Yves R. J. Bureau

Behaviors of rats with insidious, multifocal brain damage induced by seizures following single peripheral injections of lithium and pilocarpine

Several domains of behavior were measured in rats (n = 465) 10 days to 100 days after induction of limbic seizures by a single subcutaneous injection of lithium and pilocarpine. These rats displayed enhanced intragroup aggression but normal muricide; gustatory neophobia and conditioned taste aversion were virtually eliminated. Severe working and reference memory deficits were evident within the radial arm maze. Both state-dependent memory and possible situation-dependent precipitation of spontaneous seizures were suggested. The behavioral changes were considered commensurate with the multifocal pattern of thalamic, hippocampal/amygdaloid, and limbic cortical damage.

Dissociation between conditioned taste aversion and radial maze learning following seizure-induced multifocal brain damage: Quantitative tests of serial vs. parallel circuit models of memory

Multivariate analyses between conditioned taste aversion (CTA) and radial maze acquisition (RMA) scores and percentages of neuronal dropout within thalamic and telencephalic structures were completed for rats in which overt seizures had been evoked following a single systemic injection of lithium/pilocarpine. Despite multifocal damage, only the amount of damage within the hippocampus (CA1) and the basolateral amygdala was most strongly associated with attenuated CTA, whereas damage within the mediodorsal thalamus was primarily associated with RMA. There was no significant correlation between CTA or RMA. Multiple regression analyses for specific Paxinos and Watson structures and their traditional aggregates supported more precise delineation of neuronal substrates of learning/memory and a multimodal (parallel) model for these processes.

Concordance of quantitative damage within the diencephalon and telencephalon following systemic pilocarpine (380 mg/kg) or lithium (3 mEq/kg)/pilocarpine(30 mg/kg) induced seizures

We tested the hypothesis that a single systemic injection of 380 mg/kg of the muscarinic agonist pilocarpine would produce more diffuse and severe seizure-induced brain damage than a single injection of lithium (3 mEq/kg) followed 4 h later by < 1/10 the dosage of pilocarpine. The hypothesis was not supported; the pattern of quantitative brain damage 50-60 days after the seizures were elicited by either treatment was comparable within the limits of measurement error. Within the diencephalon and subcortical telencephalon the same structures were either damaged in a similar quantitative manner or were spared. Only five of the 119 damaged structures exhibited statistically significant treatment differences at P < 0.01. The results are compatible with the explanation that lithium may enhance the excitotoxic effects of subsequent muscarinic stimulation.

Geomagnetic activity and enhanced mortality in rats with acute (epileptic) limbic lability.

Presumably unrelated behaviors (e.g. psychiatric admissions, seizures, heart failures) have been correlated with increased global geomagnetic activity. We have suggested that all of these behaviors share a common source of variance. They are evoked by transient, dopamine-mediated paroxysmal electrical patterns that are generated within the amygdala and the hippocampus of the temporal lobes. Both the probability and the propagation of these discharges to distal brain regions are facilitated when nocturnal melatonin levels are suppressed by increased geomagnetic activity. In support of this hypothesis, the present study demonstrated a significant correlation of Pearsonr=0.60 between mortality during the critical 4-day period that followed induction of libic seizures in rats and the ambient geomagnetic activity during the 3 to 4 days that preceded death; the risk increased when the 24 h geomagnetic indices exceeded 20 nT for more than 1 to 2 days.

Seizure onset times for rats receiving systemic lithium and pilocarpine: Sources of variability

Injection of 30 mg/kg of pilocarpine 24 h after systemic injection of lithium (3 mEq/kg) results in overt limbic motor seizures within about 30 min. Results of several experiments indicated that whereas food deprivation or repeated nociceptive stimulation during the previous 24 h decreased seizure onset times (SOTs) by about 11 to 12 min, food restriction, continuous lighting, or, handling during the previous 7 to 14 days increased SOTs by comparable durations. Early handling before weaning but not injections of clomimpramine also decreased SOTs. A difference of 18 min in the means of SOTs was produced by injecting either 1.0 (increased SOT) or 1.5 mg/kg (decreased SOT) of dexamethasome during the previous 24 h. A strong (multiple r=.87) association between SOTs and the amount of damage within five specific thalamic-limbic nuclei was observed. These results, in conjunction with blood corticosterone levels taken before and after induction of the seizures, suggest the neurochemical mechanisms affecting the range in SOTs could involve the adrenocorticotropic hormone (ACTH)-corticosterone system and influence the amount of post-seizure-induced damage.

Prevention of sudden cardiac death by the atypical neuroleptic acepromazine following status epilepticus in rats

Normal male rats in which status epilepticus has been induced by injecting 30 mg/kg of pilocarpine after a single systemic administration of lithium (sufficient to produce blood levels of 0.2 mEq/L) invariably die within 24 hr. Real-time monitoring indicated sudden cardiac death; it was preceded by progressive intensification of arrhythmia. A single systemic injection (25 mg/kg) of the atypical phenothiazine acepromazine prevented the mortality and virtually eliminated the cardiac instability.

EMERGENT PROPERTIES FOLLOWING BRAIN INJURY: THE CLAUSTRUM AS A MAJOR COMPONENT OF A PATHWAY THAT INFLUENCES NOCICEPTIVE THRESHOLDS TO FOOT SHOCK IN RATS

Flinch (pain) thresholds for electric current delivered to the feet were correlated with the amount of necrosis within the diencephalon and telencephalon for rats in which seizures had been induced by lithium and pilocarpine about two months before the testing. The shared variance of the quantitative damage within the claustrum, the anterior part of the paraventricular nucleus of thalamus, (central) mediodorsal thalamus, and lateral amygdala (ventromedial part) explained 81% of the variance in the nociceptive (flinch) thresholds. A primary role of the claustrum within the neuropathways that mediate the response to the interoceptive and “painful” characteristics of stimuli is indicated. The concept of primary pathways versus “emergent” pathways subsequent to excitotoxic damage within the neuromatrix is discussed.

Transient blocking of persistent gnawing by haloperidol in rats with seizure-induced multifocal brain damage

Frequent but phasic gnawing of objects is displayed by rats in which severe damage within: 1) the substantia nigra reticulata, 2) all of the amygdaloid nuclei except the central group and 3) multiple thalamic nuclei, was induced by lithium/pilocarpine-induced seizures. Multiple lesions were produced by these rats upon their own tails as well as upon the tails of their cage mates. These behaviors were considered predictable sequela of the disinhibition of compacta dopamine upon orofacial mechanisms that are modulated by the corpus striatum. In a manner similar to tail pinch-induced eating, the usually quick onset of spontaneous gnawing upon food chunks in a test setting was delayed transiently by appropriate dosages of haloperidol.

Cholinergic Rebound after Chlorpromazine Exacerbates Lithium Muscarinic-Induced Limbic Seizures in Rats: Implications for Psychiatric Treatment:

When lithium serum levels were within the (human) therapeutic range, young and old adult male and female rats (housed singly or in groups) all displayed faster limbic seizure onset times in response to a muscarinic cholinergic agonist (pilocarpine 20 mg/kg) if a single systemic dosage of chlorpromazine was injected 24 hours previously. The effect was comparable to injecting an additional 10 mg/kg of pilocarpine. These results strongly suggest that cholinergic rebound from chlorpromazine administrations during lithium treatment could facilitate subclinical electrical lability and very localized neuronal necrosis within the limbic system of clinical patients, resulting in normalization of psychiatric symptoms.

Extreme hypothermia induced by a synergism of acute limbic seizures, physical restraint, and acepromazine: implications for survival following brain injury.

Core temperature was measured in rats 24 hr. after they had been assigned to one of 8 groups in a 3-way analysis of variance design that involved (1) induction of limbic seizures by a systemic injection of lithium/pilocarpine, (2) physical restraint, and (3) administration of acepromazine. An extraordinarily powerful interaction was noted among seizures, physical restraint, and acepromazine-produced hypothermia (24° C) compared to the other 7 treatments (> 35° C). The putative poikilothermic response is commensurate with the loss of mammalian behaviors that follow these seizures. Implications for survival during the acute stages of brain injury are suggested.