The Role of the Medial Preoptic Area of the Hypothalamus in Organizing the Paradoxical Phase of Sleep

Chronic experiments were performed on cats to study the effects of electrical stimulation of the medial preoptic area of the hypothalamus on the latent period, duration, and structure of paradoxical sleep, as well as the dynamics of neuron activity in this structure during the sleep-waking cycle. These investigations showed that low-frequency stimulation of the medial preoptic area during slow-wave sleep led to short-latency development of desynchronization of bioelectrical activity in the neocortex and initiated the development of paradoxical sleep or a similar state. Stimulation of this structure during paradoxical sleep led to a decrease in its duration, to the virtually complete disappearance of the tonic stage of paradoxical sleep, and to an increase in the frequency of rapid eye movements in the phasic stage. Rearrangement of neuron activity in the medial preoptic area during the sleep-waking cycle was similar to that seen in cells of the lower brainstem "executive" centers of paradoxical sleep. It is suggested that neurons in the medial preoptic area of the hypothalamus are actively involved in the mechanisms of paradoxical sleep and, in particular, in the desynchronization of neocortical bioelectrical activity which develops during this stage.     

Effects of Electrical Stimulation of the Posterior Part of the Hypothalamus on the Spike Activity of Neurons in the Oral Nucleus of the Pons

Chronic experiments were performed on four cats to study evoked spike activity in neurons in the oral nucleus of the pons to electrical stimulation of the posterior hypothalamus in the waking, slow-wave sleep, and paradoxical sleep states. A total of 42% of study neurons were found to respond to stimulation during waking. PS-on and PS-off neurons were identified in the oral nucleus of the pons, along with phasic cells showing bursts of activity during the physical manifestations of paradoxical sleep. Stimulation induced inhibitory responses in PS-on neurons, excitatory responses in PS-off neurons, and excitatory and inhibitory responses in 68% and 32% respectively of phasic neurons. The magnitudes of evoked responses in these neurons changed during the sleep-waking cycle. These data demonstrate the involvement of the posterior hypothalamus in controlling the mechanisms of paradoxical sleep, these mechanisms being located in the oral nucleus of the pons.__________Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 90, No. 9, pp. 1094–1102, September, 2004.     

Laminar analysis of intracortical auditory evoked potentials during the wakefulness-sleep cycle in the cat

Click-elicited evoked potentials (EPs) were recorded simultaneously in six different depths of the auditory cortex of freely moving cats during the wakefulness-sleep cycle. Chronically implanted multielectrodes designed especially for this purpose were used. The clicks were given through a bone conductor and middle ear muscles were cut to keep the acoustic input constant. The EPs recorded in different cortical depths changed in different ways during the wakefulness-sleep cycle as evidenced by both the early and middle latency components. The amplitude of the middle latency components was the largest in slow wave sleep (SWS) in all cortical depths. The early deep negative wave was the smallest in paradoxical sleep (PS) probably indicating a reduced sensory input. In the aroused state a negative component of approximately 60 ms appeared localized to the superficial layers. The lack of a true phase reversal of the early components, their independently changing amplitudes and the homogeneous polarity of the later waves in the different cortical depths do not support the idea of simple dipole processes that could explain their generation.     

Effect of low-frequency electrical stimulation of the caudate nucleus on cortical electrical activity and the waking-sleep cycle

In response to single electrical stimulation of the caudate nucleus of unanesthetized, freely moving cats, an evoked potential arises more easily in the sensomotor cortex than in the hippocampus. Despite this fact, hippocampal evoked potentials are facilitated and stabilized at a frequency of 4–6/sec. In the sensomotor cortex, on the other hand, the potentials are most marked at a frequency of 6–8/sec, but they are variable and during prolonged stimulation spindle-like activity is formed. The behavioral correlate of synchronization of electrical activity during low-frequency stimulation of the caudate nucleus is a drowsy state, which ceases at the end of stimulation. Similar stimulation in the paradoxical phase of sleep also evokes synchronization of the electrocorticogram, but after stimulation the structure of the paradoxical phase is restored. Synchronizing stimulation of the caudate nucleus causes considerable changes in the waking-sleep cycle in the poststimulation period: The total amount of the slow-wave phase is reduced and that of the paradoxical phase is increased.Translated from Fiziologicheskii Zhurnal SSSR imeni I. M. Sechenova, Vol. 62, No. 1, pp. 29–37, January, 1976.     

Long-lasting insomnia induced by preoptic neuron lesions and its transient reversal by muscimol injection into the posterior hypothalamus in the cat

In order to analyse the role of the anterior hypothalamus in the regulation of the sleep-waking cycle we made bilateral neuronal lesions at different levels of the anterior hypothalamus in cats, by means of microinjections of a cell-specific neurotoxin:ibotenic acid. These lesions resulted in severe insomnia in eight cats. This insomnia was characterized by a large decrease or even disappearance of paradoxical sleep and deep slow wave sleep and, to a lesser extent, by a decrease of light slow wave sleep, for 2-3 weeks. In the other five animals, we observed a large reduction of deep slow wave sleep (0-40% of control level), but a less intensive decrease of time spent in paradoxical sleep (50-75% of control level) and no marked effect on light slow wave sleep. During the first 3-6 postoperative days we also noticed hyperthermia in all cats; thereafter, the animals presented only a slight increase in brain temperature which did not appear to trigger the sleep impairment. Histological analysis of the different lesions revealed that the insomnia could be attributed to neuronal cell body destruction in the mediobasal part of the anterior hypothalamus covering; the medial preoptic area and a narrow portion of the lateral preoptic area as well as a restricted part of the anterior hypothalamic nucleus. In order to investigate the putative role of the posterior hypothalamic structures in the mechanism of insomnia after lesion of the mediobasal preoptic area neurons we injected an agonist of GABA into the ventrolateral part of the posterior hypothalamus to locally depress the neuronal activity. The bilateral intracerebral microinjection of muscimol (0.5-5 micrograms) induced a transient intensive hypersomnia (slow wave sleep and paradoxical sleep). These findings indicate that neuronal cell loss in the mediobasal preoptic area induced a long lasting insomnia. Thus, it may be hypothesized that the integrity of this structure is necessary for sleep appearance. Finally, our data are in keeping with an intrahypothalamic regulation of the sleep-waking cycle.     

Effect of ambient temperature on sleep-waking cycle in cats with electrolytic dorsolateral pontine tegmental lesions.

The effects of ambient temperature on the sleep-waking cycle were studied in intact cats and those with bilateral electrolytic lesions in the pontine tegmentum. At a room temperature of 23 degrees C, the percentage of time spent in paradoxical sleep was significantly lower in the lesioned cats than in intact animals. The mean duration of paradoxical sleep episodes was also decreased in the lesioned animals. The reduction in slow-wave sleep was not significant. At a slightly warmer ambient temperature of 30 degrees C, both the mean duration of paradoxical sleep episodes and the total duration of paradoxical sleep in the lesioned animals were increased toward normal values. Slow-wave sleep increased slightly but not significantly. At a higher ambient temperature of 35 degrees C, as well as at colder ambient temperatures of 15 and 7 degrees C, the durations of both paradoxical sleep and slow-wave sleep were significantly reduced. Under these thermal loads, the reduction in the duration of sleep was significantly greater in the lesioned cats than in the intact animals. The results suggest that: (i) pontine lesions alter the sleep cycle of cats and ambient temperature influences this alteration; (ii) the effects of thermal loads on the sleep cycle are more severe in the lesioned cats; and (iii) a moderately warm ambient temperature (30 degrees C) improves the sleep of pontine-lesioned cats.     

The role of the posterior hypothalamus in controlling the paradoxical phase of sleep

Chronic experiments were performed on seven cats to study the effects of high-frequency electrical stimulation of the posterior hypothalamic area on the characteristics of paradoxical sleep; the excitability of this structure at different stages of paradoxical sleep was determined. These studies showed that at the stage showing ECoG desynchronization and phasic events (stage 1), the response threshold for behavioral arousal resulting from stimulation of posterior hypothalamus was 20–30% higher than at the stage characterized by α-like activity in the ECoG and the absence of phasic phenomena (stage 2). Transient stimulation of the posterior hypothalamus at stage 1, at a level which was subthreshold for arousal from this state, led to a transition to stage 2 or a reduction in phasic events in paradoxical sleep without altering the qualitative characteristics of phase 1. Stimulation of the posterior hypothalamus at a level subthreshold for arousal from stage 2 and applied continuously during paradoxical sleep led to a reduction in the duration of this stage by 25–50% and to an increase in the proportion of stage 2 in the structure of paradoxical sleep. These results provide evidence that the posterior hypothalamus is involved in the inhibitory control of the ‘executive’ mechanisms of paradoxical sleep responsible for the ECoG desynchronization and the phasic manifestations of this state. It is suggested that the functional activity of the posterior hypothalamus at stage 1 also increases at stage 2, thus evidently fulfilling a ‘guard’ function. Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 84, No. 11, pp. 1165–1173, November, 1998.     

Sleep deprivation increases susceptibility to kindled and penicillin seizure events during all waking and sleep states in cats

The timing of amygdala kindled and penicillin seizures was studied throughout the sleep-wake cycle in eight cats following near total sleep deprivation and a control procedure that did not affect sleep time. Sleep loss was induced by 24-h exposure to a modified "flower pot" procedure employing a small pedestal. The control procedure consisted of 24-h exposure to a larger pedestal. Sleep loss increased susceptibility to generalized kindled and penicillin seizures during all waking and sleep states but did not alter temporal patterns of seizure susceptibility. Both before and after sleep loss, kindled cats showed maximal seizure susceptibility, indexed by lowest seizure thresholds, during slow wave sleep (SWS) and transitions from SWS to REM sleep (REMS). The spike-wave discharges and motor seizures of systemic penicillin epilepsy were always most frequent during SWS and during drowsiness after awakening. Both models were invariably most resistant to seizures during stable REMS. To explain sleep- and sleep loss-activated seizures, we summarized previous work suggesting that sleep abnormalities dictate the timing of seizures and are exacerbated by sleep loss. Abnormal behavioral arousals and pathological somatomotor system excitability occur in both models and are particularly pronounced during seizure-prone intervals. Sleep loss may magnify somatomotor system hyperexcitability patterns in all states, thus allowing abnormal motor arousals and seizures to intrude during seizure-prone and seizure-resistant sleep and waking states.     

Sleep induced by intestinal stimulation in cats.

The influence of afferent impulses of intestinal origin on the sleep stages was studied in fed and starved cats. Low-frequency electrical stimulation of the mucosal surface in a small intestinal fistula reduced the latency of sleep onset. The number of slow wave sleep episodes decreased, but their mean duration increased during stimulation. Conversely, the number of paradoxical sleep episodes increased, but their mean duration was not significantly modified by the intestinal stimulation. The role of viscerosensory events in the control of sleep is discussed in relationship to these results.     

Changes in neuronal conductance during different components of cortically generated spike-wave seizures

Neuronal conductance was studied in anesthetized cats during cortically generated spike-wave seizures arising from slow sleep oscillation. Single and dual intracellular recordings from neocortical neurons were used. The changes were similar whether the seizures occurred spontaneously, or were evoked by electrical stimulation or induced by bicuculline. In all seizures, the conductance increased from the very onset of the seizure and returned to control values only at the end of the postictal depression. Simultaneous intracellular recordings from two neurons showed that the neuron leading the other neuron displayed the largest increase in membrane conductance. The changes in neuronal conductance during the two phases of the slow sleep oscillation, i.e. highest during depolarizations and lowest during hyperpolarizations, were similar to those occurring during the "spike" and "wave" components of seizures. (1) Maximal conductance was found during the paroxysmal depolarizing shift corresponding to the electroencephalogram "spike" (median: 252 nS; range: 90 to more than 400 nS). It was highest at the onset of the depolarized plateau and decreased thereafter. (2) During the hyperpolarization corresponding to the electroencephalogram "wave", the conductance was significantly lower (median: 71 nS; range: 41 to 140 nS). (3) The conductance was elevated during the fast runs (median: 230 nS; range: 92 to 350 nS) which occurred in two-thirds of the seizures. (4) The conductance values during postictal depression were situated between those measured during the seizure hyperpolarizations and during sleep hyperpolarizations. The conductance decreased exponentially back to the values of the slow sleep oscillation over the total duration of the postictal depression.The data suggest that the major mechanism underlying the "wave"-related hyperpolarizing component of spike-wave seizures relies mainly not on active inhibition, but on a mixture of disfacilitation and potassium currents.     

Characterization of the neurons in the region of solitary tract nucleus during sleep

Single-unit recording was made from neurons in the region of solitary tract nucleus (NTS) of cats. Neurons discharging in correlation with cardiac or respiratory cycle were identified outside the NTS. They showed no obvious change in discharge rate during sleep-wakefulness cycle, and were unresponsive to electrical stimulation of the mesencephalic reticular formation (MRF), suggesting that they are not involved in slow wave sleep (SS) mechanism. More than half of the neurons recorded in the NTS showed an increase in discharge rate during, but not prior to, SS. Most of non-NTS neurons had during SS a discharge rate similar to that during wakefulness. The NTS neurons may be more related to SS mechanism than non-NTS neurons. The effectiveness of electrical stimulation of the MRF in driving or inhibiting the neurons of the NTS region was measured to be expressed by an index. Generally speaking, responses with greater S/W index ratio were excitatory, while those with smaller were inhibitory. During paradoxical sleep the effectiveness was usually reduced.     

A GABAergic habenulo-raphe pathway mediation of the hypnogenic effects of vasotocin in cat

Electrolytic lesions, performed in the lateral habenula of cats, specifically altered the sleep-wakefulness cycle and completely prevented the usual actions of intraventricularly administered vasotocin, which are to induce non-rapid eye movement sleep and to suppress rapid eye movement sleep. These alterations are (i) selectively related to lateral habenula, since similar lesions performed in thalamus 2 mm lateral to lateral habenula, were unable to prevent the actions of vasotocin or to reproduce the sleep alterations observed after habenular lesions, and (ii) reversible, since at eight days after habenular lesions there is a total return to normal of the sleep-wakefulness parameters, and vasotocin is able again to induce its hypnogenic effects. Opposite effects, characterized by an increase in non-rapid eye movement sleep and a decrease in rapid eye movement sleep, could be induced by a short (10 min) electrical stimulation of the lateral habenula, but not if the stimulating electrodes are placed 2 mm more laterally. Picrotoxin, a gamma-aminobutyrate antagonist, injected intraventricularly in normal cats was without any apparent effect on the sleep-wakefulness cycle if administered in a dose of 1 ng, but had sleep-increasing effects when administered in a dose of 100 ng. However, the smaller dose of picrotoxin (1 ng), when administered 15 min before vasotocin, completely blocked the hypnogenic effect of vasotocin. It is suggested that vasotocin acts within the brain by activating a descending gamma-aminobutyrate-containing habenulo-raphe pathway, and that this pathway plays an important role in the induction and/or organization of the sleep-wakefulness cycle.     

Increase of paradoxical sleep by electrical stimulation within lateral ventricles of rat

The effect on the sleep-waking cycle of low intensity electrical stimulation (0.2 mA intensity, 80 Hz frequency, 0.7 ms signal duration) within the lateral ventricles was studied in rats maintained under a photoperiod of 12 h light and 12 h darkness (lights on at 06.00 h). When stimulation was performed at 17.00 h for 3 min, there was a significant immediate increase in paradoxical sleep (PS) and slow wave sleep (SWS) during the hours of darkness, followed by a delayed increase in diurnal PS amounts during subsequent days. These results are discussed with reference to mechanisms involving the pineal gland and serotonergic system on both the immediate and long-lasting PS effects.     

Axonal and somato-dendritic modalities of serotonin release: their involvement in sleep preparation, triggering and maintenance

SUMMARY  SUMMARY That serotonin (5-HT) plays a determinant role in sleep was first suggested by the well-known PCPA-5HTP (p.chlorophenylalanine-5-hydroxytryptophan) paradigm. This involvement, however, is paradoxical since localized cooling of the nucleus raphe dorsalis (n.RD) is sleep inducing, and unitary activity of 5-HT neurons decreases during slow wave sleep (SWS) and paradoxical sleep (PS). Furthermore, on the basis of voltammetric 5-hydroxyindole (5-OH^lcs) measurements, it appears that 5-HT could be released throughout the sleep/wake cycle according to two different modalities: by the axonal nerve endings during the waking state (W) and by the dendrites and/or the soma during sleep. The axonal release of 5-HT might participate in sleep preparation by stimulating the synthesis of hypnogenic factors within target structures like the basal hypothalamus (BH). When such a release is increased by an immobilization stress (IS) or electrical stimulation of the n.RD, a sleep rebound is induced. The somato-dendritic release of 5-HT might be primarily responsible through an auto-inhibitory process for the decrease and abolition of the 5-HT neuronal unitary activity as well as for the reduction of the axonal release of 5-HT; both phenomena being constantly observed during sleep. Finally, the hypnogenic factors might initiate and maintain sleep by influencing the n.RD sleep gating mechanisms either through the somato-dendritic release of 5-HT, or directly.     

Application of histamine or serotonin to the hypoglossal nucleus increases genioglossus muscle activity across the wake–sleep cycle

The decrease in genioglossus (GG) muscle activity during sleep, especially rapid eye movement (REM) or paradoxical sleep, can lead to airway occlusion and obstructive sleep apnoea (OSA). The hypoglossal nucleus innervating the GG muscle is under the control of serotonergic, noradrenergic and histaminergic neurons that cease firing during paradoxical sleep. The objectives of this study were to determine the effect on GG muscle activity during different wake–sleep states of the microdialysis application of serotonin, histamine (HA) or noradrenaline (NE) to the hypoglossal nucleus in freely moving cats. Six adult cats were implanted with electroencephalogram, electro-oculogram and neck electromyogram electrodes to record wake–sleep states and with GG muscle and diaphragm electrodes to record respiratory muscle activity. Microdialysis probes were inserted into the hypoglossal nucleus for monoamine application. Changes in GG muscle activity were assessed by power spectrum analysis. In the baseline conditions, tonic GG muscle activity decreased progressively and significantly from wakefulness to slow-wave sleep and even further during slow-wave sleep with ponto-geniculo-occipital waves and paradoxical sleep. Application of serotonin or HA significantly increased GG muscle activity during the wake–sleep states when compared with controls. By contrast, NE had no excitatory effect. Our results indicate that both serotonin and HA have a potent excitatory action on GG muscle activity, suggesting multiple aminergic control of upper airway muscle activity during the wake–sleep cycle. These data might help in the development of pharmacological approaches for the treatment of OSA.     

Blood-flow and pO2 in the posterior hypothalamus of cats during paradoxical sleep

It was found in chronic experiments in cats, using the recording of local blood flow and oxygen tension (pO ₂) in the anterior and posterior hypothalamus in the sleep-wakefulness cycle, that when the phases of sleep are alternated, the changes in these parameters are in different directions: the level of blood flow and the frequency of fluctuation of the pO₂ during paradoxical sleep increase in the posterior hypothalamus, while they decrease in the anterior hypothalamus. On the other hand, the opposite pattern is observed during slow-wave sleep. The multidirectionality of the changes in local blood flow level and in the frequency of fluctuations of pO₂ in one and the same sleep phase indicate that they are of local origin and must be governed by functional-metabolic shifts in these structures; the functional state of the posterior hypothalamus during paradoxical sleep is assessed on this basis.Translated from Zhurnal Vysshei Nervnoi Deyatel'nosti imeni I. P. Pavlova, Vol. 39, No. 3, pp. 536–542, May–June, 1989.     

Effect of neurotropic drugs on sleep disturbance caused by electrical stimulation of the hypothalamus in cats

A state of stress induced in cats by electrical stimulation of the hypothalamus was shown to reduce the total duration of sleep at the expense of its paradoxical phase. Haloperidol (1, 2, or 3 mg/kg), diazepam (0.5 or 1 mg/kg), nitrazepam (1 or 6 mg/kg), Noxyron (glutethimide) (10, 30, and 60 mg/kg), and pentobarbital (5, 15, and 30 mg/kg) did not restore the structure of sleep when disturbed by stress, and lithium hydroxybutyrate (100 and 150 mg/kg), dimedrol (diphenhydramine) (1, 5, and 6 mg/kg), and imipramine (1, 3, and 6 mg/kg) increased the total duration of sleep on account of the slow-wave phase. Sodium hydroxybutyrate (100 mg/kg) restored the normal electrophysiological pattern of sleep, reduced the latent period, and increased the total duration and number of episodes of the paradoxical phase, and also reduced the number of awakenings.Laboratory for the Search and Study of Substances for the Treatment and Prevention of Drug Addiction, Institute of Pharmacology, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR V. V. Zakusov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 83, No. 5, pp. 563–566, May, 1977.     

Role of the pulvinar-lateral posterior nucleus complex in turning behavior

The behavioral response to electrical stimulation of the pulvinar-lateral posterior complex (P-LP) was studied in 11 adult cats with chronically implanted electrodes. The EEG of P-LP, caudate nucleus, superior colliculus, dorsal hippocampus and cerebral cortex was recorded during the stimulation sessions. Three cats had a cannula implanted in one P-LP through which drugs were microinjected. Threshold currents evoked contralateral head turning and conjugate eye deviation, and suprathreshold currents induced contralateral circling. Ninety-four percent of 456 stimulations in P-LP elicited contralateral head movements. P-LP EEG did not differ from controls during head turning induced by threshold currents, but it was desynchronized with slightly suprathreshold currents and occasionally showed after-discharges, concomitant with circling, with higher currents. Microinjections of ACh, KCl (25%), and penicillin into P-LP also induced contralateral circling, which was usually followed by a generalized epileptic seizure. This would support the postulate that the behavioral responses observed through electrical stimulation were mediated by synaptic activities within the P-LP. These results indicate that P-LP is involved in turning and circling behavior.     

Spontaneous and artificial activation of neocortical seizures

The aim of this study is to disclose the mechanisms underlying the recruitment of neocortical networks during slow-wave sleep oscillations evolving into spike-wave (SW) seizures. 1) We investigated the activation of SW seizures in a seizure-prone neocortex by means of electrical stimuli applied within the frequency range of spontaneous sleep oscillations. Stimuli were grouped in bursts of 10 Hz, similar to sleep spindles, and repeated every 2 s, to reproduce their rhythmic recurrence imposed by the slow (<1 Hz) sleep oscillation. Either cortical or thalamic stimuli, which were applied while the cortex displayed sleeplike activity, gradually induced paroxysmal responses in intracellularly recorded neocortical neurons, which were virtually identical to those of spontaneous seizures and consisted of a progressive buildup of paroxysmal depolarizing shifts (PDSs). 2) The ability of cortical networks to follow stimuli was tested at various stimulation frequencies (1-3 Hz) and quantified by calculating the entropy of the ensuing oscillation. Rhythmic PDSs were optimally induced, and the lowest entropy was generated, at a stimulation frequency around 1.5 Hz. Fast runs at 10-15 Hz, which often override PDSs, thus contributing to the polyspike-wave pattern of seizures, were induced by cortical stimuli, but were disturbed by thalamic stimuli. Spontaneous seizures generally evolved toward an accelerated discharge of PDSs. It is suggested that these accelerating trends during SW seizures act as protective mechanisms by provoking the uncoupling of cortical networks and eventually arresting the seizure.     

Noradrenaline and 5-hydroxytryptamine release in the hippocampus during seizures induced by hippocampal kindling stimulation: an in vivo microdialysis study

The intracerebral microdialysis technique has been used to monitor extracellular levels of noradrenaline, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the rat hippocampus in vivo in response to focal and generalized seizures induced by hippocampal kindling stimulation. In fully kindled animals a stimulus-induced generalized seizure gave rise to a three-fold increase of noradrenaline levels in the stimulated hippocampus as compared to baseline levels (15-min samples). The maximal increase of noradrenaline levels occurred within the first minutes after onset of seizure activity, as assessed in 2-min sample fractions with the noradrenaline uptake blocker desipramine added to the perfusion medium. After the peak increase, the noradrenaline levels tapered off, reaching baseline after 8-10 min. In 6-hydroxydopamine-treated animals, baseline noradrenaline levels were markedly reduced and there was no significant increase in noradrenaline release in response to a generalized seizure. These data support the hypothesis that the high extracellular levels of noradrenaline measured in seizures are of neuronal origin. There were no significant changes in extracellular 5-hydroxytryptamine or 5-hydroxyindoleacetic acid levels after a generalized seizure. In non-kindled animals the steady state noradrenaline levels during uptake blockade were two-three times higher than in the kindled rats. However, the peak noradrenaline levels measured in both hippocampi after the first two electrical kindling stimulations giving rise to focal epileptiform activity (afterdischarge) were similar to those observed in the kindled animals in response to generalized seizures. The increase of noradrenaline release in the non-kindled animals was significantly correlated to the duration of afterdischarge. In conclusion, the present study demonstrates the usefulness of the intracerebral dialysis technique for monitoring noradrenaline, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid release during seizures. The results indicate that both focal and generalized hippocampal seizures evoked by electrical kindling stimulation lead to a marked increase of transmitter release from noradrenergic but not from serotonergic neurons in the hippocampus. The ability of the noradrenergic system to respond by increased transmitter release to epileptic seizures is thus retained also in the kindled state.