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D C McIntyre

Publications and source records attributed to D C McIntyre.

At least 19 recordsLinked to original sources
PubMed1991

Suppression of amygdala kindling with massed stimulation: effect of noradrenaline antagonists.

Afterdischarge (AD) triggered by brief, daily stimulation of the amygdala progressively increases in complexity and duration and, over days, develops into generalized convulsions. This progression, called kindling, is delayed by noradrenaline (NA). When brief stimulation of the amygdala occurs too frequently (massed), there is a suppression of AD growth and little evidence of kindling. Previously we showed that depletion of NA before massed amygdala stimulation prevented the suppression of AD growth described above, and readily precipitated generalized seizures. In the present report, we examined the role of NA in maintaining this suppression of AD growth, after it was well established. We showed that suppression of AD development during the first 15 massed stimulations (interstimulus interval of 5 min) was reduced by subsequent injection of the NA alpha 2 antagonist, yohimbine, with most rats exhibiting occasional generalized convulsions. Conversely, rats exposed to the beta antagonist, propranolol, like controls, not only showed suppressed AD growth, but also elevated AD thresholds. Three weeks later, only a small positive transfer to daily kindling was observed in all groups. We conclude that alpha 2 NA receptors help maintain suppression of AD growth induced by massed stimulation of the amygdala, while beta receptors provide only a small proepileptic influence. These results and those from the 'rapid' kindling model (Lothman et al., Brain Research, 360 (1985) 83-91) are compared, and related to NA receptor subtype variations in the amygdala and hippocampus.

Amygdala↗
PubMed1989

Kindling-based status epilepticus: effect of norepinephrine depletion with 6-hydroxydopamine.

In two experiments, involvement of norepinephrine in the development of status epilepticus was determined. Rats, pretreated with intraventricular 6-hydroxydopamine to deplete brain norepinephrine or with the saline vehicle alone, were implanted with electrodes in both amygdalae. In the first experiment, one amygdala was kindled to stage 5 levels and then 2 weeks later was stimulated continuously for 60 min in an effort to produce status epilepticus (SE), while in the second experiment such SE stimulation was applied to one amygdala without prior kindling. Although depletion of norepinephrine significantly facilitated amygdala kindling in experiment 1, it had no clear effect on the probability of developing SE (generalized, partial, or nonconvulsive) or on the distribution of gross brain pathology following spontaneous recovery from partial and nonconvulsive SE in either experiment. The significance of these results compared to other SE models was discussed.

Amygdala↗
PubMed1989

Pyriform cortex involvement in kindling.

Evidence suggests that the pyriform cortex (PC) may play an important role in the genesis, if not the maintenance, of secondarily generalized limbic kindled seizures. For example, it has been shown that the fastest rates of kindling are observed from structures most directly related to the PC, and that the latter develops epileptic burst responses before all other structures, independent of the kindling site. This seizure sensitivity of the PC is reflected additionally in its inevitable loss in the face of protracted seizure, i.e., status epilepticus. In conclusion we briefly review our electrophysiological data from amygdala-pyriform cortex slices which show that the PC and overlying perirhinal cortex (PRC) possess a strong disposition for developing spontaneous rhythmic burst discharges. Further it was observed that the PRC response always led the PC event in control tissue, but rarely in kindled tissue. This suggests a functional change in the relationship between these two areas as a result of amygdala kindling. The significance of this alteration is yet undetermined.

Animals↗
PubMed1988

Effect of clonidine on amygdala kindling in normal and 6-hydroxydopamine-pretreated rats.

The role of the alpha 2 adrenergic receptor in the development and propagation of amygdala kindled seizures was determined. Male Wistar rats, depleted of norepinephrine with the neurotoxin 6-hydroxydopamine and vehicle controls, received an injection of the alpha 2 agonist, clonidine (0.001, 0.01, or 0.1 mg/kg, i.p.), or saline, 30 min prior to each amygdala stimulation (every 3 to 4 days). The largest dose of clonidine had a significant retarding effect on the development of kindling in both the vehicle- and 6-hydroxydopamine-treated groups. The majority of this effect was observed as a protracted number of trials with unilateral afterdischarge. When the discharge became bilateral, generalized seizures were soon apparent. There was no effect of clonidine on the amygdala afterdischarge threshold in both groups, or on the subsequent generalized motor seizure and associated afterdischarge durations in the vehicle groups. The largest dose of clonidine, however, reduced the severity of the convulsive response in the 6-hydroxydopamine-treated rats from violent stage 7 or 8 seizures to more moderate stage 5 responses. The significance of these data, and the involvement of the postsynaptic alpha 2 receptors in the genesis of amygdala kindled seizures, are discussed.

Amygdala↗
PubMed1987

Suppression of amygdala kindling with short interstimulus intervals: effect of norepinephrine depletion.

The rate of development of generalized kindled convulsions was profoundly influenced by the interval between amygdala stimulations. With stimulation every 10 min, nearly complete interference with the progression of kindling was observed in most rats, and hourly stimulation precipitated kindling rates three times longer than did once per day. Depletion of norepinephrine (NE), as a result of intracerebroventricular pretreatment with 6-hydroxydopamine, virtually eliminated the interference with kindling development seen in the vehicle control rats. Such depletion of NE, however, had little influence on the generalized responses once developed. At this stage, interference with seizure provocation was observed as truncated electroencephalographic seizures which were usually devoid of motor correlates. This interference was more profound in the shorter interstimulus intervals and was independent of NE depletion. Finally, when changing from the short kindling intervals of 10 min and 1 h to the longer interval of 24 h, an unexpected interference with seizure provocation was observed. The implication of these results for the biochemical basis of kindling and kindling as a model of learning are discussed.

Action Potentials↗
PubMed1987

Facilitation of secondary site kindling in the dorsal hippocampus following forebrain bisection.

Bisection of the corpus callosum and hippocampal commissure, after the kindling of one dorsal hippocampus (primary site), had no effect on the rate of generalized kindled seizure development in the contralateral dorsal hippocampus (secondary site). The rate of kindling in the secondary site was very rapid in both intact and commissure-bisected rats, resulting in a positive transfer between the two sites of approximately 90%. In addition, the afterdischarge threshold response of the secondary site, after commissurotomy but before secondary site kindling, revealed mature local epileptogenesis. These observations support the suggestion that the positive transfer observed between the dorsal hippocampi is based on bilateral epileptogenesis during primary site kindling. Bisection of the anterior corpus callosum lateralized the forelimb convulsion while the hippocampal commissure independently mediated the laterality of the hippocampal afterdischarge. Commissurotomy had no significant influence on the latency to onset or offset of these motor and electrographic responses. These results are compared with those from the amygdala, and their implication for the laterality of epileptogenesis is discussed.

Animals↗
PubMed1986

Power spectral analysis of electroencephalographic activity in kindled rats.

Power spectral analysis of the resting EEG activity of amygdala kindled rats revealed a decrease of power in the 1- to 3-Hz band and an increase in the 4- to 6-Hz band compared with 3-Hz-stimulated and operated control animals. This effect was observed only in the stimulated but not the contralateral amygdala. The alteration in power seen shortly after kindling was still evident after a 1-month stimulation-free period.

Amygdala↗
PubMed1986

Status epilepticus following stimulation of a kindled hippocampal focus in intact and commissurotomized rats.

Status epilepticus of either a nonconvulsive, partial, or generalized form was provoked in rats by 60 min of electrical stimulation of a kindled focus in the posterior-ventral hippocampus. Following spontaneous offset of the nonconvulsive status epilepticus, minor pathology occurred which was largely restricted to the hippocampus, whereas partial or generalized status epilepticus produced considerable bilateral damage in the hippocampus, basolateral amygdala, and pyriform cortex. Bisection of the anterior half of the corpus callosum lateralized the forelimb motor seizures and bisection of the hippocampal commissure lateralized the hippocampal afterdischarge and the associated brain pathology. Paradoxically, commissurotomy also increased the probability of developing status epilepticus while reducing its severity. Further, it was shown that the right hippocampus precipitated status epilepticus with a higher probability than the left hippocampus in both intact and split-brain rats.

Action Potentials↗
PubMed1986

Cellular and synaptic properties of amygdala-kindled pyriform cortex in vitro.

The evoked and spontaneous activity of neurons in the pyriform cortex of control and kindled rats was examined using a coronal slice preparation containing the amygdala-pyriform region. Electrical stimulation of the amygdala nuclei elicited synchronized burst responses in pyriform cells of slices from both control and kindled animals. The mean duration of the burst was greatly prolonged in cells from kindled preparations. The depolarizing synaptic events underlying the burst response in the kindled and control animals could be examined when Mg2+ was increased to suppress but not block synaptic transmission. Electrical stimulation evoked a short-latency graded synaptic depolarization, followed by a long-latency all-or-none depolarizing event, which appeared to be involved in generating the burst response. Norepinephrine (NE), in a 4-microM concentration, reversibly blocked the burst responses in the control preparation. Burst responses elicited from kindled preparations were also suppressed by NE. For the latter cases, higher concentrations of NE were required to produce this effect. The alpha-2-agonist clonidine mimicked the suppressive action of NE on the evoked events. In contrast the beta-agonist isoproterenol facilitated the occurrence of spontaneous synchronous bursts and prolonged evoked burst discharges in both the control and kindled preparations. NE and clonidine block the burst response by suppressing the underlying synaptic events. The facilitatory action of isoproterenol on spontaneous and evoked responses suggests that NE may also exert an excitatory effect.

Amygdala↗
PubMed1985

Supersensitivity to the anticonvulsant and proconvulsant activity of clonidine following noradrenaline depletion induced by 6-hydroxydopamine.

Electrically induced focal cortical seizures were examined in 6-hydroxydopamine (6-OHDA) pretreated or control rats in the presence of 0, 1, 2.5, 5, and 10 micrograms/kg clonidine. In baseline determinations, rats pretreated with 6-OHDA showed lower seizure thresholds and longer behavioral and electrographic seizure than controls. Consistent with other reports, the lowest dose of clonidine (1 microgram/kg) inhibited seizures in control animals; 6-OHDA potentiated the anticonvulsant effect of the lowest dose of clonidine but exacerbated seizure in the presence of the highest dose of clonidine (10 micrograms/kg). Since others have reported proconvulsant effects of clonidine at much higher doses (100 or 1,000 micrograms/kg) using control animals, the depletion of forebrain norepinephrine with 6-OHDA therefore appears to produce a supersensitivity both to the proconvulsant and to the anticonvulsant effect of clonidine. These data suggest that the receptors that mediate the proconvulsant (possibly alpha 1 adrenoceptors) and the anticonvulsant (possibly alpha 2 adrenoceptors) effects are located postsynaptically.

Animals↗
PubMed1985

Modification of local neuronal interactions by amygdala kindling examined in vitro.

Stimulation of the amygdala in coronal slices of the amygdala-pyriform region elicited burst responses in the pyriform cortex cells. The burst responses, recorded intracellularly, consisted of a train of action potentials riding on a depolarizing envelope that lasted for an average of 0.4 s. When a similar stimulus was applied to slices prepared from rats previously subjected to amygdala kindling, burst responses were significantly prolonged (average of 6.6 s). Our results indicate that the increased excitability of the chronic epileptic site developed in vivo was retained in the excised amygdala-pyriform slice.

Amygdala↗
PubMed1985

Dorsal hippocampal kindling and transfer in split-brain rats.

The rate of kindling of a primary site in the dorsal hippocampus of rats was not altered by various forebrain commissurotomies or midbrain bisection. The positive transfer in the kindling of a secondary site in the homotopic hippocampus, on the other hand, was abolished by extensive forebrain transection, whereas anterior callosal or midbrain bisection alone was ineffective. In addition, there was no evidence of an interference effect when rekindling the original primary site. These results have important implications for interhemispheric mechanisms in kindling.

Animals↗
PubMed1985

State-dependent learning following electrical stimulation of the hippocampus: intact and split-brain rats.

In experiment 1, electrical stimulation of the posterior hippocampus was shown to produce state-dependent learning (SDL) for a step-out inhibitory avoidance task in rats. Stimulation sites in either the right or left hippocampus were equally effective in producing this effect. Similarly, the presence or absence of afterdischarge (AD) following the stimulation did not differentially affect performance on the task. In experiment 2, forebrain bisection ameliorated the behavioral deficits in the animals receiving stimulation before testing but not before training (N/S group), while those stimulated before training but not before testing (S/N group) remained impaired; thus, providing a demonstration of asymmetrical SDL. Variations in extent of the commissurotomy differentially affected the laterality of the afterdischarge but not the performance in the SDL task. Speculation as to the mechanisms of this SDL effect was presented.

Animals↗
PubMed1985

Lateralized state-dependent learning produced by hippocampal kindled convulsions: effect of split-brain.

In previous experiments, it was demonstrated that convulsions kindled from a ventral hippocampal focus in rats supported state-dependent learning which tended to lateralized to, and asymmetrical in, the right hemisphere. The question of the differential contribution of the left and right hippocampus to the production of state-dependency can best be addressed through confining the seizure to one or the other hemisphere via commissurotomy. In the present investigation, then, commissurally-intact and split-brain rats were implanted with bilateral hippocampal electrodes, then a left or a right focus was kindled. Later behavioral testing in an aversive inhibitory avoidance (IA) paradigm, revealed that intact animals, both left and right kindled groups, displayed good state-dependency. Split-brain animals, however, exhibited differential state-dependent responses to convulsive stimulation. Those kindled in the left hippocampus showed good retention when the conditions of seizure during training and testing were the same (same-state conditions), while showing deficient recall in changed-state conditions (a good state-dependent profile). On the other hand, those kindled in the right hippocampus displayed good retention of the IA experience in both same- and changed-state conditions. Differential recall after a left versus a right hippocampal convulsion in split-brain animals could not be accounted for in terms of differential seizure parameters, laterality of afterdischarge, extent of extracommissural damage or the extent of the actual transection. Possible mechanisms underlying this effect were discussed.

Animals↗