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The effect of lamotrigine on naloxone-precipitated opiate withdrawal
Drug and Alcohol Dependence 52 (1998) 173 – 176
Brief communication
The effect of lamotrigine on naloxone-precipitated opiate withdrawal Marc I. Rosen *, H. Rowland Pearsall, Thomas R. Kosten Yale Uni6ersity, Department of Psychiatry, 34 Park Street, New Ha6en, CT 06519, USA Received 1 December 1997; accepted 16 March 1998
Abstract We hypothesized that lamotrigine, a putative glutamate release antagonist, would attenuate glutamate-mediated signs of opiate withdrawal. Seven heroin-dependent subjects were hospitalized, stabilized on oral levorphanol 6 mg three times daily, and thrice underwent withdrawal precipitated by naloxone 0.4 mg intravenously. Lamotrigine (placebo, 250 mg, and 500 mg) was randomly given as a pretreatment 6 h before naloxone. Lamotrigine did not significantly attenuate any measure of opiate withdrawal. Lamotrigine was well-tolerated in subjects, although one did develop an allergic rash. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Excitatory amino acid; Lamotrigine; Opioid; Withdrawal
1. Introduction Preclinically, excitatory amino acid (EAA) antagonists attenuate the development of morphine tolerance and dependence (Trujillo and Akil, 1990). Given acutely, EAA antagonists acting at both AMPA (Rasmussen et al., 1996) and NMDA (Higgins et al., 1992) receptors attenuate opiate withdrawal. A medication attenuating EAA release might attenuate NMDA- and AMPA-mediated activity without side effects associated with NMDA antagonists (Willets et al., 1990). Lamotrigine, a marketed anticonvulsant, acts presynaptically at voltage-gated sodium channels to attenuate both EAA release and repeated burst firing (Lang et al., 1993). Another sodium current modulator, diphenylhydantoin, reportedly attenuates opiate withdrawal in rats (Fertziger et al., 1974). Lamotrigine’s specific suppression of EAAs more than other neurotransmitters has been asserted (Lees and Leech, 1993) * Corresponding author. VA Connecticut Healthcare System, Psychiatry Service 116-A, Bldg. 1, 9th Floor, West Haven, CT 06516, USA. Tel.: +1 203 9325711.
and disputed (Waldmeier et al., 1995). Lamotrigine inhibits some EAA-mediated processes in rodents: prostaglandin-induced hyperalgesia (Nakamura-Craig and Follenfant, 1995), and behavioral and histological damage after focal cerebral ischemia (Wirard et al., 1995).
2. Methods Opioid-stabilized subjects underwent a double-blind acclimatization challenge with placebo lamotrigine followed by naloxone, 0.2 mg intravenously (i.v.). On 3 subsequent days, subjects received a block-randomized sequence of pretreatment with placebo, lamotrigine 250 mg, and lamotrigine 500 mg, followed by naloxone 0.4 mg per 70 kg i.v.. At least 96 h elapsed between challenges 2 and 3, and between challenges 3 and 4 to allow elimination of residual lamotrigine (Cohen et al., 1987). Data from seven heroin-dependent subjects were analyzed, including data from one who developed a rash the day after lamotrigine 500 mg and did not receive
0376-8716/98/$19.00 © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0376-8716(98)00057-X
174
M.I. Rosen et al. / Drug and Alcohol Dependence 52 (1998) 173–176
the 250 mg lamotrigine challenge. Six subjects were male: five were Caucasian and two African American. Mean age was 34 years (range 29 – 41). All used intravenous heroin (mean duration 4.4 years). Data were excluded from three other subjects who discontinued participation mid-study and one who discontinued due to lamotrigine (250 mg)-induced urticaria. Subjects gave voluntary informed consent and were paid for study participation.
Subjects underwent a comprehensive evaluation prior to enrollment. Opioid dependence was verified after hospitalization by withdrawal in response to intramuscular naloxone in 0.2 mg increments. Subjects were then stabilized on levorphanol 6 mg every 8 h and tapering doses of oxazepam. Challenges began after subjects reported ‘zero’ withdrawal for at least 1 day without oxazepam (7–14 days).
Fig. 1. Mean of withdrawal measures over time by lamotrigine pretreatment dose for six levorphanol-stabilized subjects. Placebo is indicated by open squares, 250 mg lamotrigine by open diamonds, and 500 mg lamotrigine by open circles. Lamotrigine was administered orally in divided doses 360 and 180 min prior to naloxone (NLX) 0.4 mg i.v. (time 0). Pre-NLX represents mean of measures between −20 and −10 min. Error bars indicate 9 S.E.M.
M.I. Rosen et al. / Drug and Alcohol Dependence 52 (1998) 173–176
175
Outcome measures included vital signs (Dinamap), skin temperature (YSI 4600 Precision Thermometer), a subject-rating of withdrawal severity on an anchored 100 mm visual analog scale (VAS), and observer-ratings, on a 0–4 scale, of 12 withdrawal signs. These were collected at times (in minutes), relative to naloxone, of −360, −20, − 15, − 10, +5, + 10, + 15, + 20, + 25, +30, + 40, + 50, +60. At − 360 and − 10, ratings on nine 0–4 anchored scales of 16 possible lamotrigine side effects were collected, and blood was collected in EDTA-treated tubes for determination of plasma lamotrigine levels at Harris Labs (Lincoln, NB). A time-resolved fluorescent immunoassay was used. A prior study (Rosen et al., 1996b) employing a precipitated withdrawal methodology, used almost identical screening procedures, withdrawal rating scales, and data analytic strategy.
2.1. Data analysis All measures were summarized as baseline change (difference between − 360 baseline and mean of − 20, − 15, and − 10); AUC change from baseline (− 360 as a time zero baseline) was calculated using the trapezoidal method, and then divided by 60 min. Summary values were analyzed in a one-factor repeated measures ANOVA with planned comparisons of each active lamotrigine dose to placebo. The acclimatization challenge was omitted. Univariate procedures and the Huynh–Feldt correction were used. Significance was defined as PB0.05; ‘9 ’ indicates standard error of the mean (S.E.M.).
3. Results
Fig. 2. Withdrawal by subject and lamotrigine dose. Withdrawal precipitated by naloxone in seven levorphanol-stabilized subjects by subject and lamotrigine pretreatment condition. Lamotrigine was administered orally in divided doses 360 and 180 min prior to naloxone 0.4 mg i.v. Withdrawal summarized as AUC post-naloxone divided by 60 min. Range of absolute values at a given time point was 0–100 for subject-rated withdrawal.
Subjects fasted overnight prior to challenges and were connected to an intravenous line. Lamotrigine (Lamictal) or placebo (lactose, USP), crushed and encapsulated, was administered in divided doses 6 and 3 h before naloxone was infused, over 1 min, at 14:00 h. Subjects received their scheduled levorphanol doses at 15:00 h.
Lamotrigine had little effect before naloxone. The mean total side effect change scores were only 2.2 9 1.2 for placebo, 2.7 90.9 for 250 mg, and 2.7 91.4 for 500 mg. The only symptoms for which the change score differed numerically by 0.5 between placebo and 500 mg of lamotrigine were ‘dizzy’ (higher by 0.72 with 500 mg) and ‘anxious’ (higher by 0.74). Mean lamotrigine levels at − 10 min were 22489 323 ng/ml after lamotrigine 250 mg and 37619339 ng/ml after lamotrigine 500 mg. The robust, rapid response to naloxone is indicated in Fig. 1. Lamotrigine had no significant effects on any measure of withdrawal severity. Fig. 2 suggests that overall withdrawal severity was relatively consistent within subjects across challenges, with little effect of lamotrigine.
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M.I. Rosen et al. / Drug and Alcohol Dependence 52 (1998) 173–176
4. Discussion Lamotrigine did not attenuate any measure of withdrawal. The lack of effect was consistent across subjects. None of the subjects who completed the study demonstrated dose-dependent attenuation of subjectrated or overall observer-rated withdrawal. The lamotrigine plasma levels we attained suppress interictal EEG spikes acutely (Jawad et al., 1986) and are anticonvulsant clinically (Brodie et al., 1995). However, lamotrigine’s anticonvulsant effects may not be EAA mediated (Waldmeier et al., 1995). Lamotrigine may insufficiently attenuate EAA release to attenuate withdrawal. An alternative explanation is that the repeated naloxone challenge paradigm may not be sensitive to subtle withdrawal-attenuating effects. The lack of sensitivity is not due to a ‘floor’ effect, as the paradigm produced robust, measurable withdrawal. For instance, the mean AUC change/60 in muscle twitches on placebo of 1.23 (Fig. 2) reflects an average of 1.23 twitches per 5-min period× 12 5-min periods per 60-min challenge (= 14 twitches/challenge). The paradigm has been used to demonstrate withdrawal attenuation by clonidine comparable to clonidine’s clinical profile (Rosen et al., 1996a) but did not demonstrate a previouslyreported attenuation by gamma-hydroxybutyric acid (Rosen et al., 1996b).
Acknowledgements This work was supported by NIDA grants P50DA09250 (T.R.K.), 1PO1DA08227 (T.R.K., E.J.N.), K20DA00191 (MIR). Burroughs-Wellcome funded Harris Laboratories (Lincoln, NB) to assay lamotrigine plasma levels.
References Brodie, M.J., Richens, A., Yuen, A.W.C. for UK Lamotrigine/Carbamazepine Monotherapy Trial Group, 1995. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. Lancet 345, 476–479.
.
Cohen, A., Land, G., Breimer, D., Yuen, W., Winton, C., Peck, A., 1987. Lamotrigine, a new anticonvulsant: pharmacokinetics in normal humans. Clin. Pharmacol. Ther. 42 (5), 535 – 541. Fertziger, A.P., Lynch, J.J., Stein, E., 1974. Modification of the morphine withdrawal syndrome in rats. Brain Res. 78, 331–334. Higgins, G.A., Nguyen, P., Sellers, E.M., 1992. The NMDA antagonist dizocilipine (MK801) attenuates motivational as well as somatic aspects of naloxone precipitated opioid withdrawal. Life Sci. 50, PL167 – PL172. Jawad, S., Oxley, J., Yuen, W.C., Richens, A., 1986. The effect of lamotrigine, a novel anticonvulsant, on interictal spikes in patients with epilepsy. Br. J. Clin. Pharmacol. 22, 191 – 193. Lang, D.G., Wang, C.M., Cooper, B.R., 1993. Lamotrigine, phenytoin and carbamazepine interactions on the sodium current present in N4TG1 mouse neuroblastoma cells. J. Pharmacol. Exp. Ther. 266 (2), 829 – 835. Lees, G., Leech, M.J., 1993. Studies on the mechanism of action of the novel anticonvulsant lamotrigine (Lamictal) using primary neuroglial cultures from rat cortex. Brain Res. 612, 190–199. Nakamura-Craig, M., Follenfant, R.L., 1995. Effect of lamotrigine in the acute and chronic hyperalgesia induced by PGE2 and in the chronic hyperalgesia in rats with streptozocin-induced diabetes. Pain 63, 33 – 37. Rasmussen, K., Kendrick, W.T., Kogan, J.H., Aghajanian, G.K., 1996. A selective AMPA antagonist, LY 293558, suppresses morphine withdrawal-induced activation of locus coeruleus neurons and behavioral signs of morphine withdrawal. Neuropsychopharmacology 15, 497 – 505. Rosen, M., McMahon, T.J., Hameedi, F.A., Pearsall, H.R., Woods, S., Kreek, M.J., Kosten, T., 1996a. Effect of clonidine pretreatment on naloxone-precipitated opiate withdrawal. J. Pharmacol. Exp. Ther. 276 (3), 1128 – 1135. Rosen, M., Pearsall, H., Woods, S., Kosten, T., 1996b. The effect of gamma-hydroxybutyric acid on naloxone-precipitated opiate withdrawal. Neuropsychopharmacology 14, 187 – 193. Trujillo, K.A., Akil, H., 1990. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 251, 85 – 87. Waldmeier, P.C., Baumann, P.A., Wicki, P., Feldtrauer, J.J., Stierlin, C., Schmutz, M., 1995. Similar potency of carbamazepine, oxcarbazepine, and lamotrigine in inhibiting the release of glutamate and other neurotransmitters. Neurology 45 (10), 1907 – 1913. Willets, J., Balster, R.L., Leander, J.D., 1990. The behavioral pharmacology of NMDA receptor antagonists. Trends Pharmacol. Sci. 11, 423 – 428. Wirard, R.P., Dickerson, M.C., Beck, O., Norton, R., Cooper, B.R., 1995. Neuroprotective properties of the novel antiepileptic lamotrigine in a gerbil model of global cerebral ischemia. Stroke 26 (3), 466 – 472.
Brief communication
The effect of lamotrigine on naloxone-precipitated opiate withdrawal Marc I. Rosen *, H. Rowland Pearsall, Thomas R. Kosten Yale Uni6ersity, Department of Psychiatry, 34 Park Street, New Ha6en, CT 06519, USA Received 1 December 1997; accepted 16 March 1998
Abstract We hypothesized that lamotrigine, a putative glutamate release antagonist, would attenuate glutamate-mediated signs of opiate withdrawal. Seven heroin-dependent subjects were hospitalized, stabilized on oral levorphanol 6 mg three times daily, and thrice underwent withdrawal precipitated by naloxone 0.4 mg intravenously. Lamotrigine (placebo, 250 mg, and 500 mg) was randomly given as a pretreatment 6 h before naloxone. Lamotrigine did not significantly attenuate any measure of opiate withdrawal. Lamotrigine was well-tolerated in subjects, although one did develop an allergic rash. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Excitatory amino acid; Lamotrigine; Opioid; Withdrawal
1. Introduction Preclinically, excitatory amino acid (EAA) antagonists attenuate the development of morphine tolerance and dependence (Trujillo and Akil, 1990). Given acutely, EAA antagonists acting at both AMPA (Rasmussen et al., 1996) and NMDA (Higgins et al., 1992) receptors attenuate opiate withdrawal. A medication attenuating EAA release might attenuate NMDA- and AMPA-mediated activity without side effects associated with NMDA antagonists (Willets et al., 1990). Lamotrigine, a marketed anticonvulsant, acts presynaptically at voltage-gated sodium channels to attenuate both EAA release and repeated burst firing (Lang et al., 1993). Another sodium current modulator, diphenylhydantoin, reportedly attenuates opiate withdrawal in rats (Fertziger et al., 1974). Lamotrigine’s specific suppression of EAAs more than other neurotransmitters has been asserted (Lees and Leech, 1993) * Corresponding author. VA Connecticut Healthcare System, Psychiatry Service 116-A, Bldg. 1, 9th Floor, West Haven, CT 06516, USA. Tel.: +1 203 9325711.
and disputed (Waldmeier et al., 1995). Lamotrigine inhibits some EAA-mediated processes in rodents: prostaglandin-induced hyperalgesia (Nakamura-Craig and Follenfant, 1995), and behavioral and histological damage after focal cerebral ischemia (Wirard et al., 1995).
2. Methods Opioid-stabilized subjects underwent a double-blind acclimatization challenge with placebo lamotrigine followed by naloxone, 0.2 mg intravenously (i.v.). On 3 subsequent days, subjects received a block-randomized sequence of pretreatment with placebo, lamotrigine 250 mg, and lamotrigine 500 mg, followed by naloxone 0.4 mg per 70 kg i.v.. At least 96 h elapsed between challenges 2 and 3, and between challenges 3 and 4 to allow elimination of residual lamotrigine (Cohen et al., 1987). Data from seven heroin-dependent subjects were analyzed, including data from one who developed a rash the day after lamotrigine 500 mg and did not receive
0376-8716/98/$19.00 © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0376-8716(98)00057-X
174
M.I. Rosen et al. / Drug and Alcohol Dependence 52 (1998) 173–176
the 250 mg lamotrigine challenge. Six subjects were male: five were Caucasian and two African American. Mean age was 34 years (range 29 – 41). All used intravenous heroin (mean duration 4.4 years). Data were excluded from three other subjects who discontinued participation mid-study and one who discontinued due to lamotrigine (250 mg)-induced urticaria. Subjects gave voluntary informed consent and were paid for study participation.
Subjects underwent a comprehensive evaluation prior to enrollment. Opioid dependence was verified after hospitalization by withdrawal in response to intramuscular naloxone in 0.2 mg increments. Subjects were then stabilized on levorphanol 6 mg every 8 h and tapering doses of oxazepam. Challenges began after subjects reported ‘zero’ withdrawal for at least 1 day without oxazepam (7–14 days).
Fig. 1. Mean of withdrawal measures over time by lamotrigine pretreatment dose for six levorphanol-stabilized subjects. Placebo is indicated by open squares, 250 mg lamotrigine by open diamonds, and 500 mg lamotrigine by open circles. Lamotrigine was administered orally in divided doses 360 and 180 min prior to naloxone (NLX) 0.4 mg i.v. (time 0). Pre-NLX represents mean of measures between −20 and −10 min. Error bars indicate 9 S.E.M.
M.I. Rosen et al. / Drug and Alcohol Dependence 52 (1998) 173–176
175
Outcome measures included vital signs (Dinamap), skin temperature (YSI 4600 Precision Thermometer), a subject-rating of withdrawal severity on an anchored 100 mm visual analog scale (VAS), and observer-ratings, on a 0–4 scale, of 12 withdrawal signs. These were collected at times (in minutes), relative to naloxone, of −360, −20, − 15, − 10, +5, + 10, + 15, + 20, + 25, +30, + 40, + 50, +60. At − 360 and − 10, ratings on nine 0–4 anchored scales of 16 possible lamotrigine side effects were collected, and blood was collected in EDTA-treated tubes for determination of plasma lamotrigine levels at Harris Labs (Lincoln, NB). A time-resolved fluorescent immunoassay was used. A prior study (Rosen et al., 1996b) employing a precipitated withdrawal methodology, used almost identical screening procedures, withdrawal rating scales, and data analytic strategy.
2.1. Data analysis All measures were summarized as baseline change (difference between − 360 baseline and mean of − 20, − 15, and − 10); AUC change from baseline (− 360 as a time zero baseline) was calculated using the trapezoidal method, and then divided by 60 min. Summary values were analyzed in a one-factor repeated measures ANOVA with planned comparisons of each active lamotrigine dose to placebo. The acclimatization challenge was omitted. Univariate procedures and the Huynh–Feldt correction were used. Significance was defined as PB0.05; ‘9 ’ indicates standard error of the mean (S.E.M.).
3. Results
Fig. 2. Withdrawal by subject and lamotrigine dose. Withdrawal precipitated by naloxone in seven levorphanol-stabilized subjects by subject and lamotrigine pretreatment condition. Lamotrigine was administered orally in divided doses 360 and 180 min prior to naloxone 0.4 mg i.v. Withdrawal summarized as AUC post-naloxone divided by 60 min. Range of absolute values at a given time point was 0–100 for subject-rated withdrawal.
Subjects fasted overnight prior to challenges and were connected to an intravenous line. Lamotrigine (Lamictal) or placebo (lactose, USP), crushed and encapsulated, was administered in divided doses 6 and 3 h before naloxone was infused, over 1 min, at 14:00 h. Subjects received their scheduled levorphanol doses at 15:00 h.
Lamotrigine had little effect before naloxone. The mean total side effect change scores were only 2.2 9 1.2 for placebo, 2.7 90.9 for 250 mg, and 2.7 91.4 for 500 mg. The only symptoms for which the change score differed numerically by 0.5 between placebo and 500 mg of lamotrigine were ‘dizzy’ (higher by 0.72 with 500 mg) and ‘anxious’ (higher by 0.74). Mean lamotrigine levels at − 10 min were 22489 323 ng/ml after lamotrigine 250 mg and 37619339 ng/ml after lamotrigine 500 mg. The robust, rapid response to naloxone is indicated in Fig. 1. Lamotrigine had no significant effects on any measure of withdrawal severity. Fig. 2 suggests that overall withdrawal severity was relatively consistent within subjects across challenges, with little effect of lamotrigine.
176
M.I. Rosen et al. / Drug and Alcohol Dependence 52 (1998) 173–176
4. Discussion Lamotrigine did not attenuate any measure of withdrawal. The lack of effect was consistent across subjects. None of the subjects who completed the study demonstrated dose-dependent attenuation of subjectrated or overall observer-rated withdrawal. The lamotrigine plasma levels we attained suppress interictal EEG spikes acutely (Jawad et al., 1986) and are anticonvulsant clinically (Brodie et al., 1995). However, lamotrigine’s anticonvulsant effects may not be EAA mediated (Waldmeier et al., 1995). Lamotrigine may insufficiently attenuate EAA release to attenuate withdrawal. An alternative explanation is that the repeated naloxone challenge paradigm may not be sensitive to subtle withdrawal-attenuating effects. The lack of sensitivity is not due to a ‘floor’ effect, as the paradigm produced robust, measurable withdrawal. For instance, the mean AUC change/60 in muscle twitches on placebo of 1.23 (Fig. 2) reflects an average of 1.23 twitches per 5-min period× 12 5-min periods per 60-min challenge (= 14 twitches/challenge). The paradigm has been used to demonstrate withdrawal attenuation by clonidine comparable to clonidine’s clinical profile (Rosen et al., 1996a) but did not demonstrate a previouslyreported attenuation by gamma-hydroxybutyric acid (Rosen et al., 1996b).
Acknowledgements This work was supported by NIDA grants P50DA09250 (T.R.K.), 1PO1DA08227 (T.R.K., E.J.N.), K20DA00191 (MIR). Burroughs-Wellcome funded Harris Laboratories (Lincoln, NB) to assay lamotrigine plasma levels.
References Brodie, M.J., Richens, A., Yuen, A.W.C. for UK Lamotrigine/Carbamazepine Monotherapy Trial Group, 1995. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. Lancet 345, 476–479.
.
Cohen, A., Land, G., Breimer, D., Yuen, W., Winton, C., Peck, A., 1987. Lamotrigine, a new anticonvulsant: pharmacokinetics in normal humans. Clin. Pharmacol. Ther. 42 (5), 535 – 541. Fertziger, A.P., Lynch, J.J., Stein, E., 1974. Modification of the morphine withdrawal syndrome in rats. Brain Res. 78, 331–334. Higgins, G.A., Nguyen, P., Sellers, E.M., 1992. The NMDA antagonist dizocilipine (MK801) attenuates motivational as well as somatic aspects of naloxone precipitated opioid withdrawal. Life Sci. 50, PL167 – PL172. Jawad, S., Oxley, J., Yuen, W.C., Richens, A., 1986. The effect of lamotrigine, a novel anticonvulsant, on interictal spikes in patients with epilepsy. Br. J. Clin. Pharmacol. 22, 191 – 193. Lang, D.G., Wang, C.M., Cooper, B.R., 1993. Lamotrigine, phenytoin and carbamazepine interactions on the sodium current present in N4TG1 mouse neuroblastoma cells. J. Pharmacol. Exp. Ther. 266 (2), 829 – 835. Lees, G., Leech, M.J., 1993. Studies on the mechanism of action of the novel anticonvulsant lamotrigine (Lamictal) using primary neuroglial cultures from rat cortex. Brain Res. 612, 190–199. Nakamura-Craig, M., Follenfant, R.L., 1995. Effect of lamotrigine in the acute and chronic hyperalgesia induced by PGE2 and in the chronic hyperalgesia in rats with streptozocin-induced diabetes. Pain 63, 33 – 37. Rasmussen, K., Kendrick, W.T., Kogan, J.H., Aghajanian, G.K., 1996. A selective AMPA antagonist, LY 293558, suppresses morphine withdrawal-induced activation of locus coeruleus neurons and behavioral signs of morphine withdrawal. Neuropsychopharmacology 15, 497 – 505. Rosen, M., McMahon, T.J., Hameedi, F.A., Pearsall, H.R., Woods, S., Kreek, M.J., Kosten, T., 1996a. Effect of clonidine pretreatment on naloxone-precipitated opiate withdrawal. J. Pharmacol. Exp. Ther. 276 (3), 1128 – 1135. Rosen, M., Pearsall, H., Woods, S., Kosten, T., 1996b. The effect of gamma-hydroxybutyric acid on naloxone-precipitated opiate withdrawal. Neuropsychopharmacology 14, 187 – 193. Trujillo, K.A., Akil, H., 1990. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 251, 85 – 87. Waldmeier, P.C., Baumann, P.A., Wicki, P., Feldtrauer, J.J., Stierlin, C., Schmutz, M., 1995. Similar potency of carbamazepine, oxcarbazepine, and lamotrigine in inhibiting the release of glutamate and other neurotransmitters. Neurology 45 (10), 1907 – 1913. Willets, J., Balster, R.L., Leander, J.D., 1990. The behavioral pharmacology of NMDA receptor antagonists. Trends Pharmacol. Sci. 11, 423 – 428. Wirard, R.P., Dickerson, M.C., Beck, O., Norton, R., Cooper, B.R., 1995. Neuroprotective properties of the novel antiepileptic lamotrigine in a gerbil model of global cerebral ischemia. Stroke 26 (3), 466 – 472.