estradiol-3-benzoate and Seizures

Prenatal morphine exposure (5-10 mg/kg twice daily on gestation days 11-18) can adversely affect neurological development, including seizure susceptibility. The present study examines the effects of prenatal morphine exposure on seizure susceptibility to the GABA antagonist and convulsant bicuculline and GABA(A) alpha(1) receptor mRNA in the substantia nigra (SN) of female rats. The results demonstrate that prenatally morphine-exposed ovariectomized (OVX) females and OVX females with estradiol benzoate (EB) replacement have an increased latency to seizure onset compared to controls. In addition, prenatal morphine exposure decreases the area covered by grains of GABA(A) alpha(1) receptor mRNA in the anterior SN in both OVX and EB+progesterone (P)-treated groups, and decreases the number of GABA(A) alpha(1) receptor mRNA-labeled cells/field in EB females. Furthermore, prenatally morphine- and saline-exposed EB and EB+P females had decreased GABA(A) alpha(1) receptor mRNA-labeled cells/field in the anterior SN compared to OVX animals of the same prenatal exposure. These results demonstrate that the long term effects of prenatal morphine exposure in female rats is dependent on their hormonal status, and suggest that seizure susceptibility may be altered via neuropharmacological changes in the GABA system in the SN.

Topics: Analgesics, Opioid; Animals; Bicuculline; Disease Susceptibility; Estradiol; Female; Hormone Replacement Therapy; Morphine; Ovariectomy; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; RNA, Messenger; Seizures; Substantia Nigra

We have previously shown that estradiol (E(2)) can initially increase and then decrease kindle seizure parameters in amygdala kindled male rats. This study focuses on the effects of estradiol benzoate (EB) on afterdischarge (AD) threshold and electrical kindling acquisition in intact male rats. After implantation of tripolar and monopolar electrodes in amygdala and dura surface respectively, effects of EB on AD threshold and electrical kindling acquisition were investigated by daily injection of EB (microg/kg) or sesame oil (EB solvent) in different groups of male rats. AD threshold was reduced significantly 0.25 h post EB treatment and reached to the lowest value after 24 h and remained almost constant at low values. Also, the number of trials for stage 5 (S(5)) and cumulative seconds of AD to complete kindling decreased significantly, when compared to rats without EB treatment. These results support a marked influence of E(2) on seizure process and convulsive pattern in the brain of male rats. Base on the previous reports about female rats and our findings, these E(2) effects are probably not sex dependent.

Topics: Amygdala; Animals; Estradiol; Kindling, Neurologic; Male; Rats; Rats, Sprague-Dawley; Seizures

In the female species, effect of estrogens on seizure activity is well documented, but not much is known on the effect of this ubiquitous steroid hormone on the seizure activity of the male species. In the present study, fully kindled male rats were treated with various doses (10, 30 and 50 microg/kg, i.p.) of estradiol benzoate (EB) daily, and kindled seizure parameters such as seizure stage (SS), after discharge duration (ADD) and stage 5 duration (S(5)D) were recorded at various times (0.25, 3 h and every 24 h for 96 h) after the first of daily EB treatments. While the 10-microg/kg dose of EB failed to produce any significant effect, the 30-microg/kg dose induced a triphasic effect on seizure parameters. An initially rapid increment of ADD (after 0.25 h), followed by significant decrease of all parameters at 48 h and later a significant increase in S(5)D was observed 96 h after the first of daily EB treatments. The 50-microg/kg dose of EB produced almost a similar but less marked pattern of effects. Pre-treatment with a 3-mg/kg dose of tamoxifen citrate (TAM), not only blocked the EB (30 microg/kg) effects till 72 h but also reduced the ADD and S(5)D significantly after 0.25 h, when compared to its control group. While pre-treatment with the 10-mg/kg dose of TAM only blocked the inhibitory effects of EB 48 h after the first of daily EB treatments. Administration of the latter dose of TAM alone induced a profile similar to EB treatment. These results may suggest that in male rats, estradiol treatment can both potentiate and attenuate kindled seizure parameters in a time dependent manner, and the stimulatory effects can not be blocked by TAM pre-treatment.

Topics: Amygdala; Animals; Electric Stimulation; Estradiol; Kindling, Neurologic; Male; Rats; Rats, Sprague-Dawley; Reaction Time; Seizures; Tamoxifen

The purpose of the present study was to investigate the effects of prenatal exposure to morphine on seizure susceptibility in adult female rats. Adult female rats, exposed to saline or morphine on prenatal days 11-18, were ovariectomized (OVX) and some were injected 48 h prior to seizure testing with estradiol benzoate (EB). To assess the latency to onset of stereotypy and seizures, females received systemic injections of N-methyl-D-aspartate (NMDA; 150, 175, 200 mg/kg) or kainic acid (KA; 10 or 15 mg/kg). Prenatal morphine exposure increased the latency to onset of wet-dog-shakes (WDS) in both OVX and OVX, EB-injected females after the higher dose of KA. However, prenatal morphine exposure increased the latency to onset of stereotypy only in OVX, EB-injected females after the highest dose of NMDA. Prenatal morphine exposure also increased the latency to onset of seizures after the lower dose of KA, but did not change the latency to onset of NMDA-induced seizures. Additionally, an EB injection increased the latency to onset of seizures in both saline- and morphine-exposed females after the lowest dose of NMDA, but decreased the latency to onset of seizures after the lower dose of KA. Thus, the present study demonstrates that prenatal morphine exposure has different effects on the estrogen regulation of the onset of seizures and stereotypy induced by NMDA or KA in adult, OVX female rats.

Topics: Analgesics, Opioid; Animals; Estradiol; Excitatory Amino Acid Agonists; Female; Kainic Acid; Morphine; N-Methylaspartate; Ovariectomy; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Seizures; Sodium Chloride; Stereotyped Behavior

Antiseizure effects of progesterone (P) and its metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha, 5alpha-THP) were investigated following continuous vs. discontinuous P exposure. In Experiments 1, 32 cycling Long-Evans rats were administered kainic acid (32 mg/kg SC), ictal behavior was examined, and plasma 3alpha,5alpha-THP levels were measured by radioimmunoassay. Proestrus/estrus rats showed less ictal activity and had elevated 3alpha,5alpha-THP levels prior to kainic acid compared to diestrus/metestrus subjects. In Experiment 2, 49 ovariectomized (ovx) rats were SC injected with estradiol benzoate (EB; 10 microg) and P (500 microg), to mimic estrus, or sesame oil vehicle (0.2 cc); all subjects were administered kainic acid. Rats tested with EB+P showed a reduced mean duration of full seizures and increased 3alpha,5alpha-THP, whereas those tested 24 h following EB+P had more tonic clonic seizures and lower 3alpha,5alpha-THP concentrations, comparable to ovx control animals. In Experiment 3, 49 ovx rats were stereotaxically implanted with bipolar electrodes into the perforant pathway. Prior to perforant pathway stimulation, rats received cholesterol or EB+P capsules for 1 month, continuously or intermittently. Irrespective of continuous or intermittent EB+P, the presence of progestins at the time of perforant pathway stimulation reduced partial seizure activity. Continuous EB+P capsules resulted in increased 3alpha,5alpha-THP levels compared to all other conditions, and less damage in the hilus of the hippocampus, compared to intermittent EB+P. These data confirm that P and 3alpha,5alpha-THP have antiseizure effects, and further suggest that repeated cycles of endogenous or exogenous P and/or 3alpha,5alpha-THP withdrawal influences seizure threshold and/or hippocampal integrity.

Topics: Animals; Estradiol; Estrus; Female; Kainic Acid; Ovariectomy; Perforant Pathway; Proestrus; Progesterone; Rats; Rats, Long-Evans; Seizures; Substance Withdrawal Syndrome