Corticotropin‐releasing hormone–induced seizures in infant rats originate in the amygdala

Abstract

The neuroanatomical substrate of seizures induced by picomolar amounts of corticotropinreleasing hormone in infant rats was investigated. Electrographic and behavioral phenomena were monitored in 42 rat pups aged 5 to 22 days. Rat pups carried bipolar electrodes implanted in subcortical limbic structures, as well as cortical electrodes and intracerebroventricular cannulae. The administration of corticotropin-releasing hormone produced age-specific seizures within minutes, which correlated with rhythmic amygdala discharges. Paroxysmal hippocampal and cortical discharges developed subsequently in some rats. Corticotropin-releasing hormone-induced electrographic and behavioral seizures originate in the amygdala.Corticotropin-releasing hormone (CRH) is a 41-amino acid neuropeptide, isolated originally from the mammalian hypothalamus [1], It has since been shown to be distributed nonrandomly in the central nervous system, and to perform roles other than the control of secretion of ACTH and endorphins from the anterior pituitary [2]. Specifically, central transduction of stress, anxiety, depression, and anorexia have been demonstrated [2,3].CRH activates neurons both in vivo and in vitro [4][5][6][7][8][9]. The peptide increases both spontaneous and evoked spike discharge from locus ceruleus neurons in vivo [4], CRH induces neuronal depolarization in CA1 and CA3 hippocampal pyramidal cells in the slice preparation in vitro [5]. CRH administered into the cerebral ventricles of adult rats causes epileptiform discharges in the amygdala after a 1-to 3-hour delay, which spread to the dorsal hippocampus [6]. These discharges progress over 3 to 7 hours to behavioral and electrographic seizures. The doses needed for frank seizure generation in adult rats axe 1-5 to 3-75 × 10 −9 mol (0.75-1.88 × 10 −9 mol/gm of brain weight) [6][7][8].We have previously shown that CRH is a far more rapid and potent convulsant in the neonatal rat [10]. Seizures occur with a latency of as little as 2 minutes and with CRH doses as low as 7.5 × 10 −12 mo! or 0.05 × 10 −9 mol/gm of brain weight [10]. The present study was designed to define the neurobiological matrix of the behavioral and electrographic effects of the neuropeptide. We used infant rats, starting on postnatal day 5. Materials and Methods AnimalsTimed-pregnancy Sprague-Dawley-derived rats were obtained from Zivic-Miller (Zelionplc, PA). They were housed under a 12-hour light/dark cycle and fed ad libitum. Copyright © 1992 Delivery times were monitored and were accurate to within 12 hours. The day of birth was considered day zero. The pups were kept with the mothers, and litters were culled to 12 pups. Infant rats were subjected to surgery 24 hours before recording and returned to their mothers. CRH was always administered between 9 and 10:30 AM, to minimize diurnal variations in seizure susceptibility [11] and in endogenous CRH levels [12]. Surgical ProcedureElectrodes were implanted under halothane anesthesia, using an infant rat stereotaxic apparatus as previously describe...

Gender difference in acquired seizure susceptibility in adult rats after early complex febrile seizures

“…Baseline hippocampal electroencephalograms (EEGs) were recorded 24 h later, followed by seizure induction by hyperthermia and MES [18,19] . In detail, electrodes were implanted under halothane anesthesia (2%-3% halothane inhaled through muzzle), using an infant rat stereotaxic apparatus (512600, Stoelting).…”

Neuronal activity and stress differentially regulate hippocampal and hypothalamic corticotropin-releasing hormone expression in the immature rat

“…In brief, one day prior to experiments, immature rats (n = 6) were implanted with bipolar electrodes directed at the dorsal hippocampus, using methods and coordinates described in detail previously. 4,7,9,18 After a 24-h recuperation period, hippocampal EEGs were obtained in the presence or absence of pentobarbital (30 mg/kg, i.p. ), both before and subsequent to induction of hyperthermia.…”

“…Recordings were obtained from freely moving animals, using long flexible wires, as described elsewhere. 7,9 Electrode placement was verified in all animals.…”

“…59 In addition, it has been demonstrated in both the mature and developing hippocampus that application of CRH may lead to excessive excitation of the hippocampal circuit, resulting in repetitive discharges of hippocampal neurons in vitro 1,25,50 and in seizures in vivo. 7,39 It has been suggested that excessive elevation of hippocampal CRH levels may contribute to abnormal neuronal excitation (seizures). 6 Thus, regulation of CRH levels in peptidergic hippocampal neurons may be important for both normal and pathological activation of the hippocampal circuit, 6,25,50 predicting that these levels may be subject to tight physiological control.…”

The developmental profile of the corticotropin releasing factor receptor (CRF2) in rat brain predicts distinct age-specific functions

“…The peptide has been implicated in the central mediation of the response to stress, as well as in anxiety, anorexia and neuroexcitation [16,28,33,42]. Certain actions of CRF on limbic neurons are age-dependent, such as the peptide's excitatory effects on neurons in the amygdala [4] and the hippocampus [20,39].…”