., 1989)~ Somani and Khalique (1986, 1987) have previously reported the pharmacokinetics and pharmacodynamics of Phy in rat after i.v., i.m. and oral administration. This presentation describes the interactive effects of acute exercise (AE), endurance training (ET) and Phy on time course of ChE activity in RBC and tissues of rat. Male Sprague-Dawley rats were disC:led into six groups (each consisting of 4-8 rats): Gr31, sedentary control; Gr.ll, acute exercise (80% VO2 max), Gr.lU endurance training; Gr.IV, 3H-Phy (70 g/kg, i.m.); Gr.V, acute exercise + 3H-Phy and Gr.Vl, endurance training +3H-Phy. Rats from Gr.lll and Gr.VI were trained for 6 weeks (5 days per week) at progressive intensive levels on a 9 channel motor-driven treadmill (built in SIU-SM workshop). Rats from Gr. II, IIL V and VI weze given acute bouts of exercise and were sacrificed at various time points (2-60 rain). RBC and tissues (brain, heart, diaphragm and thigh muscle) were analyzed for ChE enzyme activity by radiometric method. The results are shown below as percent of control ChE activity and also the effect of acute and trained exercise on rate of decarbamylation (K d) of ChE af',er Phy administration in RBC and tissues. Groups
Times (n~n)
RBC
Brain
Heart
Diaphragm
Muscle
il. AE llI. ET IV. Phy K d (rain - ! ) V. AE + Phy K d (rain- i ) VL ET + Phy K d (rain- ~)
2-30 5-60 2-60
114-95 66-76 72-79 0.0207 78-93 0.0239 70-71
91-97 96-92 85-78 0.0139 99-100 0.0252 75-63 0.0092
90-96 85-75 86-89 0.0185 79-101
97-95 85-78 90-81 0.0103 93-102 0.0396 81-68 0.0083
99-105 89-79 86-83 0.0126 81-80 0.0083 81-76 0.0116
2-60 2-60
71-73 0.0082
The percent gain in body weight was sinfilar in sedentary control as well as endurance trained group. It seems that acute exercise + Phy increased, whereas endurance training-~-Phy decreased the ChE activity in RBC and various tissues as compared to Phy alone. The percent ChE in.hibition was plotted on semilog graph to obtain the rate of decarbamylation of the enzyme. Acute exercise + Phy (Gr.V) decreased me half time of ChE recovery in RBC (29