Phenytoin prevents stress‐ and corticosterone‐induced atrophy of CA3 pyramidal neurons

Abstract

Repeated daily restraint stress and daily corticosterone administration to adult male Sprague-Dawley rats leads to decreases in the number of branch points and length of dendrites of CA3 pyramidal neurons of the hippocampal formation. This decrease is prevented by daily administration of the antiepileptic drug phenytoin (Dilantin), which is known to interfere with excitatory amino acid release and actions. Phenytoin had no obvious effect on behavior during and after stress and failed to prevent stress-induced reduction of body weight gain and stress-induced increases of adrenal weight relative to body weight; it also failed to attenuate glucocorticoid-induced diminution of the size of the thymus gland, indicating that it does not directly antagonize glucocorticoid actions. Stress- and corticosterone-induced effects on dendritic length and branch point number are more pronounced on the apical, as opposed to the basal, CA3 dendrites that receive the largest mossy fiber input from the dentate gyrus. Because phenytoin is also known to prevent ischemic damage, these results are consistent with a model in which stress- and corticosterone-induced CA3 dendritic atrophy is produced by excitatory amino acids released from the mossy fibers.

Brief RU 38486 Treatment Normalizes the Effects of Chronic Stress on Calcium Currents in Rat Hippocampal CA1 Neurons

“…Rather, RU 38486 seems to reverse the effects of earlier stress exposure (during days 1-17) or to block putative effects developing during the last days of the stress protocol. Normalizing effects on morphological parameters of CA3 neurons after 21 days of restraint stress were earlier observed after treatment with the antiepileptic drug phenytoin (Watanabe et al, 1992b), with benzodiazepines (Magarinos et al, 1999) or an NMDA-receptor antagonist (Magarinos and McEwen, 1995a). Similarly, the antidepressant tianeptine, which decreases the bio-availability of serotonin (Whitton et al, 1991) but also affects glutamate transmission (Kole et al, 2002), has been reported to prevent dendritic retraction of CA3 pyramidal neurons and the enhanced AMPA-receptor mediated responses of these cells after restraint stress (Magarinos et al, 1999;Kole et al, 2002).…”

A single social stress-experience alters glutamate receptor-binding in rat hippocampal CA3 area

“…Hippocampal neurons in the CA3 and CA4 area are vulnerable to effects of acute and long-term stress [11,16,17,23,24]. Long-term corticosterone treatment results in similar effects [1,11,16,24,25).…”

“…Long-term corticosterone treatment results in similar effects [1,11,16,24,25). It has been hypothesized that the glutamatergic mossy fiber input on corticosteroid receptor containing cells contributes to this effect [11].…”

“…NMDA receptors are involved in the excitotoxic actions of glutamate [12], and their upregulation after stress may have consequences for hippocampal CA3 neurons. Indeed acute and chronic stress can influence the ultrastructure of hippocampal neurons in the CA3 and CA4 area and glucorticoids seem to be involved in this effect [1, 1 1, 16,17,[23][24][25]. A possible mechanism via which chronic corticosterone administration or stress could adversely affect CA3 pyramidal cells is by altering glutamatergic mossy fiber activity, which directly influences CA3 neurons via the release of glutamate, resulting in an increased Ca -,+ influx [11].…”

“…Although the distribution of glucocorticoid receptors in the hippocampus does not explain why the CA3 area is particularly vulnerable [15], the involvement of the NMDA receptor in this exacerbating effect of glucocorticoids is convincing [1]. Recently Watanabe et al [24] have reported that an antiepileptic drug, which is known to interfere with excitatory amino acid release and actions, prevents stress-and corticosterone-induced atrophy of hippocampal CA3 pyramidal neurons. Therefore, a synergistic action of glutamate and corticosteroids seems to be involved in stressand corticosterone-induced atrophy of CA3 pyramidal neurons.…”