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Brain Research 922 (2001) 305–309 www.elsevier.com / locate / bres Short communication Prenatal morphine exposure decreases susceptibility of adult male rat offspring to bicuculline seizures a b a,b, ˇ * ´ Cheryl J. Schindler , Romana Slamberova , Ilona Vathy a Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA b Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA Accepted 12 September 2001 Abstract The purpose of this study was to investigate the effect of prenatal exposure to morphine (5–10 mg/kg twice daily on days 11–18 of gestation) on bicuculline seizure susceptibility and to examine the interaction of prenatal morphine exposure and hormonal background in adult male rats. The data demonstrate that prenatal morphine exposure does not affect clonic but decreases susceptibility to tonic–clonic bicuculline seizures in intact male rats. Thus, the present data support our previous work demonstrating alterations in seizure susceptibility of adult morphine-exposed animals. 2001 Elsevier Science B.V. All rights reserved. Theme: Neural basis of behavior Topic: Drugs of abuse: opioids and others Keywords: Epilepsy; Prenatal drug exposure; Opiate; Androgen; Testosterone Seizures result from an imbalance in the excitatory and while peripubertally decreases, susceptibility to bicuculline inhibitory neurotransmitter systems in the brain [11,14]. seizures. Previous studies in our laboratory have shown that prenatal Gonadal hormones play an important role in modulating morphine exposure in rats alters susceptibility to a variety seizure activities. Several studies have found that testo- of experimentally-induced seizures in adult offspring in a sterone has anti-convulsant effects [1,12,28,36]. Previously sex- and hormone-specific manner. We have probed the we demonstrated that altered seizure susceptibility in excitatory neurotransmitter system using an in vitro, low prenatally morphine-exposed rats is dependent on their 21 Mg seizure model [40] and systemic administration of gonadal hormone levels [39,41]. Specifically, morphine- kainic acid or N-methyl-D-aspartic acid to elicit seizures exposed males that were gonadectomized (GNX) in adult- [29]. These studies show that prenatal morphine exposure hood exhibit decreased susceptibility to fluorothyl seizures increases seizure susceptibility in male rats. compared to GNX controls, while intact males show no Interestingly, prenatal morphine exposure decreases changes. Because gonadal hormones affect seizures and susceptibility to fluorothyl seizures [39], which are interact with the effects of prenatal morphine exposure, we believed to be modulated by the GABA neurotransmitter tested the hypothesis that prenatal morphine exposure system [13,23,24,33]. Most recently, we have used the decreases susceptibility to bicuculline seizures, and that GABA antagonist bicuculline to assess the effects of this effect is influenced by the presence or absence of prenatal morphine exposure in rats on seizures during testosterone. several developmental ages [27]. This work demonstrated Twenty 8-day pregnant Sprague–Dawley rats from that prenatal morphine exposure prepubertally increases, Taconic Farm (Germantown, NY) were maintained in a temperature-controlled colony room with free access to food and water on a reversed 14 h (light):10 h (dark) cycle with lights off at 11:00 h. Pregnant rats were randomly *Corresponding author. Tel.: 11-718-430-3386; fax: 11-718-430- assigned to an experimental morphine- or a control saline- 8772. E-mail address: [email protected] (I. Vathy). treated group. Morphine sulfate was obtained from the 0006-8993 / 01 / $ – see front matter 2001 Elsevier Science B.V. All rights reserved. PII: S0006-8993(01)03183-3

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Page 1: Prenatal morphine exposure decreases susceptibility of adult male rat offspring to bicuculline seizures

Brain Research 922 (2001) 305–309www.elsevier.com/ locate /bres

Short communication

Prenatal morphine exposure decreases susceptibility of adult male ratoffspring to bicuculline seizures

a b a,b ,ˇ *´Cheryl J. Schindler , Romana Slamberova , Ilona VathyaDepartment of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA

bDepartment of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA

Accepted 12 September 2001

Abstract

The purpose of this study was to investigate the effect of prenatal exposure to morphine (5–10 mg/kg twice daily on days 11–18 ofgestation) on bicuculline seizure susceptibility and to examine the interaction of prenatal morphine exposure and hormonal background inadult male rats. The data demonstrate that prenatal morphine exposure does not affect clonic but decreases susceptibility to tonic–clonicbicuculline seizures in intact male rats. Thus, the present data support our previous work demonstrating alterations in seizure susceptibilityof adult morphine-exposed animals. 2001 Elsevier Science B.V. All rights reserved.

Theme: Neural basis of behavior

Topic: Drugs of abuse: opioids and others

Keywords: Epilepsy; Prenatal drug exposure; Opiate; Androgen; Testosterone

Seizures result from an imbalance in the excitatory and while peripubertally decreases, susceptibility to bicucullineinhibitory neurotransmitter systems in the brain [11,14]. seizures.Previous studies in our laboratory have shown that prenatal Gonadal hormones play an important role in modulatingmorphine exposure in rats alters susceptibility to a variety seizure activities. Several studies have found that testo-of experimentally-induced seizures in adult offspring in a sterone has anti-convulsant effects [1,12,28,36]. Previouslysex- and hormone-specific manner. We have probed the we demonstrated that altered seizure susceptibility inexcitatory neurotransmitter system using an in vitro, low prenatally morphine-exposed rats is dependent on their

21Mg seizure model [40] and systemic administration of gonadal hormone levels [39,41]. Specifically, morphine-kainic acid or N-methyl-D-aspartic acid to elicit seizures exposed males that were gonadectomized (GNX) in adult-[29]. These studies show that prenatal morphine exposure hood exhibit decreased susceptibility to fluorothyl seizuresincreases seizure susceptibility in male rats. compared to GNX controls, while intact males show no

Interestingly, prenatal morphine exposure decreases changes. Because gonadal hormones affect seizures andsusceptibility to fluorothyl seizures [39], which are interact with the effects of prenatal morphine exposure, webelieved to be modulated by the GABA neurotransmitter tested the hypothesis that prenatal morphine exposuresystem [13,23,24,33]. Most recently, we have used the decreases susceptibility to bicuculline seizures, and thatGABA antagonist bicuculline to assess the effects of this effect is influenced by the presence or absence ofprenatal morphine exposure in rats on seizures during testosterone.several developmental ages [27]. This work demonstrated Twenty 8-day pregnant Sprague–Dawley rats fromthat prenatal morphine exposure prepubertally increases, Taconic Farm (Germantown, NY) were maintained in a

temperature-controlled colony room with free access tofood and water on a reversed 14 h (light):10 h (dark) cyclewith lights off at 11:00 h. Pregnant rats were randomly*Corresponding author. Tel.: 11-718-430-3386; fax: 11-718-430-assigned to an experimental morphine- or a control saline-8772.

E-mail address: [email protected] (I. Vathy). treated group. Morphine sulfate was obtained from the

0006-8993/01/$ – see front matter 2001 Elsevier Science B.V. All rights reserved.PI I : S0006-8993( 01 )03183-3

Page 2: Prenatal morphine exposure decreases susceptibility of adult male rat offspring to bicuculline seizures

306 C.J. Schindler et al. / Brain Research 922 (2001) 305 –309

National Institute on Drug Abuse (Research Technology to onset of clonic seizures (Fig. 1A). However, there is aBranch, Rockville, MD) and dissolved in 0.9% saline. main effect of prenatal morphine exposure on the latencyBoth morphine and saline injections were administered to onset of tonic–clonic seizures (F(1,23)510.598; P,

subcutaneously (s.c.) twice daily (08:00 and 20:00 h) on 0.01) (Fig. 1B). Prenatally morphine-exposed male ratsgestational days 11–18 (see Ref. [37]). The first three show an increased latency to onset of bicuculline-inducedmorphine injections were 5 mg/kg each, and the remaining tonic–clonic seizures, which is selective for tonic–clonicinjections were 10 mg/kg each [37]. seizures as is demonstrated by the significant interaction

Rat pups were born on the 22nd day of gestation, and when seizure type (clonic and tonic–clonic) is consideredthe day of birth was counted as postnatal day (PND) 0. At as between factors (F(1,65)59.995; P,0.01) (data notPND 1, the morphine-exposed pups were tattooed on one shown). There is, however, no significant interactionfootpad with black India ink for identification. Morphine- between prenatal drug exposure and the presence orand saline-exposed pups were sexed, litters were crossed absence of male gonadal hormones for either clonicand reduced to 10 pups / litter [37]. Each mother raised five (F(2,34)50.496; P.0.05) (Fig. 1A) or tonic–clonicof her own and five adopted pups who had received the (F(2,23)51.108; P.0.05) (Fig. 1B) bicuculline seizures.opposite prenatal treatment. Pups were weaned on PND 25 There are no significant differences either in the incidenceand housed individually. Young adult male rats between of clonic or tonic–clonic seizures between prenatallyPND 68–78 were used in the present study. To avoid littereffects, only one animal was used from each litter. Some(24 saline and 28 morphine) of the adult male rats wereGNX 3 weeks prior to seizure testing while one group ofmales (16 saline and nine morphine) was left gonadallyintact. Some of the GNX male rats (12 saline and 14morphine) received an s.c. injection of 500 mg of testo-sterone propionate (TP) 48 h before seizure testing.

Bicuculline (Sigma, St. Louis, MO) was dissolved in 0.1N HCl, pH adjusted to 5.5, and administered intraperitone-ally at a dose of 7.5 mg/kg. The dose of bicuculline waschosen based on our previous study [27]. Each animal wasobserved for 30 min after bicuculline administration.Bicuculline seizures have two distinct phases: clonic andtonic–clonic components, each of which originates fromseparate anatomic locations in the brain [3]. Clonic sei-zures are characterized by a rapid contraction and relaxa-tion of the muscles of the head and forelimbs. Tonic–clonic seizures usually begin with wild running, followedby a tensing of the muscles (tonus), and then a long lastingclonus which normally ends in death. Loss of the rightingreflex is observed during tonic–clonic seizures [42]. Thepercentage of animals that displayed clonic seizures andthe percentage that displayed tonic–clonic seizures inresponse to the bicuculline injection was analyzed usingthe chi-square test. The latency to onset of clonic andtonic–clonic seizures was also recorded. An increasedlatency to the onset of seizure activity indicates a de-creased susceptibility to seizures. Differences in latenciesto seizure onset between experimental and control animalswere analyzed using a two-way analysis of variance(ANOVA) (prenatal drug exposure3hormonal back-ground). Because the two-way ANOVA showed a maineffect of prenatal morphine exposure, which was notequally distributed in the different hormone groups, a

Fig. 1. Main effect of prenatal morphine exposure on latency to onset ofone-way ANOVA was conducted to better understand andbicuculline seizures in adult male rats. Latency to onset of the clonicinterpret this main effect. Only animals that displayedcomponent of bicuculline seizures (n56–8/group) (A) and latency to

seizures were included in latency measures. Differences onset of the tonic–clonic component of bicuculline seizures (n54–7/were considered significant if P,0.05. group) (B) were measured. Values are expressed as mean6S.E.M. for

Prenatal morphine exposure does not affect the latency each hormonal groups (A,B). *P,0.01 (ANOVA) vs. intact saline males.

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C.J. Schindler et al. / Brain Research 922 (2001) 305 –309 307

Table 1Clonic and tonic–clonic seizure incidences in response to bicuculline injection are independent of prenatal treatment and hormonal background

Hormonal background Prenatal treatment Incidence of clonic seizures Incidence of tonic–clonic seizures

GNX Saline 7/12 (58.3%) 6/12 (50%)Morphine 7/14 (50%) 4/14 (28.6%)

GNX1TP Saline 7/12 (58.3%) 4/12 (33.3%)Morphine 6/14 (42.9%) 4/14 (28.6%)

Intact Saline 8/16 (50%) 7/16 (43.75%)Morphine 6/9 (66.7%) 5/9 (55.5%)

The values are: the number of animals with seizures / the number of animals tested (percentage of animals with seizures).

morphine-exposed and control rats, irrespective of the morphine exposure on bicuculline seizure susceptibilitypresence or absence of hormones (Table 1). switches from being proconvulsant at prepubertal ages to

The present study demonstrates that prenatal morphine anticonvulsant at older ages, it consistently decreasesexposure decreases susceptibility to bicuculline-induced susceptibility to tonic–clonic seizures from puberty on-tonic–clonic seizures in adult male offspring. Although ward. This is consistent with clinical data showing thatstatistically there is a main effect of morphine that puberty is a critical period for seizure onset and changes inindicates decreased seizure susceptibility with no inter- existing epilepsy [1].action between drug and hormone condition, the data The present study demonstrated no main effect ofshows that there is only a negligible effect of prenatal hormones in bicuculline seizure susceptibility. Similar tomorphine exposure in the GNX and GNX1TP groups. our findings, Wilson et al. [43] observed no effect of GNXThere is, however, a substantial difference between the on bicuculline seizures in male rats. However, studiessaline- and morphine-exposed intact groups, which is using a different GABA receptor antagonist, picrotoxin,A

responsible for the significant main effect of prenatal drug showed anticonvulsant effects of androgens. GNX in-exposure. Therefore, we conducted a one-way ANOVA in creased [25,36] and chronic testosterone treatment de-six groups: saline intact, morphine intact, saline GNX, creased [28] seizure susceptibility. The discrepancy be-morphine GNX, saline GNX1TP, and morphine GNX1 tween the results of androgen absence on GABA antago-A

TP. The results show that in the intact group, prenatal nist-induced seizures may be related to the different modesmorphine exposure significantly decreases seizure suscep- of antagonism; that is, bicuculline is a competitive GABAA

tibility (P,0.01) while in the GNX group and in the receptor antagonist, while picrotoxin is a noncompetitiveGNX1TP group, there is no significant difference between GABA antagonist. Finally, in other seizure models,A

saline- and morphine-exposed males (Fig. 1B). Thus, the androgen has proconvulsant effects [10,44]. Thus, thedifferences between saline- and morphine-exposed males effect of testosterone on seizure susceptibility appears toare annulled following GNX, and the TP replacement fails be seizure-model dependent.to restore this effect to the level of intact males. One One brain region that may be involved in changes inpossible explanation as to why we do not see the same bicuculline seizure susceptibility is the substantia nigra.saline /morphine differences in GNX1TP-treated males as Brainstem regions, including the substantia nigra, arein intact males could be that a single, systemic TP injection implicated in the origin of tonic seizures [3], and prenatalwas given to the rats, as had been used in a previous study morphine exposure altered tonic–clonic seizure suscep-[38]. It may be that chronic but not acute TP treatment is tibility in the present study. Within the substantia nigra, thenecessary to restore the saline /morphine difference in GABA system may play a major role in seizure suscep-seizure susceptibility after GNX. Another possibility is that tibility. The substantia nigra is thought to mediate thethe surgical manipulation itself (anesthetics, stress, or other effects of anticonvulsant GABAergic drugs [26], andcomponent) and not the altered gonadal hormone levels GABA agonist infusion into the substantia nigra is anticon-may account for the loss of saline /morphine differences in vulsant in a number of seizure models [7,15,21,33].bicuculline seizure susceptibility. This could be tested in Therefore, one could speculate that prenatal morphinefuture studies that include sham-operated males. exposure could have altered the responses of the GABA

In agreement with the present findings, our lab recently system in the substantia nigra, subsequently altering sus-showed that prenatally morphine-exposed, gonadally intact ceptibility to tonic–clonic bicuculline seizures. Futureperipubertal male rats (PND 38) had no differences in studies might test this hypothesis.susceptibility to bicuculline-induced clonic seizures, but To the best of our knowledge, no other laboratory hashad decreased susceptibility to tonic–clonic seizures [27]. examined seizure susceptibility in prenatally morphine-That study also demonstrated that prenatally morphine- exposed adult rats. However, studies from other labs thatexposed, prepubertal male rats (PND 25) show increased have shown that prenatal exposure to various compounds,susceptibility to bicuculline-induced clonic and tonic– including methylazoxymethanol [5], methotrexate [16],clonic seizures. It seems that although the effect of prenatal methylmercury [35], and cocaine [6,31,32] can alter sus-

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metabolites affect afterdischarge thresholds and the development ofceptibility to various types of seizures. In the prenatalamygdala kindled seizures, Brain Res. 838 (1999) 151–157.opiate field, recent studies have demonstrated neurophar-

[11] J. Engel Jr., Excitation and inhibition in epilepsy, Can. J. Neurol.macological changes in exposed offspring [22,34,45] that Sci. 23 (1996) 167–174.may be related to seizure susceptibility [4,8,30]. Addition- [12] C.A. Frye, T.A. Reed, Androgenic neurosteroids: anti-seizure effects

in an animal model of epilepsy, Psychoneuroendocrinology 23ally, prenatal morphine exposure disturbs the normal(1998) 385–399.functioning of the hypothalamic–pituitary–adrenocortical

´[13] D.S. Garant, S.G. Xu, E.F. Sperber, S.L. Moshe, The influence ofand gonadal axes in pups [9,18–20], which may affect thalamic GABA transmission on the susceptibility of adult rats toseizure activity as well [2,17]. fluorothyl induced seizures, Epilepsy Res. 15 (1993) 185–192.

[14] G.L. Holmes, Epilepsy in the developing brain: lessons from theTogether, our study demonstrates that prenatal morphinelaboratory and clinic, Epilepsia 38 (1997) 12–30.exposure decreases susceptibility to seizures induced by

[15] M.J. Iadarola, K. Gale, Substantia nigra: site of anticonvulsantbicuculline in adult, gonadally intact males. These differ-activity mediated by gamma-aminobutyric acid, Science 218 (1982)

ences are not present in adult males after GNX. Future 1237–1240.studies may investigate the functional relationship between ´ ´ ´ˇ ´ ´ˇ[16] R. Kabova, J. Velıskova, L. Velısek, Prenatal methotrexate exposure

decreases seizure susceptibility in young rats of two strains, Exp.bicuculline seizures and brain site specificity in prenatallyNeurol. 161 (2000) 167–173.morphine-exposed adult male rats.

[17] H.J. Krugers, S. Knollema, R.H. Kemper, G.J. Ter Horst, J. Korf,Down-regulation of the hypothalamo–pituitary–adrenal axis reducesbrain damage and number of seizures following hypoxia / ischaemiain rats, Brain Res. 690 (1995) 41–47.

Acknowledgements [18] J. Lesage, F. Bernet, V. Montel, J.P. Dupouy, Effects of prenatalmorphine on hypothalamic metabolism of neurotransmitters andgonadal and adrenal activities, during the early postnatal period inThis study was supported by the NIH Grant DA05833 tothe rat, Neurochem. Res. 21 (1996) 723–732.I.V. and by the Department of Psychiatry and Behavioral

[19] J. Lesage, F. Bernet, V. Montel, I. Dutriez-Casteloot, J.P. Dupouy,Sciences, Albert Einstein College of Medicine. The authorsInfluence of morphine treatment in pregnant rats on the miner-

wish to thank Dr. Anne M. Etgen for editing the manu- alocorticoid activity of the adrenals in their neonates, Life Sci. 66script. The procedures for animal experimentation utilized (2000) 1197–1211.

[20] J. Lesage, M. Grino, F. Bernet, I. Dutriez-Casteloot, V. Montel, J.P.in this report were reviewed and approved by the Institu-Dupouy, Consequences of prenatal morphine exposure on thetional Animal Care and Use Committee.hypothalamo–pituitary–adrenal axis in the newborn rat: effect ofmaternal adrenalectomy, J. Neuroendocrinol. 10 (1998) 331–342.

[21] R. Maggio, K. Gale, Seizures evoked from area tempestas aresubject to control by GABA and glutamate receptors in substantiaReferencesnigra, Exp. Neurol. 105 (1989) 184–188.

[22] P. Maharajan, R. Prencipe, P. Di Francesco, G. Paino, G. Ravagnan,[1] T. Backstrom, D. Rosciszewska, Effects of hormones on seizure V. Maharajan, Maternal morphine alters parvalbumin immuno-

expression, in: J.J. Engel, T. Pedley (Eds.), Epilepsy: A Comprehen- reactivity patterns in neonatal mouse brain, Synapse 35 (2000)sive Textbook, Lippincott-Raven, Philadelphia, PA, 1997, pp. 2003– 265–271.2011. ´[23] S.L. Moshe, B.J. Albala, Nigral muscimol infusions facilitate the

[2] B.J. Bowers, T.Z. Bosy, J.M. Wehner, Adrenalectomy increases development of seizures in immature rats, Brain Res. 315 (1984)bicuculline-induced seizure sensitivity in long-sleep and short-sleep 305–308.mice, Pharmacol. Biochem. Behav. 38 (1991) 593–600. ´ ´ ´ˇ ´[24] S.L. Moshe, L.L. Brown, H. Kubova, J. Velıskova, R.S. Zukin, E.F.

[3] R.A. Browning, D.K. Nelson, Modification of electroshock and Sperber, Maturation and segregation of brain networks that modifypentylenetetrazol seizure patterns in rats after precollicular transec- seizures, Brain Res. 665 (1994) 141–146.tions, Exp. Neurol. 93 (1986) 546–556. [25] D. Pericic, H. Manev, M. Bujas, Gonadal hormones and picrotoxin-

[4] A.G. Chapman, Glutamate receptors in epilepsy, Prog. Brain Res. induced convulsions in male and female rats, Brain Res. 736 (1996)116 (1998) 371–383. 174–179.

[5] N. Chevassus-au-Louis, Y. Ben-Ari, M. Vergnes, Decreased seizure [26] M. Proctor, K. Gale, Basal ganglia and brainstem anatomy andthreshold and more rapid rate of kindling in rats with cortical physiology, in: J. EngelJr., T.A. Pedley (Eds.), Epilepsy: A Com-malformation induced by prenatal treatment with methylazox- prehensive Textbook, Lippincott-Raven, Philadelphia, PA, 1998, pp.ymethanol, Brain Res. 812 (1998) 252–255. 353–368.

ˇ´ˇ ´ ´[6] M.R. de Feo, D. Del Priore, O. Mecarelli, Prenatal cocaine: seizure [27] C.J. Schindler, J. Velıskova, R. Slamberova, I. Vathy, Prenatalsusceptibility in rat offspring, Pharmacol. Res. 31 (1995) 137–141. morphine exposure alters susceptibility to bicuculline seizures in a

[7] A. Depaulis, M. Vergnes, C. Marescaux, B. Lannes, J.M. Warter, sex- and age-specific manner, Brain Res. Dev. Brain Res. 121Evidence that activation of GABA receptors in the substantia nigra (2000) 119–122.suppresses spontaneous spike-and-wave discharges in the rat, Brain [28] S. Schwartz-Giblin, A. Korotzer, D.W. Pfaff, Steroid hormoneRes. 448 (1988) 20–29. effects on picrotoxin-induced seizures in female and male rats, Brain

[8] R. Dingledine, C.J. McBain, J.O. McNamara, Excitatory amino acid Res. 476 (1989) 240–247.ˇ ´ ´ˇreceptors in epilepsy, Trends Pharmacol. Sci. 11 (1990) 334–338. [29] R. Slamberova, L. Velısek, I. Vathy, Prenatal morphine exposure

[9] I. Dutriez-Casteloot, F. Bernet, J.F. Dedieu, D. Croix, C. Laborie, V. alters N-methyl-D-aspartate- and kainate-induced seizures in adultMontel, J. Lesage, J.C. Beauvillain, J.P. Dupouy, Hypothalamic– male rats, Pharmacol. Biochem. Behav. 65 (2000) 39–42.pituitary–adrenocortical and gonadal axes and sympathoadrenal [30] R.S. Sloviter, Calcium-binding protein (calbindin-D28k) and parval-activity of adult male rats prenatally exposed to morphine, Neurosci. bumin immunocytochemistry: localization in the rat hippocampusLett. 263 (1999) 1–4. with specific reference to the selective vulnerability of hippocampal

[10] H.E. Edwards, W.M. Burnham, N.J. MacLusky, Testosterone and its neurons to seizure activity, J. Comp. Neurol. 280 (1989) 183–196.

Page 5: Prenatal morphine exposure decreases susceptibility of adult male rat offspring to bicuculline seizures

C.J. Schindler et al. / Brain Research 922 (2001) 305 –309 309

´ˇ ´ ´[31] A. Snyder-Keller, C. Sam, R.W. Keller Jr., Enhanced susceptibility [39] I. Vathy, J. Velıskova, S.L. Moshe, Prenatal morphine exposureto cocaine- and pentylenetetrazol-induced seizures in prenatally induces age-related changes in seizure susceptibility in male rats,cocaine-treated rats, Neurotoxicol. Teratol. 22 (2000) 231–236. Pharmacol. Biochem. Behav. 60 (1998) 1–4.

´ˇ ´[32] A.M. Snyder-Keller, R.W. Keller Jr., Prenatal cocaine alters later [40] L. Velısek, P.K. Stanton, S.L. Moshe, I. Vathy, Prenatal morphinesensitivity to cocaine-induced seizures, Neurosci. Lett. 191 (1995) exposure enhances seizure susceptibility but suppresses long-term149–152. potentiation in the limbic system of adult male rats, Brain Res. 869

´[33] E.F. Sperber, J.N. Wurpel, D.Y. Zhao, S.L. Moshe, Evidence for the (2000) 186–193.´ˇ ´ˇ ´ ´involvement of nigral GABAA receptors in seizures of adult rats, [41] L. Velısek, J. Velıskova, S.L. Moshe, I. Vathy, Prenatal morphine

Brain Res. 480 (1989) 378–382. exposure alters ovarian steroid hormonal regulation of seizure[34] R.A. Steingart, J. Barg, J. Maslaton, M. Nesher, J. Yanai, Pre- and susceptibility, Brain Res. 796 (1998) 247–256.

´ˇ ´ ´ˇ ˇpostsynaptic alterations in the septohippocampal cholinergic in- [42] J. Velıskova, L. Velısek, P. Mares, R. Rokyta, Ketamine suppressesnervations after prenatal exposure to drugs, Brain Res. Bull. 46 both bicuculline- and picrotoxin-induced generalized tonic–clonic(1998) 203–209. seizures during ontogenesis, Pharmacol. Biochem. Behav. 37 (1990)

[35] A. Szasz, B. Barna, Z. Szupera, G. De Visscher, Z. Galbacs, M. 667–674.Kirsch-Volders, M. Szente, Chronic low-dose maternal exposure to [43] M.A. Wilson, R. Biscardi, Effects of gender and gonadectomy onmethylmercury enhances epileptogenicity in developing rats, Int. J. responses to chronic benzodiazepine receptor agonist exposure inDev. Neurosci. 17 (1999) 733–742. rats, Eur. J. Pharmacol. 215 (1992) 99–107.

[36] J. Thomas, J.H. McLean, Castration alters susceptibility of male rats [44] D.E. Woolley, P.S. Timiras, The gonad–brain relationship: effects ofto specific seizures, Physiol. Behav. 49 (1991) 1177–1179. female sex hormones on electroshock convulsions in the rat,

[37] I. Vathy, A.M. Etgen, R.J. Barfield, Effects of prenatal exposure to Endocrinology 70 (1962) 196–209.morphine on the development of sexual behavior in rats, Pharmacol. [45] S.N. Yang, J.M. Yang, J.N. Wu, Y.H. Kao, W.Y. Hsieh, C.C. Chao,Biochem. Behav. 22 (1985) 227–232. P.L. Tao, Prenatal exposure to morphine alters kinetic properties of

´ ˇ´ ´[38] I. Vathy, A. Rimanoczy, R. Slamberova, Prenatal exposure to NMDA receptor-mediated synaptic currents in the hippocampus ofmorphine differentially alters gonadal hormone regulation of delta- rat offspring, Hippocampus 10 (2000) 654–662.opioid receptor binding in male and female rats, Brain Res. Bull. 53(2000) 793–800.