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D C McIntyre

Publications and source records attributed to D C McIntyre.

At least 37 records · Page 2Linked to original sources
PubMed1998

Stressor-induced corticotropin-releasing hormone, bombesin, ACTH and corticosterone variations in strains of mice differentially responsive to stressors.

The effects of brief stressor exposure on hypothalamic-pituitary-adrenal (HPA) functioning was assessed in two strains of mice shown to be differentially responsive to stressors. Mild stress (1 min of cold swim, 20 C) led to marked elevations of plasma ACTH and corticosterone concentrations in the stress-reactive BALB/cByJ and the stress-resistant C57Bl/6ByJ mice. Moreover, it was observed that the strains differed in basal CRH content within the amygdala and the paraventricullar nucleus (PVN). Within 1 min of cold swim, the CRH changes were detected in these brain regions in BALB/cByJ mice, but were less apparent in C57Bl/6ByJ mice. Following a chronic stressor regimen, the marked elevations of plasma ACTH associated with acute stressors in BALB/cByJ mice were diminished. In contrast, in C57Bl/6ByJ mice in which acute stressors hardly affected ACTH concentrations, the chronic stressor regimen lead to a marked increase of plasma ACTH. Taken together, data indicate that the stress reactivity differences seen in the two strains of mice are not limited to ACTH and corticosterone, but are also detected with respect to CRH within the amygdala and PVN. Furthermore, the suggestion is offered that the reactivity differences in the two strains of mice may have lead to different profiles of ACTH secretagogues and hence the response profile to later acute and chronic stressors differed in these strains of mice.

Adrenocorticotropic Hormone↗
PubMed1997

Mossy fibre sprouting: evidence against a facilitatory role in epileptogenesis.

Sprouting of mossy fibres from dentate granule cells occurs in several animal models of epilepsy and in epileptic humans. Mossy fibre sprouting might contribute to epileptogenesis but also could be a compensatory, inhibitory response. We analysed mossy fibre sprouting in the supragranular zone of the dentate gyrus using Timm's histochemical method in genetically fast and slow kindling rats. Before the start of amygdala kindling, the slow rats showed higher Timm's staining scores than did the fast kindlers. No increase of mossy fibre density was observed when the animals were stimulated until either the fast or the slow rats had reached the fully kindled state. Our data argue against the hypothesis that mossy fibre sprouting facilitates epileptogenesis.

Analysis of Variance↗
PubMed1997

Influence of psychogenic and neurogenic stressors on endocrine and immune activity: differential effects in fast and slow seizing rat strains.

Variations of plasma ACTH and corticosterone, as well as splenic macrophage activity and mitogen-induced cell proliferation, were determined in rats following 15 min of either the neurogenic stressor of restraint or by a purely psychogenic stressor consisting of exposure to a ferret. The effects of these stressors were assessed in two strains of rats that were selectively bred for either Fast or Slow kindling epileptogenesis triggered in response to amygdala stimulation. The stressors differentially influenced behavioral responses, endocrine activity, and immune functioning, and these effects varied with the strain of rat. In response to restraint the Fast rats exhibited protracted struggling, while the Slow rats tended to be immobile. In contrast, upon ferret exposure the Fast rats showed greater immobility than the Slow rats. The stressors also induced marked elevations of plasma ACTH and corticosterone. Whereas the ACTH and corticosterone increases were more pronounced in response to the ferret in the Slow rats, restraint resulted in a markedly greater rise of plasma ACTH in the Fast strain. Proliferation of splenic lymphocytes in response to Con A and LPS were elevated in Fast seizing rats, while macrophage activity, as determined by oxygen burst following addition of PMA and luminol to splenic mononuclear cells, was greater in the Slow seizing strain. While neither stressor influenced cell proliferation in either the Fast or Slow rats, macrophage activity was greatly suppressed by ferret exposure only in the Slow rats. Taken together, it appears that while stressors influence behavior and immune and endocrine functioning, these effects may vary as a function of the interaction of the strain of rat and the specific type of stressor employed.

Adrenocorticotropic Hormone↗
PubMed1996

Efferent projections of the anterior perirhinal cortex in the rat.

Because convulsive seizures develop very rapidly from kindling sites in the anterior perirhinal cortex, we studied perirhinal efferents by using the anterograde tracer Phaseolus vulgaris leucoagglutinin (PhAL). PhAL injections into the anterior perirhinal cortex labelled a prominent network of fibers within the frontal cortex that was most dense within layers I and II and layer VI. As individual PhAL injection sites within the perirhinal cortex were restricted to one or two adjacent laminae, we were able to determine that layer V was the main source of the perirhinofrontal projection. This was confirmed by frontal cortex injections of the retrograde tracer Fluorogold (FG). Other cortical areas with densely labelled fibers following perirhinal PhAL injections included the agranular insular, infralimbic, orbital, parietal, and entorhinal cortices. Moderate to mild fiber labelling was also noted in the posterior piriform, temporal and occipital cortices, and the claustrum. Subcortical labelling was seen in the nucleus accumbens; fundus striati; basal and lateral amygdala nuclei; the "acoustic thalamus"; and the central grey. Several of these cortical and subcortical projections were bilateral. The different laminar origin of these perirhinal efferents is discussed. These results confirmed our prediction of extensive direct projections from the anterior perirhinal cortex to the frontal cortex in the rat. The significance of this projection is discussed with special reference to the anatomical basis of convulsive limbic seizures.

Animals↗
PubMed1996

Seizure-induced differential expression of messenger RNAs for neurotrophins and their receptors in genetically fast and slow kindling rats.

Levels of messenger RNAs for brain-derived neurotrophic factor, nerve growth factor and neurotrophin-3, and their high-affinity receptors, TrkB and TrkC, were analysed in the brains of genetically fast and slow kindling rats using in situ hybridization. Basal expression of neurotrophins and Trk messenger RNAs in the hippocampal formation, amygdala, frontoparietal and piriform cortices did not differ between the two strains. At 2 h after the third generalized grade 5 seizure, induced by kindling stimulations in the amygdala, increased expression of brain-derived neurotrophic factor messenger RNA was detected in the dentate gyrus granule cell layer, amygdala, frontoparietal and piriform cortices of the fast kindlers. Similar seizure-evoked increases of brain-derived neurotrophic factor messenger RNA levels were also observed in the amygdala and piriform cortex of slow kindlers. However, in these animals, brain-derived neurotrophic factor messenger RNA expression was not significantly altered by the seizures in the dentate gyrus granule cell layer and frontoparietal cortex. Furthermore, the seizure-induced increase of nerve growth factor, TrkB and TrkC messenger RNAs and decrease of neurotrophin-3 messenger RNA levels in the dentate gyrus granule cell layer was only observed in fast, but not in slow, kindlers. The neurotrophins are believed to regulate synaptic plasticity and efficacy and to facilitate long-term potentiation and kindling epileptogenesis. The present data suggest that the slow and fast kindling rates in the two strains studied here might partly be due to differences in seizure-evoked neurotrophin and Trk synthesis.

Amygdala↗
PubMed1996

Differential sensitivity of various temporal lobe structures in the rat to kindling and status epilepticus induction.

Using focal brain stimulation (kindling), discrete seizures can be triggered from many neuroanatomic sites with varying degrees of facility. From several of these sites, protracted seizures or status epilepticus (SE) also can be triggered. To date, no comparison has been made between different brain sites in their sensitivity both to kindling and to SE development. In this report, we have compared the kindling profiles of three amygdala nuclei, namely the basal (BL), central (CE), and medial (ME) nuclei, to the adjacent piriform (PIR) and perirhinal (PRH) cortices. In addition, three weeks following kindling, the susceptibility of each kindled site to status epilepticus (SE) was assessed by exposing the site to 60 min of electrical stimulation. We observed that (a) during the course of daily kindling, the afterdischarge threshold dropped progressively and significantly in all structures, (b) the rate of kindling in the PRH and PIR cortices and the CE amygdala was significantly faster than either the BL or ME amygdala, (c) when discrete convulsions were triggered, the latency to forelimb clonus in the PRH cortex and CE amygdala was significantly shorter than the other three structures, and (d) despite being slower to kindle than most other sites, stimulation of the BL nucleus most readily triggered SE. The kindling data suggest that discharges triggered from the PRH and CE more readily access motor systems supporting limbic convulsions than discharges triggered from the BL, ME nuclei or the PIR cortex. On the other hand, the SE data indicate that the mechanisms and circuits associated with the development of discrete kindled seizures are not identical to those associated with the induction of limbic SE.

Amygdala↗
PubMed1996

Perirhinal cortex involvement in limbic kindled seizures.

Investigations into the anatomical substrate of temporal lobe epilepsy have yielded a number of important observations regarding the involvement of the piriform and perirhinal cortical areas in temporal lobe seizure propagation. Although early reports indirectly suggested that the circuits of the piriform cortex might act as a critical conduit for limbic seizure discharges to access motor systems, recent reports more strongly implicate the perirhinal cortex in this process. In the following report, we provide a brief summary of the earlier work involving the piriform cortex and its potential involvement in kindled limbic seizures. This is followed then by the results of several recent in vivo and in vitro electrophysiological studies that ascribe a critical importance for the perirhinal cortex in convulsive limbic seizures. Finally, since our anatomical studies indicated that the perirhinal cortex densely innervates the frontal motor cortex, we examined the involvement of this latter region in amygdala kindled seizures using the reversible functional lesion of cortical spreading depression. Based on these findings we suggest that the circuits of the perirhinal cortex may be important in the amplification and distribution of temporal lobe seizure discharges, providing access to structures that are capable of driving a convulsive response.

Amygdala↗
PubMed1994

Hippocampal kindling protects several structures from the neuronal damage resulting from kainic acid-induced status epilepticus.

In an attempt to study the effects of piriform cortex damage on kindled seizure propagation, we administered kainic acid (12 mg/kg; i.p.) to rats previously kindled from the dorsal hippocampus. Unexpectedly, the ensuing status epilepticus (SE) in the kindled rats did not result in the piriform cortex damage normally observed in naive rats. As a result of this surprising finding, a more comprehensive investigation was undertaken to compare dorsal hippocampal kindled and control rats on their electrographic and behavioral SE development and subsequent brain damage. The SE induction profile and the pattern of brain damage observed in our control rats was similar to previous reports [Neuroscience, 14 (1985) 375-403; Brain Res., 218 (1981) 299-318]. By contrast, although fewer kindled rats than controls responded to the initial dose of kainic acid with electrographic and behavioral seizures, those many kindled rats that did respond, showed a pattern of SE induction that was different from controls. Kindled rats manifested fewer 'wet dog shakes', more generalized convulsions and a faster development of severe limbic status (SLS) than controls. In addition, without pharmacological intervention, the SLS continued longer in kindled rats than in controls. Histological examination revealed brain damage in kindled rats that was markedly different from controls. Unlike controls, kindled rats had no damage in the piriform cortex or substantia nigra reticulata and minimal hippocampal damage, yet showed midline thalamic and anterior olfactory nuclei damage similar to controls. These differences were observed from 1 to 28 days after kindling. Although the mechanism(s) of this kindling-based neuroprotection is not known, its discovery should add importantly to our understanding of epilepsy-induced alterations of subsequent neuronal function.

Animals↗
PubMed1993

Long-lasting changes in the origin of spontaneous discharges from amygdala-kindled rats: piriform vs. perirhinal cortex in vitro.

The origin of spontaneous field potentials in coronal slices of the amygdala-piriform-perirhinal area (A-P area) from amygdala-kindled and control rats was assessed. In Expt. 1, the field potentials initially originated in the perirhinal (PRh) cortex of control tissue while they originated in the piriform (Pir) cortex of amygdala-kindled tissue. In Expt. 2, this kindling-based change was observed in the A-P area ipsilateral but not contralateral to the kindled amygdala. In both experiments, subsequent exposure to perfusion medium containing 0 Mg2+ resulted in the genesis of strong discharges in both control and kindled tissues. After 2-3 h of such treatment, the origin of spontaneous discharges in control tissue changed from the PRh to the Pir area and persisted in a reduced form during reperfusion with medium containing Mg2+. This change in origin of the discharges in control tissue appeared similar to that seen in previously kindled tissue. In Expt. 3, during exposure to 0 Mg2+, the response of the basolateral amygdala (BLA) was compared with the Pir and PRh areas. Independent of the PRh discharge, the BLA discharge closely followed the Pir discharge both in time and morphology. These lasting changes in the ipsilateral A-P area in vitro must be related in vivo to the change which allows the kindled A-P area to participate in the triggering of generalized limbic-kindled convulsions.

Amygdala↗
PubMed1993

Kindling in the perirhinal cortex.

In vitro experiments have indicated that the perirhinal cortex is highly excitable and its relationship to the basolateral amygdala and piriform cortex is altered by previous amygdala or dorsal hippocampal kindling. As a result, we felt it was important to assess the excitability of the perirhinal cortex in vivo by comparing its kindling profile to that of the basal amygdala, piriform cortex or dorsal hippocampus. We observed that the after-discharge (AD) threshold of the perirhinal cortex was higher than the other 3 structures but the AD duration was not different. Subsequently, the perirhinal cortex kindled more rapidly than the other 3 structures, and with extremely short latencies to onset of forelimb clonus. With the view that synchronized discharge in the perirhinal-piriform area provides the critical trigger for limbic kindled convulsions, the relationship of kindling rate and convulsion latencies and durations between the 4 structures was discussed.

Amygdala↗
PubMed1993

Learning and memory after adrenalectomy-induced hippocampal dentate granule cell degeneration in the rat.

Adrenalectomy (ADX) of normal adult rats causes selective hippocampal dentate granule cell degeneration that is prevented by corticosterone. The ability to destroy this one hippocampal cell type noninvasively made it possible to address the role of the dentate granule cells in learning and memory. Four months after ADX, 31 of 45 rats failed to show obvious granule cell loss and displayed behavior in the Morris water maze that was similar to 16 sham-operated control rats and 16 ADX rats maintained on corticosterone throughout the study. Conversely, 14 of the 45 ADX rats experienced a loss of granule cells that varied from minimal to extensive. Although there were no obvious differences between groups in motoric and motivational characteristics or search strategies, ADX rats with moderate to extensive granule cell loss acquired place learning slightly slower than controls or ADX rats with minimal or no obvious cell loss. Furthermore, the ADX rats with moderate to extensive cell loss were temporarily impaired following alteration of either intramaze or extramaze cues compared to controls. In contrast, the rats with granule cell loss remembered an old place and learned a new place as quickly as controls. These results suggest that a normal complement of dentate granule cell may not be necessary for the acquisition or retention of spatial information in the Morris water maze.

Adrenalectomy↗
PubMed1993

Are differences in dorsal hippocampal kindling related to amygdala-piriform area excitability?

It has been suggested that several structures associated with the amygdala-piriform (A-P) area are important, if not critical, for convulsive generalization of limbic seizures. In experiment 1, when examining the development of convulsive seizures kindled from the dorsal hippocampus (cornus ammonis; DH), a broad range of kindling rates was observed. Independent of electrode location within the hippocampus, kindling rates were correlated positively with both local and, more dramatically, distant excitability (measured by the duration of the primary and secondary hippocampal afterdischarges, respectively) at all stages of epileptogenesis. Because kindling rates were bimodally distributed, we bisected the distribution into 'faster' and 'slower' kindling rats. Here we examined the magnitude of both electrophysiological and behavioral differences between 'faster' and 'slower' rats and their changes over time. The 'faster' rats had longer primary and secondary afterdischarge (AD) durations than 'slower' rats throughout all stages of kindling. With the appearance of generalized convulsions, the 'faster' rats showed longer latencies to clonus onset, with longer clonus and AD durations than 'slower' rats. Also, the generalized convulsions of 'faster' rats appeared during a much enlarged secondary AD period, while 'slower' rats convulsed during primary AD. In both groups, convulsions were invariably associated with increased discharge in A-P associated structures. We interpreted the differences between 'faster' and 'slower' DH rats to reflect genetic differences in excitability in both local and A-P associated structures. If the DH kindling profile of the 'faster' rats differed from 'slower' rats largely because of naturally greater excitability in A-P associated structures, then experimentally increased excitability in those structures (via amygdala kindling) in a random sample of rats should duplicate much of the 'faster' DH kindling profile. In experiment 2, this outcome was observed. In conclusion, we suggest that either natural or induced differences in the excitability of A-P associated structures affect both the genesis and the profile of convulsive generalization of limbic kindled seizures.

Amygdala↗
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↗