- Email: [email protected]
Nifedipine potentiates the toxic effects of cocaine in mice
Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 357 – 362
Nifedipine potentiates the toxic effects of cocaine in mice Twum-Ampofo Ansaha,*, Littleton H. Wadeb, Prapaporn Kopsombuta, Dolores C. Shockleya a
Department of Pharmacology, Meharry Medical College, 1005 DB Todd Boulevard, Nashville, TN 37208, USA Department of Veterans Affairs, A.C. York Medical Center, Pathology and Laboratory Medical Services, Murfreesboro, TN, USA
b
Abstract The calcium channel blockers (CCBs) have been shown to be effective in attenuating the behavioral effects of cocaine in rodents and subjective effects in cocaine-using volunteers. There have been reports indicating that, in the presence of toxic doses of cocaine, the CCBs could actually potentiate cocaine toxicity in rats. The present study was undertaken to make toxicological assessment of the potentiating effect of CCBs in mice. Nifedipine and nimodipine dose-dependently increased the lethalities produced by 80 mg/kg cocaine. In the presence of 40 mg/kg nifedipine, the LD50 of cocaine was decreased from 80.7 to 66.3 mg/kg. Nifedipine potentiated cocaine toxicities in both ICR and Swiss – Webster mice. The increased toxicity was not accompanied by alterations in blood electrolytes. The mechanism of increased cocaine toxicity by CCBs remains to be determined. However, our results corroborate previous findings in rats and suggest that the possibility of an antidote exacerbating the toxic effects of cocaine has to be taken into consideration when screening for therapeutic agents. D 2001 Elsevier Science Inc. All rights reserved. Keywords: Calcium channel blockers; Cocaine; Lethal median dose; Mice; Nifedipine; Toxicity
1. Introduction Cocaine is a psychomotor stimulant, which is widely abused because of its euphoric effects (Johanson and Fischman, 1989; Kuhar et al., 1991). Though cocaine abuse continues to be a major health care problem, the availability of an effective pharmacotherapeutic agent remains elusive. Several preclinical studies using various models of addiction have provided evidence to suggest that the L-type calcium channel blockers (CCBs) may have potential in the pharmacotherapy of cocaine abuse. The CCBs belonging to the 1,4-dihydropyridine group such as nimodipine and isradipine have been shown to attenuate cocaine-induced motor behavior (Pani et al., 1990a,b; Rossetti et al., 1990; Ansah et al., 1993; Mills et al., 1998). Pani et al. (1991) reported that isradipine dose-dependently blocked cocaineinduced conditioned place preference. Nifedipine, another 1,4-dihydropyridine, was also effective in this paradigm (Suzuki et al., 1992; Biala and Langwinski, 1996). Although a recent study has indicated that nimodipine’s effect on conditioned place preference might have been confounded
Abbreviations: CCBs; calcium channel blockers * Corresponding author. E-mail address: [email protected] (T.-A. Ansah).
by the ability of nimodipine to produce conditioned place aversion (Martin-Iverson et al., 1997), other CCBs, namely isradipine (Calcagnetti and Schechter, 1993), nifedipine, flunarizine and diltiazem (Suzuki et al., 1992), have been found to be essentially neutral in conditioned place preference paradigms. Pretreatment of animals trained to discriminate between the stimulus of cocaine and its vehicle with nimodipine (Callahan and Cunningham, 1990) or isradipine (Schechter, 1993) attenuated cocaine-induced discriminative cue. In addition, the reinforcing effects of cocaine as measured by cocaine self-administration was significantly decreased by nimodipine (Kuzmin et al., 1992) and isradipine (Martellotta et al., 1994). To date, data on the beneficial effects of CCBs on cocaine dependence in humans have been equivocal. In 1991, Muntaner and coworkers (1991) showed that nifedipine pretreatment attenuated cocaine-induced increases in subjective effects in cocaine-dependent subjects. On the contrary, in a double-blind, placebo-controlled study examining the role of nimodipine in attenuating cocaine craving in cocainedependent patients, Rosse et al. (1994) found that nimodipine was not superior to placebo in reducing cocaine craving. However, it was noticed that the doses used were lower than equivalent doses reported to have suppressed cocaine selfadministration in laboratory animals (Kuzmin et al., 1992) and that higher doses could be tolerated by patients (Banger
0278-5846/02/$ – see front matter D 2001 Elsevier Science Inc. All rights reserved. PII: S 0 2 7 8 - 5 8 4 6 ( 0 1 ) 0 0 2 8 1 - 0
358
T.-A. Ansah et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 357–362
et al., 1992). More recently, it has been shown that a combination of isradipine and naltrexone, an opioid antagonist, is synergistic in blocking the enhancing effect of cocaine on rat intracranial stimulation (Pabello et al., 1998). This combination regimen has the advantage of allowing the use of small doses of isradipine. The effectiveness of this combination has not yet been tested in humans. In view of the fact that there is not yet an effective chemotherapeutic agent for cocaine addiction, the therapeutic potential of the CCBs continues to be of great interest. However, Ansah et al. (1993) and Derlet and Albertson (1989) have reported that in rats, cocaine toxicity can be potentiated by CCBs. In this study, we have done further toxicological assessment of the interaction of toxic doses of cocaine and nifedipine, a prototypical L-type CCB in mice.
(10 ml/kg). After 30 min, they were injected with saline and 0.5 ml of blood was collected from the sinus orbital with heparinized capillary tubes into eppendorf tubes and placed on ice. Similarly, the control for nifedipine (Group II) received 10% Tween 80. After 30 min, they were administered saline. Group III received saline prior to cocaine (80 mg/kg). Group IV received nifedipine (40 mg/kg) prior to saline and Group V received nifedipine prior to cocaine. The samples were collected within 5 min after cocaine or vehicle administration. The samples were centrifuged at 1500 rpm for 10 min and the plasma was collected and stored at 80 C until assayed. The concentrations of Na + , K + , Cl , Ca2 + and Mg2 + were determined using Ektachem 500 (Ortho-Johnson and Johnson, Newark, NJ) Clinical Chemistry Analyzer. 2.5. Statistical analysis
2. Methods 2.1. Animals Experimentally, naı¨ve male mice (ICR and Swiss –Webster) weighing 20 – 30 g were obtained from Harlan Sprague –Dawley (Indianapolis, IN). The mice were housed six per cage and maintained in a temperature-controlled room with a 12-h light/dark cycle (lights on at 07:00 h) and allowed free access to food and water. All animal experiments were performed during the same period of day. All animal experiments were conducted in accordance with guidelines of the Institutional Care and Use Committee at Meharry Medical College, provided by the National Institutes of Health. 2.2. Drugs Cocaine hydrochloride (Sigma, St. Louis, MO) and diltiazem hydrochloride (Marion Merrell Dow, Kansas City, MO) were dissolved in saline. Nimodipine (Miles, West Haven, CT) and nifedipine (Sigma) were dissolved in 10% Tween 80 (Sigma). All drugs were injected intraperitoneally in a volume of 10 ml/kg. 2.3. Cocaine-induced lethality Mice (n = 10/group) were injected intraperitoneally with vehicle (10 ml/kg 10% Tween 80) or CCBs (nifedipine, nimodipine and diltiazem). After 30 min, cocaine (60 – 120 mg/kg) was administered. Mice were observed for lethalities over a 24-h period. The number of lethalities at each dose of cocaine either in the presence or absence of CCBs was recorded. 2.4. Analysis of blood electrolytes Male ICR mice were divided into five groups (n = 5). The control for the cocaine group (Group I) received saline
The data on blood electrolytes were presented as the group means and the standard error of the mean (S.E.M.). Statistical analysis of the data was evaluated by using analysis of variance (ANOVA). The effects of the CCBs on cocaine-induced lethalities were analyzed using the c2 distribution. Differences were considered statistically significant when the statistical probability of error was less than .05 ( P < .05).
3. Results The doses of nifedipine used were based on dose – response experiments done by the authors and published data. The doses of CCBs and Tween 80 used in the study did not produce any observable effects in naı¨ve mice. As expected, cocaine-induced lethalities showed dose-dependence when the dose of cocaine was increased from 60 to 120 mg/kg. The LD50 of cocaine in ICR mice was 80.7 mg/kg (Fig. 1). In the presence of 40 mg/kg nifedipine, the LD50 of cocaine decreased to 66.3 mg/kg suggesting that nifedipine potentiated the toxicity of cocaine (Fig. 1). For example, 75 mg/kg cocaine caused 42% lethalities. In the presence of 40 mg/kg nifedipine, the proportion of lethalities increased to 70%. At a dose of cocaine (120 mg/kg) that produced 100% lethalities, the mean time of death was 6.53 ± 2.44 min (range = 2.5 –16.3 min). The time of death did not significantly change in the presence of 40 mg/kg nifedipine (6.98 ± 1.84 min; P > .05). The potentiating effect of nifedipine on cocaineinduced toxicity was dose-dependent (Fig. 2). Pretreatment of mice with 30 mg/kg nifedipine increased the percentage of mortalities produced by 80 mg/kg cocaine from 40% to 50%. At 40 mg/kg nifedipine, the percentage of lethalities was further increased to 80%. Since nifedipine is a 1,4-dihydropyridine that blocks L-type calcium channels, we investigated the effect of nimodipine, which belongs to this class of compounds and has similar pharmacological
T.-A. Ansah et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 357–362
Fig. 1. Probit transformation of percentage of mortalities produced by increasing concentrations of cocaine in ICR mice. Mice were administered vehicle (ip) (10% Tween 80; &) or 40 mg/kg nifedipine ( . ). After 30 min, mice were injected with cocaine (60 – 120 mg/kg) and the number of lethalities at each dose of cocaine was recorded. Ten mice were used at each dose of cocaine. The data of probit versus log dose of cocaine were analyzed by linear regression and LD50 was derived from probit 5.
.
effects. As shown in Fig. 3, nimodipine dose-dependently enhanced the toxicity of cocaine. The doses of nimodipine required were much lower than those of nifedipine, reflecting their relative potencies at blocking L-type calcium channels. To further ascertain whether the actions of nifedipine and nimodipine on cocaine-induced toxicity can be attributed to the blockade of L-type calcium channels, the effect of another L-type CCB with chemical structure different from that of the 1,4-dihydropyridines was used. Indeed, diltiazem, a benzothiazepine, also potentiated the lethal effects of cocaine. Diltazem (50 mg/kg) increased the percentage of mortalities of 70 mg/kg cocaine from 40% to 60%. Different strains of mice show marked differences in sensitivity to the acute effects of cocaine (Shuster et al., 1977; George and Ritz, 1991). We therefore investigated
Fig. 2. Dose-dependence of the potentiation of cocaine-induced lethalities by nifedipine. Mice, 10 per group, were pretreated with saline (cocaine control), 10% Tween 80 (nifedipine + cocaine control) or nifedipine. After 30 min, all the mice received 80 mg/kg cocaine and the number of lethalities was recorded. Asterisk indicates statistically significant difference when compared with control (* P < .05, Fisher’s Exact Test).
359
Fig. 3. Dose-dependence of the potentiation of cocaine-induced lethalities by nimodipine. Mice, 10 per group, were pretreated with saline (cocaine control), 10% Tween 80 (nimodipine + cocaine control) or nimodipine. After 30 min, all the mice received 80 mg/kg cocaine and the number of lethalities was recorded. Asterisk indicates statistically significant difference when compared with control (* P < .05, Fisher’s Exact Test).
whether strain differences will have an impact on the potentiation of the lethal effects of cocaine by nifedipine. Fig. 4 compares cocaine-induced mortalities in ICR and Swiss – Webster mice. The ICR mice were more sensitive to the toxic effects of cocaine than the Swiss – Webster mice. The LD50 of cocaine in ICR mice was lower (80.7 mg/kg) than that in Swiss – Webster mice (112.9 mg/kg). At
Fig. 4. Comparison of the effects of nifedipine on cocaine-induced mortalities in ICR mice (A) and Swiss – Webster mice (B). Mice (10 per group) were pretreated with nifedipine (40 mg/kg). After 30 min, they were injected with the indicated doses of cocaine. Asterisks indicate statistically significant difference from respective controls (* P < .05, Fisher’s Exact Test).
360
T.-A. Ansah et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 357–362
Table 1 Blood electrolytes of ICR mice after drug treatment Treatment
Sodium (mmol/l)
Potassium (mmol/l)
Chloride (mmol/l)
Calcium (mg/dl)
Magnesium (mg/dl)
Saline Tween 80 Nifedipine Cocaine Nifedipine + cocaine
150.2 ± 1.8 145.8 ± 2.3 143.3 ± 0.7 149.3 ± 1.5 143.7 ± 0.7
7.3 ± 0.4 7.2 ± 0.8 7.3 ± 0.4 8.0 ± 0.8 7.5 ± 0.5
117.2 ± 1.1 112.8 ± 2.9 108.0 ± 1.1 118.5 ± 2.1 109.0 ± 1.5
8.3 ± 0.3 9.3 ± 0.4 9.6 ± 0.5 8.9 ± 0.3 9.7 ± 0.7
2.1 ± 0.1 2.1 ± 0.2 2.4 ± 0.1 2.2 ± 0.1 2.2 ± 0.2
ICR mice (five per group) were treated as described in Section 2. The dose of nifedipine was 40 mg/kg and that of cocaine was 80 mg/kg. Blood samples were collected within 5 min of cocaine administration. Data are represented as mean ± S.E.M. ANOVA revealed no drug effects.
80 mg/kg, cocaine did not produce lethalities in Swiss – Webster mice. By contrast, the same dose of cocaine produced 40% mortalities in ICR mice. Pretreatment with 40 mg/kg nifedipine potentiated the lethal effects of cocaine in both strains of mice. In the Swiss – Webster mice, a dose of cocaine (80 mg/kg) that was otherwise nonlethal produced 20% lethalities in the presence of nifedipine. It also appeared that the potentiating effect of nifedipine on cocaine-induced toxicity was greater in ICR mice than in Swiss –Webster mice (Fig. 4). Since cocaine has powerful effects on the cardiovascular system (Welder et al., 1993), we determined if changes in blood electrolyte balance could contribute to the increased cocaine toxicity produced by the CCBs. Table 1 shows no differences in plasma electrolyte concentrations after drug treatment. However, the possibility of alterations in tissue levels of calcium or other ions cannot be ruled out.
4. Discussion 4.1. CCBs and cocaine effects The CCBs have been shown to be effective in attenuating the behavioral effects of cocaine in rodents (Pani et al., 1990a; Ansah et al.,1993; Biala and Langwinski, 1996; Kuzmin et al., 1992; Martellotta et al.,1994). In humans, the CCBs appear to attenuate the acute subjective effects of intravenously administered cocaine (Muntaner et al., 1991), but not cocaine craving in cocaine-dependent patients (Rosse et al., 1994). There have been reports suggesting a protection against the cardiac and lethal toxicity of cocaine during simultaneous constant infusion of cocaine and the CCB, nitrendipine in rats (Trouve and Nahas, 1986). Using a different experimental paradigm, Ansah et al. (1993) and Derlet and Albertson (1989) have shown that on the contrary, pretreatment of rats with the CCBs diltiazem, nifedipine, verapamil, nimodipine and nitrendipine potentiated the lethal toxicities of intraperitoneally administered cocaine. The current study in the mouse model corroborates our previous findings of enhanced cocaine-induced toxicity by CCBs. Pretreatment of mice with nifedipine lowered the LD50 of cocaine from 80.7 to 66.3 mg/kg. The doses of CCBs used were either lower than (nifedipine and nimodipine) or
similar to (diltiazem) doses previously reported to decrease amphetamine-induced behavioral activity (Grebb, 1986) or to suppress cocaine intravenous self-administration (Kuzmin et al., 1992) in mice. Potentiation of the lethal toxicities of cocaine by nifedipine and nimodipine was dose-dependent. In addition, nimodipine appeared to be more potent than nifedipine. In view of the fact that nimodipine has a higher affinity for L-type calcium channels than nifedipine (Scriabine et al., 1989), it can be concluded that the potentiation of cocaine toxicity by nifedipine and nimodipine is mediated by L-type calcium channels. Although ICR mice were more sensitive (LD50 = 80.7 mg/kg) to the toxic effects of cocaine than Swiss – Webster mice (LD50 = 113 mg/kg), potentiation of the lethal effects of cocaine by nifedipine was observed in both strains of mice. It is worth noting that the LD50 values obtained in this study are similar to those reported recently in Swiss – Webster mice (Gasior et al., 2000; Miller et al., 2000). Thus, doses of the CCBs shown to block the behavioral effects of cocaine can also potentiate the toxic effects of cocaine. This occurs only when the doses of cocaine are high enough to cause convulsions (Ansah et al., 1993) or lethalities (Ansah et al., 1993, this study). 4.2. Mechanism of potentiation of cocaine-induced toxicity by CCBs The mechanism of the enhanced toxicities of cocaine by CCBs is unknown. Our studies failed to show that alterations in electrolyte balance could be a contributing factor. CCBs are mainly used for the treatment of cardiovascular diseases because of their potent vasodilator effect (Bonaduce et al., 1983). Vasodilation induced by CCBs leading to enhanced delivery of cocaine to cerebral tissues has been suggested (Derlet and Albertson, 1989), although no direct evidence exists at the moment. The neurotoxic effect of cocaine is multifactorial, many aspects of which can be impacted by CCBs. Cocaine produces a number of central nervous system-mediated toxic effects such as hyperthermia, seizures and respiratory dysfunction (Tella et al., 1992). Peripherally, toxic doses of cocaine can produce a variety of cardiovascular complications including angina, acute myocardial ischemia, cardiac arrhythmias and myocarditis (Welder et al., 1993). It is possible that under these conditions, the negative inotropic effects of CCBs could exacerbate the cardiotoxic effects of cocaine.
T.-A. Ansah et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 357–362
Despite intensive search for specific drug therapies, there is still no uniformly effective medication for the acute neurotoxic effects of cocaine. Agents that have been identified to afford significant protection against cocaineinduced lethalities include inhibitors of adrenergic neurotransmission (Derlet and Albertson, 1990a; Tella et al., 1992), diazepam (Derlet and Albertson, 1990b), the dopamine D1 antagonist, SCH 23390 (Derlet et al., 1990) N-methyl-D-aspartate antagonists (Witkin et al., 1999), antagonists of 5HT2 receptors (O’Dell et al., 2000) and the GABAergic anticonvulsant, chlormethiazole (Gasior et al., 2000). The varied possible therapeutic agents being studied underscores the complexity of the mechanism of cocaine toxicity. Our data suggesting a potentiating effect of CCBs on cocaine toxicity present a potential avenue of cocaine toxicity that needs further study. In addition, our data demonstrate that the possibility of an antidote exacerbating the toxic effects of cocaine has to be taken into consideration when screening for therapeutic agents.
5. Conclusion The LD50 of cocaine in ICR mice was decreased in the presence of nifedipine. The potentiating effect of nifedipine and nimodipine on cocaine toxicity was dose-dependent. It was also shown that whereas ICR mice were more sensitive to the toxic effects of cocaine than Swiss – Webster mice, nifedipine was capable of potentiating the toxic effects of cocaine in the two strains of mice. Though the antagonistic properties of the CCBs on the behavioral effects of cocaine are well documented, the possibility of exacerbation of cocaine toxicities by the agents needs to be considered.
Acknowledgments This work was supported by a grant from the National Institute on Drug Abuse (DA06686). The authors wish to thank Marion (diltiazem) and Miles (nimodipine) for the generous gift of drugs.
References Ansah, T.-A., Wade, L.H., Shockley, D.C., 1993. Effects of calcium channel entry blockers on cocaine and amphetamine-induced motor activities and toxicities. Life Sci. 53, 1947 – 1956. Banger, M., Benkert, O., Roschke, J., 1992. Nimodipine in acute alcohol withdrawal state. J. Psychiatr. Res. 26, 117 – 123. Biala, G., Langwinski, R., 1996. Effects of calcium channel antagonists on the reinforcing properties of morphine, ethanol and cocaine as measured by place conditioning. J. Physiol. Pharmacol. 47, 497 – 502. Bonaduce, D., Ferrara, N., Petretta, M., Romano, E., Postiglione, M., 1983. Hemodynamic study of nifedipine administration in hypertensive patients. Am. Heart J. 105, 865 – 867. Calcagnetti, D.J., Schechter, M.D., 1993. Extinction of cocaine-induced
361
place approach in rats: a validation of the ‘‘biased’’ conditioning procedure. Brain Res. Bull. 30, 695 – 700. Callahan, P.M., Cunningham, K.A., 1990. The discriminative-stimulus properties of cocaine: effects of BAY K 8644 and nimodipine. Eur. J. Pharmacol. 186, 143 – 147. Derlet, R.W., Albertson, T.E., 1989. Potentiation of cocaine toxicity with calcium channel blockers. Am. J. Emerg. Med. 7, 464 – 468. Derlet, R.W., Albertson, T.E., 1990a. Acute cocaine toxicity: antagonism by agents interacting with adrenoceptors. Pharmacol., Biochem. Behav. 36, 225 – 231. Derlet, R.W., Albertson, T.E., 1990b. Antagonism of cocaine, amphetamine, and methamphetamine toxicity. Pharmacol., Biochem. Behav. 36, 745 – 749. Derlet, R.W., Albertson, T.E., Rice, P., 1990. The effect of SCH 23390 against toxic doses of cocaine, D-amphetamine and methamphetamine. Life Sci. 47, 821 – 827. Gasior, M., Ungard, J.T., Witkin, J.M., 2000. Chlormethiazole: effectiveness against toxic effects of cocaine in mice. J. Pharmacol. Exp. Ther. 295, 153 – 161. George, F.R., Ritz, M.C., 1991. Cocaine produces locomotor stimulation in SS/Ibg but not LS/Ibg mice. Psychopharmacology 101, 18 – 22. Grebb, J.A., 1986. Nifedipine and flunarizine block amphetamine-induced behavioral stimulation in mice. Life Sci. 38, 2375 – 2381. Johanson, C.-E., Fischman, M.W., 1989. The pharmacology of cocaine related to its abuse. Pharmacol. Rev. 41, 3 – 52. Kuhar, M., Ritz, M., Boja, J., 1991. The dopamine hypothesis of the reinforcing properties of cocaine. Trends Neurosci. 14, 299 – 302. Kuzmin, A., Zvartau, E., Gessa, G.L., Martellotta, M.C., Fratta, W., 1992. Calcium antagonists isradipine and nimodipine suppress cocaine and morphine intravenous self-administration in drug-naı¨ve mice. Pharmacol., Biochem. Behav. 41, 497 – 500. Martellotta, M.C., Kuzmin, A., Muglia, P., Gessa, G.L., Fratta, W., 1994. Effects of the calcium antagonist isradipine on cocaine intravenous selfadministration in rats. Psychopharmacology 113, 378 – 380. Martin-Iverson, M.T., Reimer, A.R., Sharma, S., 1997. Unbiased cocaine conditioned place preferences (CPP) obscures conditioned locomotion, and nimodipine blockade of cocaine CPP is due to conditioned place aversions. Psychopharmacology 130, 327 – 333. Miller, K.A., Witkin, J.M., Ungard, J.T., Gasior, M., 2000. Pharmacological and behavioral characterization of cocaine-kindled seizures in mice. Psychopharmacology 148, 74 – 82. Mills, K., Ansah, T.-A., Ali, S.F., Shockley, D.C., 1998. Calcium channel antagonist isradipine attenuates cocaine-induced motor activity in rats: correlation with brain monoamine levels. Ann. N.Y. Acad. Sci. 844, 201 – 207. Muntaner, C., Kumor, K.M., Nagoshi, C., Jaffe, J.H., 1991. Effects of nifedipine pretreatment on subjective and cardiovascular responses to intravenous cocaine in humans. Psychopharmacology 105, 37 – 41. O’Dell, L.E., Kreifeldt, M.J., George, F.R., Ritz, M.C., 2000. The role of serotonin2 receptors in mediating cocaine-induced convulsions. Pharmacol., Biochem. Behav. 65, 677 – 681. Pabello, N.G., Hubbell, C.L., Cavallaro, C.A., Barringer, T.M., Mendez, J.J., Reid, L.D., 1998. Responding for rewarding brain stimulation: cocaine and isradipine plus naltrexone. Pharmacol., Biochem. Behav. 61, 181 – 192. Pani, L., Carboni, S., Kuzmin, A.V., Gessa, G.L., Rossetti, Z.L., 1990a. Nimodipine inhibits cocaine-induced dopamine release and motor stimulation. Eur. J. Pharmacol. 176, 245 – 246. Pani, L., Kuzmin, A., Diana, M., De-Montis, G., Gessa, G.L., Rossetti, Z.L., 1990b. Calcium receptor antagonists modify cocaine effects in the central nervous system differently. Eur. J. Pharmacol. 190, 217 – 221. Pani, L., Kuzmin, A., Martellotta, M.C., Gessa, G.L., Fratta, W., 1991. The calcium antagonist PN 200-110 inhibits the reinforcing properties of cocaine. Brain Res. Bull. 26, 445 – 447. Rosse, R.B., Alim, T.N., Fay-McCarthy, M., Collins, J.P., 1994. Nimodipine pharmacotherapeutic adjuvant therapy for inpatient treatment of cocaine dependence. Clin. Neuropharmacol. 17, 348 – 358.
362
T.-A. Ansah et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 357–362
Rossetti, Z.L., Pani, L., Kuzmin, A., Carboni, S., Gessa, G.L., 1990. Dihydropyridine calcium antagonists prevent cocaine, but not amphetamine-, induced dopamine release and motor activity in rats. Acta Physiol. Hung. 75, 249 – 250. Schechter, M.D., 1993. Cocaine discrimination is attenuated by isradipine and CGS 10746B. Pharmacol., Biochem. Behav. 44, 661 – 664. Scriabine, A., Schuurman, T., Taber, J., 1989. Pharmacological basis for the use of nimodipine in central nervous system disorders. FASEB J. 3, 1799 – 1806. Shuster, L., Yu, G., Bates, A., 1977. Sensitization to cocaine stimulation in mice. Psychopharmacology 52, 185 – 190. Suzuki, T., Shiozaki, Y., Masukawa, Y., Misawa, M., 1992. Effects of
calcium antagonists on cocaine- and methamphetamine-induced conditioned place preference. Jpn. J. Alcohol Drug Depend. 27, 81 – 90. Tella, S.R., Korupolu, G.R., Schindler, C.W., Goldberg, S.R., 1992. Pathophysiological and pharmacological mechanisms of acute cocaine toxicity in conscious rats. J. Pharmacol. Exp. Ther. 262, 936 – 946. Trouve, R., Nahas, G., 1986. Nitrendipine: an antidote to cardiac and lethal toxicity of cocaine. Exp. Biol. Med. 183, 392 – 397. Welder, A.A., Grammas, P., Melchert, R.B., 1993. Cellular mechanisms of cocaine cardiotoxicity. Toxicol. Lett. 69, 227 – 238. Witkin, J.M., Gasior, M., Heifets, B., Tortella, F.C., 1999. Anticonvulsant efficacy of N-methyl-D-aspartate antagonists against convulsions induced by cocaine. J. Pharmacol. Exp. Ther. 289, 703 – 711.
Nifedipine potentiates the toxic effects of cocaine in mice Twum-Ampofo Ansaha,*, Littleton H. Wadeb, Prapaporn Kopsombuta, Dolores C. Shockleya a
Department of Pharmacology, Meharry Medical College, 1005 DB Todd Boulevard, Nashville, TN 37208, USA Department of Veterans Affairs, A.C. York Medical Center, Pathology and Laboratory Medical Services, Murfreesboro, TN, USA
b
Abstract The calcium channel blockers (CCBs) have been shown to be effective in attenuating the behavioral effects of cocaine in rodents and subjective effects in cocaine-using volunteers. There have been reports indicating that, in the presence of toxic doses of cocaine, the CCBs could actually potentiate cocaine toxicity in rats. The present study was undertaken to make toxicological assessment of the potentiating effect of CCBs in mice. Nifedipine and nimodipine dose-dependently increased the lethalities produced by 80 mg/kg cocaine. In the presence of 40 mg/kg nifedipine, the LD50 of cocaine was decreased from 80.7 to 66.3 mg/kg. Nifedipine potentiated cocaine toxicities in both ICR and Swiss – Webster mice. The increased toxicity was not accompanied by alterations in blood electrolytes. The mechanism of increased cocaine toxicity by CCBs remains to be determined. However, our results corroborate previous findings in rats and suggest that the possibility of an antidote exacerbating the toxic effects of cocaine has to be taken into consideration when screening for therapeutic agents. D 2001 Elsevier Science Inc. All rights reserved. Keywords: Calcium channel blockers; Cocaine; Lethal median dose; Mice; Nifedipine; Toxicity
1. Introduction Cocaine is a psychomotor stimulant, which is widely abused because of its euphoric effects (Johanson and Fischman, 1989; Kuhar et al., 1991). Though cocaine abuse continues to be a major health care problem, the availability of an effective pharmacotherapeutic agent remains elusive. Several preclinical studies using various models of addiction have provided evidence to suggest that the L-type calcium channel blockers (CCBs) may have potential in the pharmacotherapy of cocaine abuse. The CCBs belonging to the 1,4-dihydropyridine group such as nimodipine and isradipine have been shown to attenuate cocaine-induced motor behavior (Pani et al., 1990a,b; Rossetti et al., 1990; Ansah et al., 1993; Mills et al., 1998). Pani et al. (1991) reported that isradipine dose-dependently blocked cocaineinduced conditioned place preference. Nifedipine, another 1,4-dihydropyridine, was also effective in this paradigm (Suzuki et al., 1992; Biala and Langwinski, 1996). Although a recent study has indicated that nimodipine’s effect on conditioned place preference might have been confounded
Abbreviations: CCBs; calcium channel blockers * Corresponding author. E-mail address: [email protected] (T.-A. Ansah).
by the ability of nimodipine to produce conditioned place aversion (Martin-Iverson et al., 1997), other CCBs, namely isradipine (Calcagnetti and Schechter, 1993), nifedipine, flunarizine and diltiazem (Suzuki et al., 1992), have been found to be essentially neutral in conditioned place preference paradigms. Pretreatment of animals trained to discriminate between the stimulus of cocaine and its vehicle with nimodipine (Callahan and Cunningham, 1990) or isradipine (Schechter, 1993) attenuated cocaine-induced discriminative cue. In addition, the reinforcing effects of cocaine as measured by cocaine self-administration was significantly decreased by nimodipine (Kuzmin et al., 1992) and isradipine (Martellotta et al., 1994). To date, data on the beneficial effects of CCBs on cocaine dependence in humans have been equivocal. In 1991, Muntaner and coworkers (1991) showed that nifedipine pretreatment attenuated cocaine-induced increases in subjective effects in cocaine-dependent subjects. On the contrary, in a double-blind, placebo-controlled study examining the role of nimodipine in attenuating cocaine craving in cocainedependent patients, Rosse et al. (1994) found that nimodipine was not superior to placebo in reducing cocaine craving. However, it was noticed that the doses used were lower than equivalent doses reported to have suppressed cocaine selfadministration in laboratory animals (Kuzmin et al., 1992) and that higher doses could be tolerated by patients (Banger
0278-5846/02/$ – see front matter D 2001 Elsevier Science Inc. All rights reserved. PII: S 0 2 7 8 - 5 8 4 6 ( 0 1 ) 0 0 2 8 1 - 0
358
T.-A. Ansah et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 357–362
et al., 1992). More recently, it has been shown that a combination of isradipine and naltrexone, an opioid antagonist, is synergistic in blocking the enhancing effect of cocaine on rat intracranial stimulation (Pabello et al., 1998). This combination regimen has the advantage of allowing the use of small doses of isradipine. The effectiveness of this combination has not yet been tested in humans. In view of the fact that there is not yet an effective chemotherapeutic agent for cocaine addiction, the therapeutic potential of the CCBs continues to be of great interest. However, Ansah et al. (1993) and Derlet and Albertson (1989) have reported that in rats, cocaine toxicity can be potentiated by CCBs. In this study, we have done further toxicological assessment of the interaction of toxic doses of cocaine and nifedipine, a prototypical L-type CCB in mice.
(10 ml/kg). After 30 min, they were injected with saline and 0.5 ml of blood was collected from the sinus orbital with heparinized capillary tubes into eppendorf tubes and placed on ice. Similarly, the control for nifedipine (Group II) received 10% Tween 80. After 30 min, they were administered saline. Group III received saline prior to cocaine (80 mg/kg). Group IV received nifedipine (40 mg/kg) prior to saline and Group V received nifedipine prior to cocaine. The samples were collected within 5 min after cocaine or vehicle administration. The samples were centrifuged at 1500 rpm for 10 min and the plasma was collected and stored at 80 C until assayed. The concentrations of Na + , K + , Cl , Ca2 + and Mg2 + were determined using Ektachem 500 (Ortho-Johnson and Johnson, Newark, NJ) Clinical Chemistry Analyzer. 2.5. Statistical analysis
2. Methods 2.1. Animals Experimentally, naı¨ve male mice (ICR and Swiss –Webster) weighing 20 – 30 g were obtained from Harlan Sprague –Dawley (Indianapolis, IN). The mice were housed six per cage and maintained in a temperature-controlled room with a 12-h light/dark cycle (lights on at 07:00 h) and allowed free access to food and water. All animal experiments were performed during the same period of day. All animal experiments were conducted in accordance with guidelines of the Institutional Care and Use Committee at Meharry Medical College, provided by the National Institutes of Health. 2.2. Drugs Cocaine hydrochloride (Sigma, St. Louis, MO) and diltiazem hydrochloride (Marion Merrell Dow, Kansas City, MO) were dissolved in saline. Nimodipine (Miles, West Haven, CT) and nifedipine (Sigma) were dissolved in 10% Tween 80 (Sigma). All drugs were injected intraperitoneally in a volume of 10 ml/kg. 2.3. Cocaine-induced lethality Mice (n = 10/group) were injected intraperitoneally with vehicle (10 ml/kg 10% Tween 80) or CCBs (nifedipine, nimodipine and diltiazem). After 30 min, cocaine (60 – 120 mg/kg) was administered. Mice were observed for lethalities over a 24-h period. The number of lethalities at each dose of cocaine either in the presence or absence of CCBs was recorded. 2.4. Analysis of blood electrolytes Male ICR mice were divided into five groups (n = 5). The control for the cocaine group (Group I) received saline
The data on blood electrolytes were presented as the group means and the standard error of the mean (S.E.M.). Statistical analysis of the data was evaluated by using analysis of variance (ANOVA). The effects of the CCBs on cocaine-induced lethalities were analyzed using the c2 distribution. Differences were considered statistically significant when the statistical probability of error was less than .05 ( P < .05).
3. Results The doses of nifedipine used were based on dose – response experiments done by the authors and published data. The doses of CCBs and Tween 80 used in the study did not produce any observable effects in naı¨ve mice. As expected, cocaine-induced lethalities showed dose-dependence when the dose of cocaine was increased from 60 to 120 mg/kg. The LD50 of cocaine in ICR mice was 80.7 mg/kg (Fig. 1). In the presence of 40 mg/kg nifedipine, the LD50 of cocaine decreased to 66.3 mg/kg suggesting that nifedipine potentiated the toxicity of cocaine (Fig. 1). For example, 75 mg/kg cocaine caused 42% lethalities. In the presence of 40 mg/kg nifedipine, the proportion of lethalities increased to 70%. At a dose of cocaine (120 mg/kg) that produced 100% lethalities, the mean time of death was 6.53 ± 2.44 min (range = 2.5 –16.3 min). The time of death did not significantly change in the presence of 40 mg/kg nifedipine (6.98 ± 1.84 min; P > .05). The potentiating effect of nifedipine on cocaineinduced toxicity was dose-dependent (Fig. 2). Pretreatment of mice with 30 mg/kg nifedipine increased the percentage of mortalities produced by 80 mg/kg cocaine from 40% to 50%. At 40 mg/kg nifedipine, the percentage of lethalities was further increased to 80%. Since nifedipine is a 1,4-dihydropyridine that blocks L-type calcium channels, we investigated the effect of nimodipine, which belongs to this class of compounds and has similar pharmacological
T.-A. Ansah et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 357–362
Fig. 1. Probit transformation of percentage of mortalities produced by increasing concentrations of cocaine in ICR mice. Mice were administered vehicle (ip) (10% Tween 80; &) or 40 mg/kg nifedipine ( . ). After 30 min, mice were injected with cocaine (60 – 120 mg/kg) and the number of lethalities at each dose of cocaine was recorded. Ten mice were used at each dose of cocaine. The data of probit versus log dose of cocaine were analyzed by linear regression and LD50 was derived from probit 5.
.
effects. As shown in Fig. 3, nimodipine dose-dependently enhanced the toxicity of cocaine. The doses of nimodipine required were much lower than those of nifedipine, reflecting their relative potencies at blocking L-type calcium channels. To further ascertain whether the actions of nifedipine and nimodipine on cocaine-induced toxicity can be attributed to the blockade of L-type calcium channels, the effect of another L-type CCB with chemical structure different from that of the 1,4-dihydropyridines was used. Indeed, diltiazem, a benzothiazepine, also potentiated the lethal effects of cocaine. Diltazem (50 mg/kg) increased the percentage of mortalities of 70 mg/kg cocaine from 40% to 60%. Different strains of mice show marked differences in sensitivity to the acute effects of cocaine (Shuster et al., 1977; George and Ritz, 1991). We therefore investigated
Fig. 2. Dose-dependence of the potentiation of cocaine-induced lethalities by nifedipine. Mice, 10 per group, were pretreated with saline (cocaine control), 10% Tween 80 (nifedipine + cocaine control) or nifedipine. After 30 min, all the mice received 80 mg/kg cocaine and the number of lethalities was recorded. Asterisk indicates statistically significant difference when compared with control (* P < .05, Fisher’s Exact Test).
359
Fig. 3. Dose-dependence of the potentiation of cocaine-induced lethalities by nimodipine. Mice, 10 per group, were pretreated with saline (cocaine control), 10% Tween 80 (nimodipine + cocaine control) or nimodipine. After 30 min, all the mice received 80 mg/kg cocaine and the number of lethalities was recorded. Asterisk indicates statistically significant difference when compared with control (* P < .05, Fisher’s Exact Test).
whether strain differences will have an impact on the potentiation of the lethal effects of cocaine by nifedipine. Fig. 4 compares cocaine-induced mortalities in ICR and Swiss – Webster mice. The ICR mice were more sensitive to the toxic effects of cocaine than the Swiss – Webster mice. The LD50 of cocaine in ICR mice was lower (80.7 mg/kg) than that in Swiss – Webster mice (112.9 mg/kg). At
Fig. 4. Comparison of the effects of nifedipine on cocaine-induced mortalities in ICR mice (A) and Swiss – Webster mice (B). Mice (10 per group) were pretreated with nifedipine (40 mg/kg). After 30 min, they were injected with the indicated doses of cocaine. Asterisks indicate statistically significant difference from respective controls (* P < .05, Fisher’s Exact Test).
360
T.-A. Ansah et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 357–362
Table 1 Blood electrolytes of ICR mice after drug treatment Treatment
Sodium (mmol/l)
Potassium (mmol/l)
Chloride (mmol/l)
Calcium (mg/dl)
Magnesium (mg/dl)
Saline Tween 80 Nifedipine Cocaine Nifedipine + cocaine
150.2 ± 1.8 145.8 ± 2.3 143.3 ± 0.7 149.3 ± 1.5 143.7 ± 0.7
7.3 ± 0.4 7.2 ± 0.8 7.3 ± 0.4 8.0 ± 0.8 7.5 ± 0.5
117.2 ± 1.1 112.8 ± 2.9 108.0 ± 1.1 118.5 ± 2.1 109.0 ± 1.5
8.3 ± 0.3 9.3 ± 0.4 9.6 ± 0.5 8.9 ± 0.3 9.7 ± 0.7
2.1 ± 0.1 2.1 ± 0.2 2.4 ± 0.1 2.2 ± 0.1 2.2 ± 0.2
ICR mice (five per group) were treated as described in Section 2. The dose of nifedipine was 40 mg/kg and that of cocaine was 80 mg/kg. Blood samples were collected within 5 min of cocaine administration. Data are represented as mean ± S.E.M. ANOVA revealed no drug effects.
80 mg/kg, cocaine did not produce lethalities in Swiss – Webster mice. By contrast, the same dose of cocaine produced 40% mortalities in ICR mice. Pretreatment with 40 mg/kg nifedipine potentiated the lethal effects of cocaine in both strains of mice. In the Swiss – Webster mice, a dose of cocaine (80 mg/kg) that was otherwise nonlethal produced 20% lethalities in the presence of nifedipine. It also appeared that the potentiating effect of nifedipine on cocaine-induced toxicity was greater in ICR mice than in Swiss –Webster mice (Fig. 4). Since cocaine has powerful effects on the cardiovascular system (Welder et al., 1993), we determined if changes in blood electrolyte balance could contribute to the increased cocaine toxicity produced by the CCBs. Table 1 shows no differences in plasma electrolyte concentrations after drug treatment. However, the possibility of alterations in tissue levels of calcium or other ions cannot be ruled out.
4. Discussion 4.1. CCBs and cocaine effects The CCBs have been shown to be effective in attenuating the behavioral effects of cocaine in rodents (Pani et al., 1990a; Ansah et al.,1993; Biala and Langwinski, 1996; Kuzmin et al., 1992; Martellotta et al.,1994). In humans, the CCBs appear to attenuate the acute subjective effects of intravenously administered cocaine (Muntaner et al., 1991), but not cocaine craving in cocaine-dependent patients (Rosse et al., 1994). There have been reports suggesting a protection against the cardiac and lethal toxicity of cocaine during simultaneous constant infusion of cocaine and the CCB, nitrendipine in rats (Trouve and Nahas, 1986). Using a different experimental paradigm, Ansah et al. (1993) and Derlet and Albertson (1989) have shown that on the contrary, pretreatment of rats with the CCBs diltiazem, nifedipine, verapamil, nimodipine and nitrendipine potentiated the lethal toxicities of intraperitoneally administered cocaine. The current study in the mouse model corroborates our previous findings of enhanced cocaine-induced toxicity by CCBs. Pretreatment of mice with nifedipine lowered the LD50 of cocaine from 80.7 to 66.3 mg/kg. The doses of CCBs used were either lower than (nifedipine and nimodipine) or
similar to (diltiazem) doses previously reported to decrease amphetamine-induced behavioral activity (Grebb, 1986) or to suppress cocaine intravenous self-administration (Kuzmin et al., 1992) in mice. Potentiation of the lethal toxicities of cocaine by nifedipine and nimodipine was dose-dependent. In addition, nimodipine appeared to be more potent than nifedipine. In view of the fact that nimodipine has a higher affinity for L-type calcium channels than nifedipine (Scriabine et al., 1989), it can be concluded that the potentiation of cocaine toxicity by nifedipine and nimodipine is mediated by L-type calcium channels. Although ICR mice were more sensitive (LD50 = 80.7 mg/kg) to the toxic effects of cocaine than Swiss – Webster mice (LD50 = 113 mg/kg), potentiation of the lethal effects of cocaine by nifedipine was observed in both strains of mice. It is worth noting that the LD50 values obtained in this study are similar to those reported recently in Swiss – Webster mice (Gasior et al., 2000; Miller et al., 2000). Thus, doses of the CCBs shown to block the behavioral effects of cocaine can also potentiate the toxic effects of cocaine. This occurs only when the doses of cocaine are high enough to cause convulsions (Ansah et al., 1993) or lethalities (Ansah et al., 1993, this study). 4.2. Mechanism of potentiation of cocaine-induced toxicity by CCBs The mechanism of the enhanced toxicities of cocaine by CCBs is unknown. Our studies failed to show that alterations in electrolyte balance could be a contributing factor. CCBs are mainly used for the treatment of cardiovascular diseases because of their potent vasodilator effect (Bonaduce et al., 1983). Vasodilation induced by CCBs leading to enhanced delivery of cocaine to cerebral tissues has been suggested (Derlet and Albertson, 1989), although no direct evidence exists at the moment. The neurotoxic effect of cocaine is multifactorial, many aspects of which can be impacted by CCBs. Cocaine produces a number of central nervous system-mediated toxic effects such as hyperthermia, seizures and respiratory dysfunction (Tella et al., 1992). Peripherally, toxic doses of cocaine can produce a variety of cardiovascular complications including angina, acute myocardial ischemia, cardiac arrhythmias and myocarditis (Welder et al., 1993). It is possible that under these conditions, the negative inotropic effects of CCBs could exacerbate the cardiotoxic effects of cocaine.
T.-A. Ansah et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 357–362
Despite intensive search for specific drug therapies, there is still no uniformly effective medication for the acute neurotoxic effects of cocaine. Agents that have been identified to afford significant protection against cocaineinduced lethalities include inhibitors of adrenergic neurotransmission (Derlet and Albertson, 1990a; Tella et al., 1992), diazepam (Derlet and Albertson, 1990b), the dopamine D1 antagonist, SCH 23390 (Derlet et al., 1990) N-methyl-D-aspartate antagonists (Witkin et al., 1999), antagonists of 5HT2 receptors (O’Dell et al., 2000) and the GABAergic anticonvulsant, chlormethiazole (Gasior et al., 2000). The varied possible therapeutic agents being studied underscores the complexity of the mechanism of cocaine toxicity. Our data suggesting a potentiating effect of CCBs on cocaine toxicity present a potential avenue of cocaine toxicity that needs further study. In addition, our data demonstrate that the possibility of an antidote exacerbating the toxic effects of cocaine has to be taken into consideration when screening for therapeutic agents.
5. Conclusion The LD50 of cocaine in ICR mice was decreased in the presence of nifedipine. The potentiating effect of nifedipine and nimodipine on cocaine toxicity was dose-dependent. It was also shown that whereas ICR mice were more sensitive to the toxic effects of cocaine than Swiss – Webster mice, nifedipine was capable of potentiating the toxic effects of cocaine in the two strains of mice. Though the antagonistic properties of the CCBs on the behavioral effects of cocaine are well documented, the possibility of exacerbation of cocaine toxicities by the agents needs to be considered.
Acknowledgments This work was supported by a grant from the National Institute on Drug Abuse (DA06686). The authors wish to thank Marion (diltiazem) and Miles (nimodipine) for the generous gift of drugs.
References Ansah, T.-A., Wade, L.H., Shockley, D.C., 1993. Effects of calcium channel entry blockers on cocaine and amphetamine-induced motor activities and toxicities. Life Sci. 53, 1947 – 1956. Banger, M., Benkert, O., Roschke, J., 1992. Nimodipine in acute alcohol withdrawal state. J. Psychiatr. Res. 26, 117 – 123. Biala, G., Langwinski, R., 1996. Effects of calcium channel antagonists on the reinforcing properties of morphine, ethanol and cocaine as measured by place conditioning. J. Physiol. Pharmacol. 47, 497 – 502. Bonaduce, D., Ferrara, N., Petretta, M., Romano, E., Postiglione, M., 1983. Hemodynamic study of nifedipine administration in hypertensive patients. Am. Heart J. 105, 865 – 867. Calcagnetti, D.J., Schechter, M.D., 1993. Extinction of cocaine-induced
361
place approach in rats: a validation of the ‘‘biased’’ conditioning procedure. Brain Res. Bull. 30, 695 – 700. Callahan, P.M., Cunningham, K.A., 1990. The discriminative-stimulus properties of cocaine: effects of BAY K 8644 and nimodipine. Eur. J. Pharmacol. 186, 143 – 147. Derlet, R.W., Albertson, T.E., 1989. Potentiation of cocaine toxicity with calcium channel blockers. Am. J. Emerg. Med. 7, 464 – 468. Derlet, R.W., Albertson, T.E., 1990a. Acute cocaine toxicity: antagonism by agents interacting with adrenoceptors. Pharmacol., Biochem. Behav. 36, 225 – 231. Derlet, R.W., Albertson, T.E., 1990b. Antagonism of cocaine, amphetamine, and methamphetamine toxicity. Pharmacol., Biochem. Behav. 36, 745 – 749. Derlet, R.W., Albertson, T.E., Rice, P., 1990. The effect of SCH 23390 against toxic doses of cocaine, D-amphetamine and methamphetamine. Life Sci. 47, 821 – 827. Gasior, M., Ungard, J.T., Witkin, J.M., 2000. Chlormethiazole: effectiveness against toxic effects of cocaine in mice. J. Pharmacol. Exp. Ther. 295, 153 – 161. George, F.R., Ritz, M.C., 1991. Cocaine produces locomotor stimulation in SS/Ibg but not LS/Ibg mice. Psychopharmacology 101, 18 – 22. Grebb, J.A., 1986. Nifedipine and flunarizine block amphetamine-induced behavioral stimulation in mice. Life Sci. 38, 2375 – 2381. Johanson, C.-E., Fischman, M.W., 1989. The pharmacology of cocaine related to its abuse. Pharmacol. Rev. 41, 3 – 52. Kuhar, M., Ritz, M., Boja, J., 1991. The dopamine hypothesis of the reinforcing properties of cocaine. Trends Neurosci. 14, 299 – 302. Kuzmin, A., Zvartau, E., Gessa, G.L., Martellotta, M.C., Fratta, W., 1992. Calcium antagonists isradipine and nimodipine suppress cocaine and morphine intravenous self-administration in drug-naı¨ve mice. Pharmacol., Biochem. Behav. 41, 497 – 500. Martellotta, M.C., Kuzmin, A., Muglia, P., Gessa, G.L., Fratta, W., 1994. Effects of the calcium antagonist isradipine on cocaine intravenous selfadministration in rats. Psychopharmacology 113, 378 – 380. Martin-Iverson, M.T., Reimer, A.R., Sharma, S., 1997. Unbiased cocaine conditioned place preferences (CPP) obscures conditioned locomotion, and nimodipine blockade of cocaine CPP is due to conditioned place aversions. Psychopharmacology 130, 327 – 333. Miller, K.A., Witkin, J.M., Ungard, J.T., Gasior, M., 2000. Pharmacological and behavioral characterization of cocaine-kindled seizures in mice. Psychopharmacology 148, 74 – 82. Mills, K., Ansah, T.-A., Ali, S.F., Shockley, D.C., 1998. Calcium channel antagonist isradipine attenuates cocaine-induced motor activity in rats: correlation with brain monoamine levels. Ann. N.Y. Acad. Sci. 844, 201 – 207. Muntaner, C., Kumor, K.M., Nagoshi, C., Jaffe, J.H., 1991. Effects of nifedipine pretreatment on subjective and cardiovascular responses to intravenous cocaine in humans. Psychopharmacology 105, 37 – 41. O’Dell, L.E., Kreifeldt, M.J., George, F.R., Ritz, M.C., 2000. The role of serotonin2 receptors in mediating cocaine-induced convulsions. Pharmacol., Biochem. Behav. 65, 677 – 681. Pabello, N.G., Hubbell, C.L., Cavallaro, C.A., Barringer, T.M., Mendez, J.J., Reid, L.D., 1998. Responding for rewarding brain stimulation: cocaine and isradipine plus naltrexone. Pharmacol., Biochem. Behav. 61, 181 – 192. Pani, L., Carboni, S., Kuzmin, A.V., Gessa, G.L., Rossetti, Z.L., 1990a. Nimodipine inhibits cocaine-induced dopamine release and motor stimulation. Eur. J. Pharmacol. 176, 245 – 246. Pani, L., Kuzmin, A., Diana, M., De-Montis, G., Gessa, G.L., Rossetti, Z.L., 1990b. Calcium receptor antagonists modify cocaine effects in the central nervous system differently. Eur. J. Pharmacol. 190, 217 – 221. Pani, L., Kuzmin, A., Martellotta, M.C., Gessa, G.L., Fratta, W., 1991. The calcium antagonist PN 200-110 inhibits the reinforcing properties of cocaine. Brain Res. Bull. 26, 445 – 447. Rosse, R.B., Alim, T.N., Fay-McCarthy, M., Collins, J.P., 1994. Nimodipine pharmacotherapeutic adjuvant therapy for inpatient treatment of cocaine dependence. Clin. Neuropharmacol. 17, 348 – 358.
362
T.-A. Ansah et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 357–362
Rossetti, Z.L., Pani, L., Kuzmin, A., Carboni, S., Gessa, G.L., 1990. Dihydropyridine calcium antagonists prevent cocaine, but not amphetamine-, induced dopamine release and motor activity in rats. Acta Physiol. Hung. 75, 249 – 250. Schechter, M.D., 1993. Cocaine discrimination is attenuated by isradipine and CGS 10746B. Pharmacol., Biochem. Behav. 44, 661 – 664. Scriabine, A., Schuurman, T., Taber, J., 1989. Pharmacological basis for the use of nimodipine in central nervous system disorders. FASEB J. 3, 1799 – 1806. Shuster, L., Yu, G., Bates, A., 1977. Sensitization to cocaine stimulation in mice. Psychopharmacology 52, 185 – 190. Suzuki, T., Shiozaki, Y., Masukawa, Y., Misawa, M., 1992. Effects of
calcium antagonists on cocaine- and methamphetamine-induced conditioned place preference. Jpn. J. Alcohol Drug Depend. 27, 81 – 90. Tella, S.R., Korupolu, G.R., Schindler, C.W., Goldberg, S.R., 1992. Pathophysiological and pharmacological mechanisms of acute cocaine toxicity in conscious rats. J. Pharmacol. Exp. Ther. 262, 936 – 946. Trouve, R., Nahas, G., 1986. Nitrendipine: an antidote to cardiac and lethal toxicity of cocaine. Exp. Biol. Med. 183, 392 – 397. Welder, A.A., Grammas, P., Melchert, R.B., 1993. Cellular mechanisms of cocaine cardiotoxicity. Toxicol. Lett. 69, 227 – 238. Witkin, J.M., Gasior, M., Heifets, B., Tortella, F.C., 1999. Anticonvulsant efficacy of N-methyl-D-aspartate antagonists against convulsions induced by cocaine. J. Pharmacol. Exp. Ther. 289, 703 – 711.