Gerald K. Weiss

Effect of locus ceruleus stimulation on the development of kindled seizures

The effects of locus ceruleus stimulation on amygdala kindling development were investigated. Twenty to thirty minutes of locus ceruleus stimulation was delivered prior to each amygdala kindling session. Locus ceruleus-stimulated animals spent a significantly longer time in stage 1 than did nonstimulated or reticular formation stimulated controls. However, the total number of stimulations to produce the first stage 5 did not differ between groups. The afterdischarge duration in locus ceruleus-stimulated animals increased even though the behavioral stages did not progress. There appeared to be an uncoupling of the electrographic and behavioral manifestations of the kindling process in the locus ceruleus-stimulated animals. These data support the view of an inhibitory role of the central noradrenergic system in the development of kindled seizures.

Antikindling effects of locus coeruleus stimulation: Mediation by ascending noradrenergic projections

Electrical stimulation of the noradrenergic locus coeruleus (LC) delays the generalization of partial seizures during amygdaloid kindling by increasing the time spent in the earliest stages of seizure development. To determine whether noradrenergic axons projecting to the midbrain and forebrain are involved in this antikindling effect, we examined the effects of lesions of the dorsal noradrenergic bundle, induced by intracerebral infusions of 6-hydroxydopamine (6-OHDA), on kindling and the antikindling action of stimulation of the LC. Stimulation of the LC during amygdaloid kindling increased the number of afterdischarges (ADs) spent in the early stages of partial seizure and decreased the number of ADs spent in later stages of generalized seizure, as has been described previously. LC-stimulated rats also displayed longer durations of AD during early stages of kindling. The antikindling effect of LC stimulation was blocked by lesions of the dorsal bundle, whereas the facilitatory effects of LC stimulation on generalization and on the duration of AD were unaffected by the lesions. These results suggest that the antikindling action of LC stimulation is mediated by the ascending projections of noradrenergic neurons, presumably through enhanced release of noradrenaline. On the other hand, the facilitatory effects of LC stimulation on the development of later stages of seizure and on the duration of AD appear to be independent of the ascending dorsal bundle.

Habituation of the prolactin response in rats to psychological stress

It is well known that stress is a stimulant for prolactin release. However, relatively few studies have investigated the role of psychological factors in prolactin secretion, and investigators have typically used one-time exposure and a single collection period in their studies. In our studies, attempts were made to carefully characterize the prolactin response to different psychological stressors by serially sampling blood from an indwelling cannula and to determine if repeated exposure to the stressor leads to habituation of the prolactin response. Exposure of the male rats to different novel situations such as being placed in a new cage, being placed on a platform in water, or being handled resulted in increased prolactin levels. As the rats habituated behaviorally to repeated exposure to similar situations, the prolactin response also attenuated. These findings show that psychological factors do play a role in influencing prolactin secretion and are consistent with the idea that as the psychological stress imposed by a stimulus becomes habituated, the prolactin response to that stimulus also becomes habituated.

Effect of corticosterone on the prolactin response to psychological and physical stress in rats.

Both corticosterone and prolactin (PRL) levels increase in response to stress. In these studies we examined the effect of corticosterone on the PRL response to both physical (footshock) and psychological (novel environment) stress. Three groups of rats were used: sham adrenalectomized (SHAM), adrenalectomized (ADX), and adrenalectomized with corticosterone replacement (ADX+CORT). The corticosterone-treated animals received 80 micrograms corticosterone/ml drinking water. Blood samples were drawn via an indwelling cannula and PRL values determined using radioimmunoassay. ADX rats showed a consistently greater PRL response to being placed on a platform above water (novel environment) or when receiving intermittant footshock than did ADX+CORT rats. The PRL response of the latter group was similar to that of the SHAM animals. These findings indicate that corticosterone levels of an animal can significantly attenuate the magnitude of the PRL response to both physical and psychological stress. These findings further emphasize that the PRL response to stress is dependent not only upon the immediate action of the stressor, but also the prior stress history of the animal.

The effect of adrenalectomy on the circadian variation in the rate of kindled seizure development

The hypothalamic-pituitary adrenal axis (HPAA) is activated during kindled seizures and the circadian changes in this axis may contribute to the circadian variation in the kindling rate. Changes in the rate of seizure development were examined in rats that were amygdala kindled in the a.m., at midday and in the p.m.. Sham operated control groups were compared to adrenalectomized groups. Adrenalectomy had no effect on the midday rate but abolished the normal circadian variation by accelerating the rate in the a.m. and decreasing the rate in the p.m.. These results suggest a complicated relationship of kindled seizure rate to the hormones of the HPAA axis.

The effect of two different types of stress on locus coeruleus alpha-2 receptor binding

The central noradrenergic neurons of the locus coeruleus (LC) are important in regulating an animals response to a stressor. Changes in alpha-2 autoreceptors on LC neurons during stress could alter the functional state of the LC. We investigated the changes in binding of LC alpha-2 receptors immediately following 1 h and 4 h of two stressors: novelty + cold and prone restraint. We measured the specific binding of the alpha-2 receptor antagonist [3H]idazoxan in the LC of rats using in vitro autoradiography. Specific binding was increased after 1 h of novelty + cold exposure but decreased after 4 h, and after both 1 and 4 h of prone restraint. The increase after 1 h of stress may be due to the ability of LC neurons to regulate their own activity because this would produce a dampening of the high LC activity produced by the stressor. However, extended time and/or intensity of a stressor may overwhelm this initial response and produce an agonist-induced decrease in receptor binding.

Amygdala kindling rate is altered in rats with a deficit in the responsiveness of the hypothalamo-pituitary-adrenal axis.

Fisher and Lewis rats were amygdala kindled in the morning and in the evening. Fisher rats displayed a diurnal variation in the rate of kindling through stage 2 which did not exist in the Lewis rats. Lewis rats also take much longer to kindle through stage 2 and a subcutaneous corticosterone pellet accelerates this rate. These observations are consistent with the hypothesis that the hormones of the hypothalamo-pituitary-adrenal (HPA) axis, particularly the glucocorticoids, play a role in epileptogenesis.

Chronic imipramine treatment induces downregulation of alpha-2 receptors in rat's locus coeruleus and A2 region of the tractus solitarius

Imipramine is an effective antidepressant agent that blocks the reuptake of monoamines. In order to understand some of its basic mechanisms of action, we investigated the effects of chronic imipramine administration (10 mg/kg, i.p.; 21 days) on the alpha-2 receptor population of several brain sites. Alpha-2 receptor density was estimated by in vitro autoradiography using [3H]Idazoxan. The densitometric analysis revealed a decreased receptor density in the A2 region of the tractus solitarius (20%) and locus coeruleus (16%). No changes were observed in the amygdala, pyriform cortex, periacueductal gray and the bed nucleus of the stria terminalis. These results suggest that chronic imipramine treatment selectively modulates the alpha-2 receptor population localized in the brain stem norepinephrine-rich nuclei and not in the population present on limbic structures innervated by noradrenergic terminal projections. The possible physiological consequences of this selective modulation of alpha-2 receptors are discussed.

Noradrenaline and Kindling Revisited

One of the most consistent findings in the literature on kindling has been the observation that the process of seizure development is facilitated by treatments that interfere with the actions of noradrenaline (NA). This body of research has given rise to the hypothesis that part of the mechanism of kindling may be a decrease in the effects of NA, produced either by a progressive suppression of the presynaptic release of NA1 or a decline in the postsynaptic response to NA2. In the present chapter we provide an update on recent evidence that NA may modulate kindling.

The effect of amygdala kindled seizures on locus coeruleus activity

Locus coeruleus (LC) neuronal activity was recorded in anesthetized and in awake behaving rats during the production of amygdala afterdischarges (ADs) using kindling protocol. Both LC multiple and single unit discharges were temporally correlated with the appearance of ADs in the amygdala. Seizures were manifested in single unit activity as significant increases in firing rate. In awake animals, a bursting pattern of discharges was observed. We postulate that the observed changes in the LC activity pattern may have a modulatory role in the development of kindled seizures.