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EVIDENCE FOR ANTIAGGRESSIVE PROPERTY OF SOME CALCIUM CHANNEL BLOCKERS
Pharmacological Research, Vol. 35, No. 5, 1997
EVIDENCE FOR ANTIAGGRESSIVE PROPERTY OF SOME CALCIUM CHANNEL BLOCKERS S. K. SRIVASTAVA*, C. NATH† and J. N. SINHA† Department of Pharmacology, P. S. Medical College Karamsad, Kheda 388 325, India and †Department of Pharmacology, K. G.’s Medical College Lucknow, 226 066, India Accepted 17 February 1997 The effect of calcium channel blockers on foot shock induced (aggression (FSA) were studied in mice. Verapamil, (10, 20 and 40 mg kg−1 i.p.) diltiazem (20 and 40 mg kg−1 i.p.) and nifedipine (25 and 50 mg kg−1 i.p.) significantly reduced fighting episodes. Diltiazem and nifedipine blocked the amphetamine induced facilitation of FSA, while verapamil blocked both amphetamine as well as physostigmine induced facilitation of FSA. These findings suggest that calcium channel blockers possess potent antiaggressive activity, which may be attributed to decrease in central dopaminergic and/or cholinergic mechanism. 1997 The Italian Pharmacological Research KEY WORDS: Foot shock aggression, calcium channel blockers, amphetamine, physostigmine, verapamil.
INTRODUCTION
MATERIALS AND METHODS
It has been reported that calcium is involved in neuronal activities and calcium channel as well as specific binding sites for calcium channel blockers (CCB) are present in the animal as well as human brain [1]. Several biochemical and binding studies have shown that CCB alter synthesis, release and neuronal uptake of various neurotransmitters in the central nervous system (CNS). Nimodipine inhibited catecholamine synthesis in mouse brain [2]. Diltiazem inhibited norepinephrine released from brain vesicular preparation [3]. It has been reported that Bay K 8644, a dihydropyridine calcium channel agonist increased the release of norepinephrine, choline and serotonin from rat brain slices which was blocked by nifedipine, verapamil and diltiazem [4, 5]. In the last few years behavioural effects of CCB have been reported [6, 7]. The anticonvulsant properties of CCB [8] and analgesic activity including interaction with opioid system have been studied extensively [9]. The involvement of central neurotransmitters in the foot shock aggression is well established. Both inhibitory and facilitatory central neurotransmitters systems to foot shock aggression have been reported [10]. The present study was conducted to determine the effect of calcium channel blockers on aggressive behaviour in mice.
The study was conducted on male Swiss albino mice weighing 20–30 g. The animals were fed and allowed water ad libitum. Aggression was produced by applying electroshock (2 mA at a frequency of 5 shocks S−1) for 1 minute to the feet of randomly selected pairs of mice in an aggressometer according to the method described by Anand et al. [11]. The pairs which showed at least three fighting counts during 1 min of foot shock exposure were included in the study. Six pairs were used for each dose of a drug. Each pair of mice was exposed to foot shock prior to (control) and 30 min after the drug administration. Fighting bouts were counted during the period of shock. Mean fighting counts were calculated for each group and significance of the difference between the mean values of different groups was determined by the Student’s ttest. A fighting episode was counted when the mice converged abruptly to close quarters, stood face to face on their hindlimb and sparred and bit each other. Return to the quadruped posture was taken as termination of the fighting episode. The following drugs were used in the study: verapamil (Boehringer-Knoll); diltiazem (Torrent), nifedipine (Torrent), amphetamine (Sigma) and physostigmine (Sigma). All the drugs were dissolved in normal saline except nifedipine where polyethylene glycol was used as a solvent. All drugs were administered by intraperitoneal (i.p.) route.
*To whom all correspondence should be addressed. 1043–6618/97/050435–04/$25·00/0/fr970149
1997 The Italian Pharmacological Society
436
Pharmacological Research, Vol. 35, No. 5, 1997
RESULTS
Effect of CCB on physostigmine induced facilitation of FSA
Effect of calcium channel blockers on foot shock aggression (FSA)
Verapamil in doses of 10, 20 and 40 mg kg−1 i.p. decreased significantly the fighting episodes in a dose dependent manner as compared to control (pretreatment) values. Significant decrease in fighting episode was also observed with diltiazem (20 and 40 mg kg−1 i.p.) and nifedipine (25 and 50 mg kg−1 i.p.) (Table I).
Facilitatory effect on FSA was also produced by physostigmine in a dose of 0·05 mg kg−1 intraperitoneally. This facilitatory effect of physostigmine was significantly blocked by verapamil (40 and 80 mg kg−1 i.p.) indicating a dose dependent inhibition but there was no reduction in fighting episode. Other calcium channel blockers diltiazem (40 mg kg−1 i.p.) and nifedipine (50 mg kg−1 i.p.) did not block the facilitatory effect of physostigmine (Table III).
Effect of CCB on amphetamine induced facilitation of FSA
DISCUSSION
Amphetamine in a dose of 5 mg kg−1 i.p. produced a significant increase of fighting behaviour. Verapamil (40 mg kg−1 i.p.) administered 30 min before amphetamine blocked its facilitatory effect and also reduced significantly the fighting episodes. Facilitatory effect of amphetamine was also significantly blocked by diltiazem (40 mg kg−1 i.p.) and nifedipine (50 mg kg−1 i.p.) indicating a dose dependent inhibition but fighting episode was not reduced (Table II).
Verapamil, diltiazem and nifedipine suppressed the aggression elicited by foot shock in mice. Inhibition of foot shock aggression by another calcium channel blocker nimodipine has been reported by Hoffmeister et al. [6]. The possible mechanism involved may be (a) analgesia (b) nonspecific depression of CNS or (c) modification of central neurotransmitter mechanism concerned in foot shock aggression. The first two
Table I Effect of calcium channel blockers on foot shock aggression (FSA) in mice Drugs
Dose (mg kg−1 i.p.)
1. 2. 3.
N.Saline Polyethylene glycol Verapamil
4.
Diltiazem
5.
Nifedipine
−1
5 ml kg 2 ml kg−1 10 20 40 10 20 40 25 50
Fighting episodes (Mean± SE) Pretreatment (control)
Post treatment
10·8±1·4 12·2±2·1 14·2±1·9 11·3±1·4 12·0±1·6 11·2±1·6 13·6±2·2 12·8±1·8 13·4±1·6 11·3±1·3
11·4±1·1 11·6±1·4 8·4±0·8* 5·2±0·9** 5·4±0·8** 9·8±1·1 7·8±1·2* 6·9±0·8** 8·6±1·4* 5·3±1·1**
*P<0·05, **P<0·01 Significant difference from control values.
Table II Effect of calcium channel blockers on amphetamine induced facilitation of FSA Drugs
1. 2. 3. 4.
Amphetamine Verapamil+ Amphetamine Diltiazem+ Amphetamine Nifedipine+ Amphetamine
Dose (mg kg−1 i.p.)
5 40 5 40 5 50 5
Fighting episodes (Mean± SE) Pretreatment (control)
Post treatment
10·2±1·4 13·4±1·8
18·4±2·2** 0·8±0·8*†
12·3±1·6
14·2±1·6†
12·4±1·8
11·2±1·3†
*P<0·05, **P<0·01 Significant difference from control values. †P<0·05 Significant difference from corresponding amphetamine values (amphetamine was given after 30 min).
Pharmacological Research, Vol. 35, No. 5, 1997
437
possibilities seem to be unlikely because these drugs are not potent analgesics and even the non-analgesic dose (10 mg mg−1 i.p.) of verapamil showed significant inhibition of foot shock aggression. These blockers have not produced any neurological deficit, and it is very unlikely that generalized depression of CNS should occur without any neurological deficit. There are several biochemical in vitro studies which show that calcium channel blockers inhibit the release of neurotransmitters [3, 12]. Central neurotransmitter mechanisms which enhance the aggression are dopaminergic [11, 13] as well as cholinergic [14]. Amphetamine facilitated the foot shock aggression and in order to elucidate the central neurotransmitter mechanism, calcium channel blockers were administered 30 min prior to amphetamine. All the three calcium channel antagonists blocked the facilitatory effect of amphetamine indicating that antiaggressive activity may be attributed to inhibition of dopamine release [12] as amphetamine facilitated FSA through dopaminergic mechanisms [15]. Besides, nimodipine has been shown to inhibit catecholamine synthesis in rat brain [2]. Furthermore, it has been reported that nifedipine blocked amphetamine induced hypermotility in mice [16]. Central cholinergic mechanism also enhances the foot shock aggression. Effects of CCB were studied on physostigmine induced facilitation of FSA. Physostigmine was preferred because it increases the synaptic level of acetylcholine by inhibiting acetylcholine esterase enzyme [17] and hence its action essentially depends upon the amount of acetylcholine released. Verapamil blocked the physostigmine induced facilitation of foot shock aggression. Failure of physostigmine to enhance aggression in verapamil pretreated animals may be attributed to decrease in the release of acetylcholine after the calcium channel blockade. This is in conformity with the biochemical [12] and in vitro studies [18]. Diltiazem and nifedipine did not block
physostigmine induced facilitation of FSA indicating that they do not affect the cholinergic mechanism. In view of the above results it may be concluded that calcium channel blockers possess potent antiaggressive activity, which may be attributed to decrease in central dopaminergic mechanism and at least in part due to decrease in cholinergic activity as only verapamil blocked physostigmine induced facilitation of FSA. This novel property of calcium channel blockers may be worth evaluating in neuropsychiatric disorders such as schizophrenia. Moreover, few clinical reports are available suggesting the use of calcium antagonists, particularly verapamil in maniac episodes [19, 20].
REFERENCES 1. Godfraind T, Miller R, Wibo M. Calcium antagonism and calcium entry blockade. Pharmacol Rev 1986; 38: 321–416. 2. Pileblad E, Carlsson A. The Ca2+ antagonist nimodipine decreases and the Ca2+ agonist Bay K 8644 increases catecholamine synthesis in mouse brain. Neuropharmacology 1987; 26: 101–5. 3. Ebstein RP, Daly JW. Release of norepinephrine and dopamine from brain vesicular preparation. Effect of calcium antagonists. Cell Mol Neurobiol 1982; 2: 205–13. 4. Middlemiss DN, Spedding M. A functional correlate for the dihydropyridine binding sites in rat brains. Nature 1905; 314: 94–6. 5. Middlemiss DN. The calcium channel activator Bay K 8644 enhances K+ evoked efflux of acetylcholine and noradrenaline from rat brain slices. Naunyn-Schmiedeberg’s Arch Pharmacol 1985; 331: 114–16. 6. Hoffmeister F, Benz U, Heise A, Krause HP, Neuser V. Behavioural effects of nimodipine in animals. Arzneim Forsch 1982; 32: 347–60. 7. Bolger GT, Weissman BA, Skolnick P. The behavioural effects of calcium agonist Bay K 8644 in the mouse: antagonism by the calcium antagonist nifedipine. Nau-
Table III Effect of calcium channel blockers on physostigmine induced facilitation of FSA Drugs
1. 2. 3. 4. 5. 6.
Physostigmine Verapamil+ Physostigmine Verapamil+ Physostigmine Verapamil+ Physostigmine Diltiazem+ Physostigmine Nifedipine+ Physostigmine
Dose (mg kg−1 i.p.)
0·05 20 0·05 40 0·05 80 0·05 40 0·05 50 0·05
Fighting episodes (Mean± SE) Pretreatment (control)
Post treatment
11·2±1·8 10·8±1·6
18·0±1·2** 17·4±2·6*
12·6±2·2
12·2±1·0†
12·5±1·7
8·7±1·1††
12·8±1·6
22·6±2·4**
11·4±1·4
18·4±1·3**
*P<0·05, **P<0·01 Significant difference from control values. †P<0·05, ††P<0·01 Significant difference from the corresponding Physostigmine values (Physostigmine was given after 30 min).
438
8. 9. 10. 11.
12.
13.
Pharmacological Research, Vol. 35, No. 5, 1997
nyn Schmiedeberg’s Arch Pharmacol 1985; 328: 373–7. De Sarro GB, Meldrum BS, Nistico G. Anti-convulsant effect of some calcium entry blockers in DBA/2 mice. Br J Pharmacol 1988; 96: 247–56. Del Pozo E, Caro G, Baeyens JM. Analgesic effect of several calcium channel blockers in mice. Eur J Pharmacol 1987; 137: 155–60. Pradhan SN. Aggression and central neurotransmitters. Int Rev Neurobiol 1975; 18: 213–62. Anand M, Gupta GP, Bhargava KP. Modification of electroshock fighting by drugs known to interact with dopaminergic and noradrenergic neurons in normal and brain lesioned rats. J Pharm Pharmacol 1977; 29: 437–9. Stark K, Spath L, Wickmam T. Effect of verapamil, diltiazem and ryosidine on the release of dopamine and acetylcholine in rabbit caudate nucleus slices. NaunynSchmiedeberg’s Arch Pharmacol 1984; 325: 124–30. Ammiraju C, Gupta GP, Bhargava KP. Pharmacological characterisation of central receptors in aggressive behaviour. In: Bradley PB, Dhawan BN (eds). Drugs
14.
15. 16. 17. 18. 19. 20.
and central synaptic transmission. London-Basingstoke: McMillan Press, 1976, pp. 203–90. Powel DA, Milligan WL, Walters K. The effect of muscarinic cholinergic blockade upon shock elicited aggression. Pharmacol Biochem Behav 1973; 1: 303–14. Rolinski Z. Analysis of aggressive-stereotypy complex induced in mice by amphetamine or hialamide and Ldopa. Pol J Pharmacol Pharm 1973; 25: 551–8. Grebb JA. Nifedipine and flunarizine block amphetamine induced behavioural stimulation in mice. Life Sci 1986; 38: 2375–81. Wilson JB, Hateh MA, Ginsburg S. Carbamylation of acetylcholinesterase. J Biol Chem 1961; 236: 2242–95. Wachtel RE. Effect of diltiazem and verapamil on responses to acetylcholine. Br J Pharmacol 1987; 92: 561–6. Giannini AJ, Houser WL, Loiselle RH, Giannini MC, Price WA. Antimaniac effect of verapamil. Am J Psychiatry 1984; 141: 1602–3. Dubovsky SL. Calcium antagonists in maniac depressive illness. Neuropsychobiology 1993; 27: 184–92.
EVIDENCE FOR ANTIAGGRESSIVE PROPERTY OF SOME CALCIUM CHANNEL BLOCKERS S. K. SRIVASTAVA*, C. NATH† and J. N. SINHA† Department of Pharmacology, P. S. Medical College Karamsad, Kheda 388 325, India and †Department of Pharmacology, K. G.’s Medical College Lucknow, 226 066, India Accepted 17 February 1997 The effect of calcium channel blockers on foot shock induced (aggression (FSA) were studied in mice. Verapamil, (10, 20 and 40 mg kg−1 i.p.) diltiazem (20 and 40 mg kg−1 i.p.) and nifedipine (25 and 50 mg kg−1 i.p.) significantly reduced fighting episodes. Diltiazem and nifedipine blocked the amphetamine induced facilitation of FSA, while verapamil blocked both amphetamine as well as physostigmine induced facilitation of FSA. These findings suggest that calcium channel blockers possess potent antiaggressive activity, which may be attributed to decrease in central dopaminergic and/or cholinergic mechanism. 1997 The Italian Pharmacological Research KEY WORDS: Foot shock aggression, calcium channel blockers, amphetamine, physostigmine, verapamil.
INTRODUCTION
MATERIALS AND METHODS
It has been reported that calcium is involved in neuronal activities and calcium channel as well as specific binding sites for calcium channel blockers (CCB) are present in the animal as well as human brain [1]. Several biochemical and binding studies have shown that CCB alter synthesis, release and neuronal uptake of various neurotransmitters in the central nervous system (CNS). Nimodipine inhibited catecholamine synthesis in mouse brain [2]. Diltiazem inhibited norepinephrine released from brain vesicular preparation [3]. It has been reported that Bay K 8644, a dihydropyridine calcium channel agonist increased the release of norepinephrine, choline and serotonin from rat brain slices which was blocked by nifedipine, verapamil and diltiazem [4, 5]. In the last few years behavioural effects of CCB have been reported [6, 7]. The anticonvulsant properties of CCB [8] and analgesic activity including interaction with opioid system have been studied extensively [9]. The involvement of central neurotransmitters in the foot shock aggression is well established. Both inhibitory and facilitatory central neurotransmitters systems to foot shock aggression have been reported [10]. The present study was conducted to determine the effect of calcium channel blockers on aggressive behaviour in mice.
The study was conducted on male Swiss albino mice weighing 20–30 g. The animals were fed and allowed water ad libitum. Aggression was produced by applying electroshock (2 mA at a frequency of 5 shocks S−1) for 1 minute to the feet of randomly selected pairs of mice in an aggressometer according to the method described by Anand et al. [11]. The pairs which showed at least three fighting counts during 1 min of foot shock exposure were included in the study. Six pairs were used for each dose of a drug. Each pair of mice was exposed to foot shock prior to (control) and 30 min after the drug administration. Fighting bouts were counted during the period of shock. Mean fighting counts were calculated for each group and significance of the difference between the mean values of different groups was determined by the Student’s ttest. A fighting episode was counted when the mice converged abruptly to close quarters, stood face to face on their hindlimb and sparred and bit each other. Return to the quadruped posture was taken as termination of the fighting episode. The following drugs were used in the study: verapamil (Boehringer-Knoll); diltiazem (Torrent), nifedipine (Torrent), amphetamine (Sigma) and physostigmine (Sigma). All the drugs were dissolved in normal saline except nifedipine where polyethylene glycol was used as a solvent. All drugs were administered by intraperitoneal (i.p.) route.
*To whom all correspondence should be addressed. 1043–6618/97/050435–04/$25·00/0/fr970149
1997 The Italian Pharmacological Society
436
Pharmacological Research, Vol. 35, No. 5, 1997
RESULTS
Effect of CCB on physostigmine induced facilitation of FSA
Effect of calcium channel blockers on foot shock aggression (FSA)
Verapamil in doses of 10, 20 and 40 mg kg−1 i.p. decreased significantly the fighting episodes in a dose dependent manner as compared to control (pretreatment) values. Significant decrease in fighting episode was also observed with diltiazem (20 and 40 mg kg−1 i.p.) and nifedipine (25 and 50 mg kg−1 i.p.) (Table I).
Facilitatory effect on FSA was also produced by physostigmine in a dose of 0·05 mg kg−1 intraperitoneally. This facilitatory effect of physostigmine was significantly blocked by verapamil (40 and 80 mg kg−1 i.p.) indicating a dose dependent inhibition but there was no reduction in fighting episode. Other calcium channel blockers diltiazem (40 mg kg−1 i.p.) and nifedipine (50 mg kg−1 i.p.) did not block the facilitatory effect of physostigmine (Table III).
Effect of CCB on amphetamine induced facilitation of FSA
DISCUSSION
Amphetamine in a dose of 5 mg kg−1 i.p. produced a significant increase of fighting behaviour. Verapamil (40 mg kg−1 i.p.) administered 30 min before amphetamine blocked its facilitatory effect and also reduced significantly the fighting episodes. Facilitatory effect of amphetamine was also significantly blocked by diltiazem (40 mg kg−1 i.p.) and nifedipine (50 mg kg−1 i.p.) indicating a dose dependent inhibition but fighting episode was not reduced (Table II).
Verapamil, diltiazem and nifedipine suppressed the aggression elicited by foot shock in mice. Inhibition of foot shock aggression by another calcium channel blocker nimodipine has been reported by Hoffmeister et al. [6]. The possible mechanism involved may be (a) analgesia (b) nonspecific depression of CNS or (c) modification of central neurotransmitter mechanism concerned in foot shock aggression. The first two
Table I Effect of calcium channel blockers on foot shock aggression (FSA) in mice Drugs
Dose (mg kg−1 i.p.)
1. 2. 3.
N.Saline Polyethylene glycol Verapamil
4.
Diltiazem
5.
Nifedipine
−1
5 ml kg 2 ml kg−1 10 20 40 10 20 40 25 50
Fighting episodes (Mean± SE) Pretreatment (control)
Post treatment
10·8±1·4 12·2±2·1 14·2±1·9 11·3±1·4 12·0±1·6 11·2±1·6 13·6±2·2 12·8±1·8 13·4±1·6 11·3±1·3
11·4±1·1 11·6±1·4 8·4±0·8* 5·2±0·9** 5·4±0·8** 9·8±1·1 7·8±1·2* 6·9±0·8** 8·6±1·4* 5·3±1·1**
*P<0·05, **P<0·01 Significant difference from control values.
Table II Effect of calcium channel blockers on amphetamine induced facilitation of FSA Drugs
1. 2. 3. 4.
Amphetamine Verapamil+ Amphetamine Diltiazem+ Amphetamine Nifedipine+ Amphetamine
Dose (mg kg−1 i.p.)
5 40 5 40 5 50 5
Fighting episodes (Mean± SE) Pretreatment (control)
Post treatment
10·2±1·4 13·4±1·8
18·4±2·2** 0·8±0·8*†
12·3±1·6
14·2±1·6†
12·4±1·8
11·2±1·3†
*P<0·05, **P<0·01 Significant difference from control values. †P<0·05 Significant difference from corresponding amphetamine values (amphetamine was given after 30 min).
Pharmacological Research, Vol. 35, No. 5, 1997
437
possibilities seem to be unlikely because these drugs are not potent analgesics and even the non-analgesic dose (10 mg mg−1 i.p.) of verapamil showed significant inhibition of foot shock aggression. These blockers have not produced any neurological deficit, and it is very unlikely that generalized depression of CNS should occur without any neurological deficit. There are several biochemical in vitro studies which show that calcium channel blockers inhibit the release of neurotransmitters [3, 12]. Central neurotransmitter mechanisms which enhance the aggression are dopaminergic [11, 13] as well as cholinergic [14]. Amphetamine facilitated the foot shock aggression and in order to elucidate the central neurotransmitter mechanism, calcium channel blockers were administered 30 min prior to amphetamine. All the three calcium channel antagonists blocked the facilitatory effect of amphetamine indicating that antiaggressive activity may be attributed to inhibition of dopamine release [12] as amphetamine facilitated FSA through dopaminergic mechanisms [15]. Besides, nimodipine has been shown to inhibit catecholamine synthesis in rat brain [2]. Furthermore, it has been reported that nifedipine blocked amphetamine induced hypermotility in mice [16]. Central cholinergic mechanism also enhances the foot shock aggression. Effects of CCB were studied on physostigmine induced facilitation of FSA. Physostigmine was preferred because it increases the synaptic level of acetylcholine by inhibiting acetylcholine esterase enzyme [17] and hence its action essentially depends upon the amount of acetylcholine released. Verapamil blocked the physostigmine induced facilitation of foot shock aggression. Failure of physostigmine to enhance aggression in verapamil pretreated animals may be attributed to decrease in the release of acetylcholine after the calcium channel blockade. This is in conformity with the biochemical [12] and in vitro studies [18]. Diltiazem and nifedipine did not block
physostigmine induced facilitation of FSA indicating that they do not affect the cholinergic mechanism. In view of the above results it may be concluded that calcium channel blockers possess potent antiaggressive activity, which may be attributed to decrease in central dopaminergic mechanism and at least in part due to decrease in cholinergic activity as only verapamil blocked physostigmine induced facilitation of FSA. This novel property of calcium channel blockers may be worth evaluating in neuropsychiatric disorders such as schizophrenia. Moreover, few clinical reports are available suggesting the use of calcium antagonists, particularly verapamil in maniac episodes [19, 20].
REFERENCES 1. Godfraind T, Miller R, Wibo M. Calcium antagonism and calcium entry blockade. Pharmacol Rev 1986; 38: 321–416. 2. Pileblad E, Carlsson A. The Ca2+ antagonist nimodipine decreases and the Ca2+ agonist Bay K 8644 increases catecholamine synthesis in mouse brain. Neuropharmacology 1987; 26: 101–5. 3. Ebstein RP, Daly JW. Release of norepinephrine and dopamine from brain vesicular preparation. Effect of calcium antagonists. Cell Mol Neurobiol 1982; 2: 205–13. 4. Middlemiss DN, Spedding M. A functional correlate for the dihydropyridine binding sites in rat brains. Nature 1905; 314: 94–6. 5. Middlemiss DN. The calcium channel activator Bay K 8644 enhances K+ evoked efflux of acetylcholine and noradrenaline from rat brain slices. Naunyn-Schmiedeberg’s Arch Pharmacol 1985; 331: 114–16. 6. Hoffmeister F, Benz U, Heise A, Krause HP, Neuser V. Behavioural effects of nimodipine in animals. Arzneim Forsch 1982; 32: 347–60. 7. Bolger GT, Weissman BA, Skolnick P. The behavioural effects of calcium agonist Bay K 8644 in the mouse: antagonism by the calcium antagonist nifedipine. Nau-
Table III Effect of calcium channel blockers on physostigmine induced facilitation of FSA Drugs
1. 2. 3. 4. 5. 6.
Physostigmine Verapamil+ Physostigmine Verapamil+ Physostigmine Verapamil+ Physostigmine Diltiazem+ Physostigmine Nifedipine+ Physostigmine
Dose (mg kg−1 i.p.)
0·05 20 0·05 40 0·05 80 0·05 40 0·05 50 0·05
Fighting episodes (Mean± SE) Pretreatment (control)
Post treatment
11·2±1·8 10·8±1·6
18·0±1·2** 17·4±2·6*
12·6±2·2
12·2±1·0†
12·5±1·7
8·7±1·1††
12·8±1·6
22·6±2·4**
11·4±1·4
18·4±1·3**
*P<0·05, **P<0·01 Significant difference from control values. †P<0·05, ††P<0·01 Significant difference from the corresponding Physostigmine values (Physostigmine was given after 30 min).
438
8. 9. 10. 11.
12.
13.
Pharmacological Research, Vol. 35, No. 5, 1997
nyn Schmiedeberg’s Arch Pharmacol 1985; 328: 373–7. De Sarro GB, Meldrum BS, Nistico G. Anti-convulsant effect of some calcium entry blockers in DBA/2 mice. Br J Pharmacol 1988; 96: 247–56. Del Pozo E, Caro G, Baeyens JM. Analgesic effect of several calcium channel blockers in mice. Eur J Pharmacol 1987; 137: 155–60. Pradhan SN. Aggression and central neurotransmitters. Int Rev Neurobiol 1975; 18: 213–62. Anand M, Gupta GP, Bhargava KP. Modification of electroshock fighting by drugs known to interact with dopaminergic and noradrenergic neurons in normal and brain lesioned rats. J Pharm Pharmacol 1977; 29: 437–9. Stark K, Spath L, Wickmam T. Effect of verapamil, diltiazem and ryosidine on the release of dopamine and acetylcholine in rabbit caudate nucleus slices. NaunynSchmiedeberg’s Arch Pharmacol 1984; 325: 124–30. Ammiraju C, Gupta GP, Bhargava KP. Pharmacological characterisation of central receptors in aggressive behaviour. In: Bradley PB, Dhawan BN (eds). Drugs
14.
15. 16. 17. 18. 19. 20.
and central synaptic transmission. London-Basingstoke: McMillan Press, 1976, pp. 203–90. Powel DA, Milligan WL, Walters K. The effect of muscarinic cholinergic blockade upon shock elicited aggression. Pharmacol Biochem Behav 1973; 1: 303–14. Rolinski Z. Analysis of aggressive-stereotypy complex induced in mice by amphetamine or hialamide and Ldopa. Pol J Pharmacol Pharm 1973; 25: 551–8. Grebb JA. Nifedipine and flunarizine block amphetamine induced behavioural stimulation in mice. Life Sci 1986; 38: 2375–81. Wilson JB, Hateh MA, Ginsburg S. Carbamylation of acetylcholinesterase. J Biol Chem 1961; 236: 2242–95. Wachtel RE. Effect of diltiazem and verapamil on responses to acetylcholine. Br J Pharmacol 1987; 92: 561–6. Giannini AJ, Houser WL, Loiselle RH, Giannini MC, Price WA. Antimaniac effect of verapamil. Am J Psychiatry 1984; 141: 1602–3. Dubovsky SL. Calcium antagonists in maniac depressive illness. Neuropsychobiology 1993; 27: 184–92.