Overt Convulsions Research Articles

Delta Opioid Receptor (DOR) Agonist Activity of Buprenorphine in Mice

Buprenorphine is an approved method of treatment for opioid use disorder (OUD), and it is under investigation for cocaine use disorder-- for which there are no FDA-approved, pharmacological treatments. Buprenorphine is considered a mixed efficacy opioid ligand, and its partial agonist activity at the mu opioid receptor (MOR) is thought to mediate the therapeutic effects for OUD. There is also evidence that it acts as a kappa opioid receptor (KOR) and delta opioid receptor (DOR) antagonist and a nociception/orphanin FQ receptor (NOPR) agonist. However, one recent report found buprenorphine to act as a partial DOR agonist in cells expressing human opioid receptors (Bidlack et al., 2018). The goal of the present study was to investigate the in vivo activity of buprenorphine at DOR in rodents. Male C57BL6/N mice were used to evaluate the effects of buprenorphine on pentylenetetrazol (PTZ)-induced convulsive activity and in the mouse forced swim test. Buprenorphine did not produce overt convulsions in mice but dose-dependently increased PTZ-induced convulsions with 32 mg/kg buprenorphine as the maximally effective dose, and these effects were attenuated by the DOR antagonist naltrindole. Also, buprenorphine (0.01-0.1 mg/kg) decreased immobility in the mouse forced swim test, which was blocked by pretreatment with naltrindole. Together, these data demonstrate that buprenorphine produces DOR-mediated antidepressant-like effects and potentiates PTZ-induced convulsions, suggesting that buprenorphine acts as a partial DOR agonist in mice. Interestingly, there is a large separation between doses that produce potential antidepressant-like effects and pro-convulsive effects. Future studies will investigate whether this large separation between DOR-mediated effects are due to the complex pharmacology of buprenorphine. Further, these data offer additional insight into the activity of buprenorphine, which could help elucidate the mechanism needed for successful treatment of opioid or cocaine use disorder. These studies were supported in part by R21 DA041565 and DA007315.

Magnesium sulfate treatment against sarin poisoning: dissociation between overt convulsions and recorded cortical seizure activity

Sarin, a potent organophosphate cholinesterase inhibitor, induces an array of toxic effects including convulsions. Many antidotal treatments contain anticonvulsants to block seizure activity and the ensuing brain damage. Magnesium sulfate (MGS) is used to suppress eclamptic seizures in pregnant women with hypertension and was shown to block kainate-induced convulsions. Magnesium sulfate was evaluated herein as an anticonvulsant against sarin poisoning and its efficacy was compared with the potent anticonvulsants midazolam (MDZ) and caramiphen (CRM). Rats were exposed to a convulsant dose of sarin (96 μg/kg, im) and 1 min later treated with the oxime TMB4 and atropine to increase survival. Five minutes after initiation of convulsions, MGS, CRM, or MDZ were administered. Attenuation of tonic-clonic convulsions was observed following all these treatments. However, radio-telemetric electro-corticography (ECoG) monitoring demonstrated sustained seizure activity in MGS-injected animals while this activity was completely blocked by MDZ and CRM. This disrupted brain activity was associated with marked increase in brain translocator protein levels, a marker for brain damage, measured 1 week following exposure. Additionally, histopathological analyses of MGS-treated group showed typical sarin-induced brain injury excluding the hippocampus that was partially protected. Our results clearly show that MGS demonstrated misleading features as an anticonvulsant against sarin-induced seizures. This stems from the dissociation observed between overt convulsions and seizure activity. Thus, the presence or absence of motor convulsions may be an unreliable indicator in the assessment of clinical status and in directing adequate antidotal treatments following exposure to nerve agents in battle field or terror attacks.

The Convulsive and Electroencephalographic Changes Produced by Nonpeptidic δ-Opioid Agonists in Rats: Comparison with Pentylenetetrazol

delta-Opioid agonists produce convulsions and antidepressant-like effects in rats. It has been suggested that the antidepressant-like effects are produced through a convulsant mechanism of action either through overt convulsions or nonconvulsive seizures. This study evaluated the convulsive and seizurogenic effects of nonpeptidic delta-opioid agonists at doses that previously were reported to produce antidepressant-like effects. In addition, delta-opioid agonist-induced electroencephalographic (EEG) and behavioral changes were compared with those produced by the chemical convulsant pentylenetetrazol (PTZ). For these studies, EEG changes were recorded using a telemetry system before and after injections of the delta-opioid agonists [(+)-4-[(alphaR)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)methyl]-N,N-diethylbenz (SNC80) and [(+)-4-[alpha(R)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide [(+)-BW373U86]. Acute administration of nonpeptidic delta-opioid agonists produced bilateral ictal and paroxysmal spike and/or sharp wave discharges. delta-Opioid agonists produced brief changes in EEG recordings, and tolerance rapidly developed to these effects; however, PTZ produced longer-lasting EEG changes that were exacerbated after repeated administration. Studies with antiepileptic drugs demonstrated that compounds used to treat absence epilepsy blocked the convulsive effects of nonpeptidic delta-opioid agonists. Overall, these data suggest that delta-opioid agonist-induced EEG changes are not required for the antidepressant-like effects of these compounds and that neural circuitry involved in absence epilepsy may be related to delta-opioid agonist-induced convulsions. In terms of therapeutic development, these data suggest that it may be possible to develop delta-opioid agonists devoid of convulsive properties.

NMDA receptors mediate heat shock protein induction in the mouse brain following administration of the ibotenic acid analogue AMAA

Expression of inducible heat shock protein-70 (HSP-70) and hsp-70 mRNA were studied in the adult mouse brain following systemic administration of the ibotenic acid analogue (±)-2-amino-3-hydroxy-5-methyl-4-isoxazoleacetic acid (AMAA), which is a potent N-methyl- d-aspartate (NMDA) agonist. At the dose of 20 mg/kg, AMAA produced excitatory behaviours in adult mice but overt convulsions were not seen. This treatment did not result in any detectable morphological brain damage at 4 days following administration. At 2.5 h and 5 h following treatment induction of hsp-70 mRNA expression was found in the pyramidal cell layers of CA1 and, to a lesser extent, CA3 fields of hippocampal Ammon's horn, amygdala, olfactory lobes, tenia tecta, hypothalamic nuclei and a superficial layer of cingulate, frontal and retrosplenial cortices. The presence of HSP-70 was detected by immunohistochemistry at 24 h following drug administration in those regions previously showing hsp-70 mRNA induction. AMAA-induced hsp-70 mRNA expression was prevented by pre-treatment with the non-competitive NMDA antagonist MK-801. These results suggest that NMDA receptors are involved in the stress response induced by AMAA.

Malaoxon-Induced Brain Phosphoinositide Turnover and Changes in Brain Calcium Levels by Female Gender in Pregnant and Non-Pregnant Convulsing and Non-Convulsing Rats

Alterations in malaoxon-(MO)-induced brain regional phosphoinositide (PI) turnover and in brain calcium levels were studied in female non-pregnant and pregnant rats, and in their offspring. The adult rats were followed for 1 or 4 h after MO for tonic-clonic convulsions. A dose of 8.2 mg kg-1 of MO caused similar convulsions in 74% of the pregnant rats as we have reported in young male rats with a dose of 39.2 mg kg-1. However, convulsions did not occur in non-pregnant female rats. Inositol and inositol monophosphate levels were similar in all control rats. MO decreased brain inositol both in pregnant and non-pregnant female rats, and in the cerebellum of the offspring. In contrast to the findings in male rats, MO only randomly increased brain inositol-1-phosphate in female rats, or in their offspring. However, cerebral inositol-4-phosphate levels were similarly increased both in the non-pregnant and the pregnant rats irrespectively of convulsions. MO did not elevate cerebral Ca2+ in female rats or their offspring, in contrast to the male rats. The present results suggest that female rats are more sensitive than male rats to MO-induced PI signalling, and during pregnancy, also to MO-induced overt convulsions, but not to changes in cerebral Ca2+.

The effects of FG 7142 upon local cerebral glucose utilization suggest overlap between limbic structures important in anxiety and convulsions

The effects of the ß-carboline benzodiazepine receptor ligand FG 7142 upon local cerebral glucose utilization have been examined in conscious rats using the quantitative [ 14C]2-deoxyglucose autoradiographic technique. FG 7142 (1–10 mg/kg i.v.) produced behavioural changes consistent with an anxiogenic action. At the largest dose of FG 7142 (10 mg/kg) 30% of the animals experienced overt convulsions. In the data analysis animals were divided according to the behavioural response elicited by the drug. In animals not expressing convulsions, FG 7142 (1–10 mg/kg) effected increases in glucose utilization in 33 of the 65 regions examined. The majority of changes were confined to limbic structures with pronounced effects occurring in the mammillary body, anterior thalamic nuclei, septal nuclei and the oriens and molecular layers of the hippocampus. Glucose use in other structures associated with auditory and visual processing, such as the medial and lateral geniculate body, and associated cortical areas, was also significantly increased. However, brain regions involved in motor control were minimally affected. The patterns of local cerebral glucose use in animals expressing FG 7142-induced convulsions were contrasted with those from an equivalent non-seizure group. Some limbic structures which were significantly affected by FG 7142 (non-seizure group) displayed a further increase in glucose utilization during convulsions. These included the mammillary body and septum. Many other limbic structures (anterior thalamic nuclei, CA fields of the hippocampus and basolateral amygdala) did not display this further rise in glucose utilization. In the cortical amygdala, lateral preoptic area of the hypothalamus, nucleus accumbens and lateral habenula elevations in glucose utilization were restricted to those animals experiencing overt convulsions. Similarly, glucose use in structures associated with motor control such as the globus pallidus and substantia nigra was markedly increased only during seizures. It would appear that some limbic structures are functionally involved in the expression of both the anxiogenic and convulsive properties of FG 7142.

Attenuation of cerebral glucose use in kainic acid-treated rats by diazepam

Diazepam's impact on kainic acid seizure-induced local cerebral glucose utilization (LCGU) was assessed by a quantitative [ 14C]2-deoxyglucose method. Male rats were injected i.p. with either kainic acid (12 mg/kg) or its vehicle, 3 or 48 h before LCGU determination. Diazepam (3.2 mg/kg) or its vehicle were injected i.m. 15 min before, 1 and 2.5 h after kainic acid. Diazepam blocked kainic acid-induced overt convulsions, attenuated LCGU increases at 3 h and prevented 48 h LCGU decreases in piriform cortex and amygdala. LCGU in (% of vehicle): CA 3 (438%), CA 4 (537%) and CA 1-ventral (340%) of hippocampus, interpeduncular nucleus (200%) and lateral lemniscus (213%) were still significantly above vehicle levels in the 3 h diazepam-kainic acid group. These results suggest that diazepam suppresses the spread of kainic acid-induced seizure activity from the proposed CA 3 epileptogenic focus. In addition, diazepam reduces, but does not abolish, hypermetabolic activity at the foci itself.

Regional cerebral metabolic rate for glucose during hyperbaric oxygen-induced convulsions

Hyperbaric oxygen-induced convulsions in awake unrestrained rats are preceded by electrocorticographic changes including paroxysmal electrical discharges (PED). During oxygen induced convulsions, alterations in regional cerebral metabolic rate for glucose (rCMRgl) were autoradiographically measured and compared with rCMRgl results obtained during pre-convulsive periods in an earlier study. Statistically elevated rCMRgl during oxygen-induced convulsions were found in globus pallidus, substantia nigra, limbic structures, and cerebellar cortex. Significant reductions were found largely in auditory structures and cerebral cortex. This pattern of changes in rCMRgl resembles the pattern of changes during successive PED in the absence of overt convulsions. This similarity may indicate that a common sequence of biochemical changes leads to both oxygen-induced pre-convulsive as well as convulsive electrical discharges.

Delayed post hypoxic transient amnesia is not associated with electrical brain seizures

Rats rendered hypoxic by brief exposure to N 2 after learning an avoidance response go into convulsions and subsequently become amnestic. Overt convulsions can be avoided whilst yet producing delayed post-hypoxic transient amnesia (DPHTA) by using 2% O 2 in N 2 in place of pure N 2. The experiments reported here show that with this gas mixture, the ECoG shows hardly any of the electrical activity associated with seizures which occurs with N 2. It is concluded that electrical seizures are not associated with the mechanism responsible for DPHTA.

Pentylenetetrazol-induced amnesia: a case for overt seizures.

In this study, the possible role of overt convulsions following pentylenetetrazol (PTZ) in retrograde amnesia was investigated. Following a single passive avoidance conditioning, when overt convulsions were blocked with sodium pentobarbital (Nem), the amnesic effect of pentylenetetrazol was also blocked. Subconvulsive doses of the drug did not produce amnesia. Animals that received a typically convulsive dose of the drug but failed to convulse were not amnesic; only animals with overt convulsions were different from saline controls. The data suggest that overt convulsions may be necessary for the development of pentylenetetrazol-induced retrograde amnesia.

Intensification of the alcohol withdrawal syndrome by repeated brain stimulation.

SINCE the discovery that electrical stimulation of discrete sites of the brain can influence behaviour, there have been numerous reports of its application1. Such procedures, however, may lead to kindling2; stimulation of some sites at currents initially too low to produce a behavioural response may lead to a gradual development and then intensification of seizures evoked by the stimulation3. Thus when the brain is repeatedly stimulated for therapeutic purposes, seizures may be elicited unless procedures not conducive to kindling are used2. Two questions arise: can kindling leave an organism more susceptible to seizures produced by agents other than local brain stimulation, and are elicited convulsions necessary for this change in susceptibility? Our findings indicate that whether or not overt convulsions are produced by brain stimulation, repeated electrical stimulation of the brain potentiates the effects of subsequent alcohol withdrawal.

Amnesia produced in cats by local seizure activity initiated from the amygdala

Cats were thoroughly trained to enter a small compartment for food. They then received an aversive mouth-shock while eating in the compartment. All cats used as controls showed great hesitation for entering the compartment when tested 24 hr subsequent to such a stimulus. When tonic-clonic convulsions were induced by stimulation applied across the brain, either alone or within 4 sec after an aversive mouth-shock, they unhesitantly entered the compartment 24 hr later, thus displaying full amnesia for the experience, and absence of aversiveness for the convulsion. Convulsions per se, however, are insufficient to produce such amnesia since cats subjected to mouth-shocks followed by tonic-clonic seizures initiated from the frontal cortex or clonic seizures from stimulation of the mesencephalic reticular formation had the same hesitancy as did control animals and thus presumably remembered the punishment. On the other hand, amnesia was produced if, within 4 sec after the mouth-shock, electrical afterdischarges without the production of overt convulsions were initiated by stimulation of the dorsal hippocampus or amygdala; but not if initiated from the septum, fornix, or ventral hippocampus. Present interpretation is that near normal function in the amygdala is necessary for fixation of an aversive experience, and that seizure activity must engage it fully to produce amnesia for such an experience.

Light-induced seizures

Review of 20,000 electroencephalograms obtained during an 11 year period revealedrecords of 250 patients with abnormal patterns following photic stimulation. Of this number, 25subjects exhibited overt convulsions in association with photic stimulation. Seven had definite evidence of mental retardation, and in two the light-sensitive seizures were self-induced. Clinical and electroencephalographic findings of several patients are described. The remaining 225 children had electroencephalographic evidence of seizure discharge in response to light-stimulation, but without overt convulsive activity. The mechanism of convulsive activity, relationship to cerebral damage, genetic aspects, causative factors, and management are reviewed.