Klára Bernášková

Does prenatal methamphetamine exposure affect seizure susceptibility in adult rats with acute administration of the same drug

The aim of the present study was to investigate whether sensitivity to flurothyl seizures after an acute methamphetamine (MA) administration is different in prenatally MA-exposed adult rats than in controls without prenatal drug exposure. Adult male and female rats exposed prenatally to MA (5mg/kg), saline or neither (controls) were divided into groups; one group received acute MA (1mg/kg s.c.) injection and the other group received saline. Rats were then challenged with flurothyl at a constant flow rate to induce seizures. The threshold of the first focal clonus, clonic seizures and tonic-clonic seizures were analyzed. EFFECTS OF PRENATAL DRUG EXPOSURE: In animals without acute MA administration prior to seizure testing, prenatal MA exposure decreased threshold of the first clonus relative to control animals. This decrease in threshold was not apparent in groups pretreated with acute MA injection. EFFECTS OF ACUTE MA ADMINISTRATION: There was an increased threshold to both, first focal clonus and clonic seizures in animals with acute MA injection than in animals without it. The increase induced by acute MA pretreatment was higher in prenatally MA-exposed animals relative to controls. Further, clonic seizures were shorter and developed faster into tonic-clonic seizures in these acutely injected animals compared to animals without acute MA injection. EFFECTS OF HORMONES: The threshold of all measured attributes was decreased in males. Estrous cycle influences did not lead to changes between groups of prenatal exposure or acute MA administration. Threshold of tonic-clonic seizures was increased in females in proestrus/estrus stage of the estrous cycle relative to diestrous females. Our study suggests that prenatal MA exposure affects the sensitivity of adult rats to the effect of acute MA treatment prior to flurothyl seizures relative to controls.

Proconvulsant effect of aminophylline on cortical epileptic afterdischarges varies during ontogeny

Effect of aminophylline on epileptic afterdischarges (ADs) induced repeatedly by rhythmic electrical stimulation of sensorimotor cortical area was studied in rat pups 12, 18 and 25 days old. The proconvulsant effect of aminophylline (50 and/or 100 mg/kg i.p.) was more expressed in 12- and 18-day-old rats than in the oldest group. In 12-day-old rat pups there was an enormous increase of transition of the spike-and-wave type of ADs into the second, limbic type, a situation observed only exceptionally under control conditions. A prolongation of ADs was related to this transition (limbic ADs are always longer than spike-and-wave ones). Eighteen-day-old rats exhibit this transition less frequently but a marked prolongation of spike-and-wave ADs was recorded in a part of these animals forming a pattern of status lasting some tens of minutes. Aminophylline led only to a transient prolongation of spike-and-wave ADs in the oldest group. The transition into the limbic type of ADs was seen in this age group only exceptionally what is in contrast to age-matched controls in which this transition is common. The effect of aminophylline on cortical ADs which is most marked in the youngest group changes qualitatively during postnatal development.

Postnatal challenge dose of methamphetamine amplifies anticonvulsant effects of prenatal methamphetamine exposure on epileptiform activity induced by electrical stimulation in adult male rats

Administration of psychostimulants is often associated with increased seizure susceptibility. In our previous studies prenatal methamphetamine (MA) exposure increased seizure susceptibility of adult rats in models of primarily or secondarily generalized seizures induced by convulsant drugs. The effect of a single MA challenge dose in adulthood on chemically induced generalized seizures however, depends on the prenatal MA exposure history. Thus, the present study used a model of focal electrical stimulation to determine whether prenatal MA exposure with or without the adult challenge MA dose has the same outcome in a focal seizure model. Total of six groups of adult male rats were tested (prenatally MA-exposed, prenatally saline-exposed and rats without prenatal injections), each of these groups was either postnatally challenged with MA or with vehicle injection (MA-MA, MA-S; S-MA, S-S; C-MA, C-S). Seizures were induced by repetitive electrical stimulation (15 s/8 Hz) of sensorimotor cortex. Stimulation threshold, duration of afterdischarges (ADs), and presence and duration of spontaneous ADs (SAD) were evaluated. Additionally, behaviors associated with stimulation and ADs, and occurrence of wet-dog shakes (WDS) were analyzed. Our data demonstrate that daily injection of MA (5 mg/kg) within prenatal period decreased the occurrence of WDS and SADs, and shortened the duration of ADs and SADs suggesting anticonvulsant effects. Moreover, the challenge dose of MA (1 mg/kg) increased seizure threshold in all groups of rats, shortened duration of ADs in controls and prenatally saline-exposed animals, shortened duration of SADs in prenatally saline-exposed rats and totally eliminated WDS in all groups. Thus, the present study demonstrates that both chronic prenatal MA exposure and a single dose of MA in adulthood decrease focally induced epileptiform activity in adult male rats.

Challenge dose of methamphetamine affects kainic acid-induced seizures differently depending on prenatal methamphetamine exposure, sex, and estrous cycle.

Even though it is obvious that glutamate plays an important role in the effect of psychostimulants on seizures, the role of non-NMDA receptors remains uncertain. The aim of the present study was to determine whether acute methamphetamine (MA) administration changes sensitivity to seizures induced with kainic acid in prenatally MA-exposed adult rats. Adult male and female rats (prenatally MA exposed, prenatally saline exposed, and controls) were divided into groups that received a challenge dose (1mg/kg) of MA and groups that did not receive the MA challenge (saline injected). Systemic administration of 15 mg/kg kainic acid was used as a seizure model. Our results demonstrated that a single injection of MA (1mg/kg) affects kainic acid-induced seizures differently depending on prenatal exposure, sex, and female estrous cycle. Even though daily injections of MA (5mg/kg) in maternal rats did not have a long-term effect on susceptibility to seizures induced with kainic acid in adult progeny, sensitivity to the challenge dose of MA differed between the prenatal exposure groups.

Increased seizure susceptibility induced by prenatal methamphetamine exposure in adult female rats is not affected by early postnatal cross-fostering

Our previous studies repeatedly demonstrated that prenatal methamphetamine (MA) exposure alters seizure susceptibility in adult rats. Both the inhibitory GABA system and the excitatory NMDA system play a role in the effect of MA on epileptic seizures. On the basis of our previous behavioral results, the effect of cross-fostering on seizure susceptibility in adult female rats was examined in the present study. Bicuculline (GABA(A) receptor antagonist) and NMDA (NMDA receptor agonist) were used to induce seizures in adult female offspring exposed to MA in the prenatal and/or preweaning periods. Female dams were injected with MA (5mg/kg daily) or physiological saline (S) for approximately 9 weeks [about 3 weeks prior to impregnation, for the entire gestation period (22 days), and in the preweaning period (21 days)]. Absolute controls (C) did not receive any injections. On postnatal day 1, pups were cross-fostered so that each mother received pups from all three treatments. Thus, nine groups (based on the prenatal and postnatal drug exposures) of adult female rats were tested in each seizure test: C/C, C/S, C/MA, S/C, S/S, S/MA, MA/C, MA/S, MA/MA. The present study demonstrated that both the excitatory NMDA system and the inhibitory GABA system are involved in the proconvulsive effect of MA during prenatal and partially also postnatal development in female rats. However, because our results did not show any improvement in seizure susceptibility in prenatally MA-exposed animals that were fostered by control mothers (MA/C) relative to their siblings fostered by MA-treated mothers (MA/MA), our hypothesis of the cross-fostering effect seems to be incorrect in contrast to our behavioral studies.

Effect of cross-fostering on seizures in adult male offspring of methamphetamine-treated rat mothers

Stimulant drugs are often associated with increased seizure susceptibility. Inhibitory γ‐aminobutyric acid (GABA) and excitatory N‐methyl‐d‐aspartate (NMDA) systems play a role in the effect of stimulants in the genesis of epileptic seizures. Our previous studies showed that prenatal methamphetamine (MA) exposure induced long‐term changes in seizure susceptibility. The aim of the present study was to investigate the effect of cross‐fostering on the prenatal and postnatal MA‐exposed rats, respectively, on their seizures in adulthood. Bicuculline (GABAA receptor antagonist), NMDA (NMDA receptor agonist) and flurothyl (a convulsant gas) were used to induce seizures in adult male offsprings. Female dams were injected with MA (5 mg/kg daily) or physiological saline (S) for approx. 9 week [about 3 week prior to impregnation, for the entire gestation period (22 days) and in preweaning period (21 days)]. Absolute controls (C) did not receive any injections. On postnatal day 1, pups were cross‐fostered so that each mother received pups from all three treatments. Thus, nine groups (based on the prenatal and postnatal drug exposure) of adult male rats were tested in each seizure test: C/C; C/S; C/MA; S/C; S/S; S/MA; MA/C; MA/S; MA/MA. The present study demonstrates that the effect of prenatal and/or postnatal MA exposure is seizure model specific. In addition, our data show that there is an effect of cross‐fostering on seizures; particularly, the effect of prenatal MA exposure shown in animals fostered by control mothers is no longer apparent in animals fostered postnatally by MA‐treated mothers. Such effect of postnatal treatment is not manifested in prenatal controls. In summary, it seems that: (1) prenatal MA exposure alters seizure susceptibility more than postnatal MA exposure; (2) especially in seizures induced by chemicals that affect GABAergic system (bicuculline, flurothyl) notable effect of adoption (cross‐fostering) is apparent; (3) in seizure models that are associated with NMDA system (NMDA, flurothyl), effect of prenatal stress seems to play a role.

Effect of prenatal methamphetamine exposure and challenge dose of the same drug in adulthood on epileptiform activity induced by electrical stimulation in female rats

Our previous study demonstrated that chronic prenatal methamphetamine (MA) exposure and a single dose of MA in adulthood decrease focally induced epileptiform activity in adult male rats. As seizures are known to be dependent on sex and female estrous cycle, the goal of the present study was to examine the combined effect of prenatal MA exposure (5mg/kg) and the MA challenge dose (1mg/kg) in adulthood on electroencephalography (EEG) recordings and consequences of brain stimulation in freely moving adult female rats with respect to the estrous cycle. Overall, 12 groups of adult female rats were tested: prenatally MA-exposed, prenatally saline-exposed and rats without prenatal injections, each of these groups was either postnatally challenged with MA or with saline injection (MA-MA, MA-S; S-MA, S-S; C-MA, C-S) and further divided according to the stage of the estrous cycle to metestrus/diestrus (M/D) or proestrus/estrus (P/E). Seizures were induced by repetitive electrical stimulation (15s/8Hz) of sensorimotor cortex. Stimulation threshold, duration of afterdischarges (ADs), and presence and duration of spontaneous ADs (SADs) were evaluated. Additionally, behavior associated with stimulation and ADs, and occurrence of wet-dog-shakes (WDS) were analyzed. The present study demonstrates that the prenatal MA exposure decreased the seizure threshold in females in M/D, but not in females in P/E. In addition, prenatally MA-exposed M/D females injected with saline in adulthood had increased the duration of ADs as well as SADs. The challenge dose of MA also decreased the seizure threshold. Moreover, prenatal as well as adult MA administration decreased the number and occurrence of WDS, respectively. Thus, the present study demonstrates that the effect of prenatal MA exposure and challenge dose of the same drug on focally induced epileptiform activity in adult female rats depends on the estrous cycle.

Are changes in excitability in the hippocampus of adult male rats induced by prenatal methamphetamine exposure or stress

Prenatal stress and drug exposure induce permanent alterations of the brain. Even though different brain structures are involved, alterations almost always refer to the hippocampus. The aim of this study was to investigate the excitability of hippocampal slices in low-magnesium epilepsy model of prenatally methamphetamine (MA, 5mg/kg sc.) or saline (sc., stress model) exposed animals in adult male rats. The second aim was to investigate, if a low dose of MA (1ml/kgs.c.) administered in adulthood changes the hippocampal activity of these animals. Adult Wistar male rats were divided into groups according to their prenatal treatment (C - naïve control; Sa - saline; MA - MA administration). One half of the animals was treated with a challenge dose of MA (1mg/kg sc.) 45min before hippocampal slices were cut. The activity of 350μ thick transversal slices of CA1 hippocampi was recorded (latencies of the first epileptiform discharge and the regular epileptiform activity) and evaluated in ACSF with low-magnesium concentration. Effects of prenatal exposure: The highest excitability was found in the Sa (prenatally stressed) group in respect to C and MA groups. This group developed also the highest number of seizure-like events. In addition, the prenatally MA treated group had also higher excitability than C group. Effects of the MA challenge dose: The challenge dose decreased the excitability of prenatally SA- exposed group. To conclude, even a mild prenatal stress significantly increases hippocampal excitability in adulthood and a challenge dose of MA is able to dampen it.