Gestational stress induces post-partum depression-like behaviour and alters maternal care in rats.

Gestational stress (GS) produces profound behavioural impairments in the offspring and may permanently programme hypothalamic-pituitary-adrenal (HPA) axis function. We investigated whether or not GS produced changes in the maternal behaviour of rat dams, and measured depression-like behaviour in the dam, which might contribute to effects in the progeny. We used the Porsolt test, which measures immobility in a forced-swim task, and models depression in rodents, while monitoring maternal care (arched-back nursing, licking/grooming, nesting/grouping pups). Pregnant rats underwent daily restraint stress (1 h/day, days 10-20 of gestation), or were left undisturbed (control). On post-parturition days 3 and 4, dams were placed into a swim tank, and time spent immobile was measured. GS significantly elevated immobility scores by approximately 25% above control values on the second test day. Maternal behaviours, in particular arched-back nursing and nesting/grouping pups, were reduced in GS dams over post-natal days 1-10. Adult offspring showed increased immobility in the Porsolt test, and also hypersecreted ACTH and CORT in response to an acute stress challenge. These data show that GS can alter maternal behaviour in mothers, and this might contribute to alterations in the offspring. GS may be an important factor in maternal post-natal depression, which may in turn detrimentally effect the offspring because depressed mothers do not sufficiently care for their offspring.

Changes in hippocampal theta following intrahippocampal corticotropin-releasing hormone (CRH) infusions in the rat.

Hippocampal theta activity is a large amplitude, sinusoidal wave that occurs during attentive immobility and exploratory behaviour in the rat, and it is thought to be involved in memory formation. Recent reports suggest that corticotropin-releasing hormone (CRH) has pro-mnemonic effects in rodents. Because memory-enhancing substances/manipulations generally alter either theta frequencies or amplitudes, these variables were monitored in urethane-anaesthetised rats following intrahippocampal infusions of CRH. Adult male, Lister hooded rats were implanted with a hippocampal recording electrode and a guide cannula, both aimed at the dentate gyrus. When CRH was infused into the hippocampus, the main change in the hippocampal EEG was a slow onset increase in the amplitude of spontaneous theta and, paradoxically, a significant decrease in the amount of time spent displaying theta. These data suggest that CRH has the ability to modulate ongoing hippocampal theta, but, considering the slow effect, the involvement of hippocampal CRH receptors is suspect. Regardless of locus, the described electrophysiological changes suggest that hippocampal cholinergic systems may play a role in the memory-enhancing effects of CRH.

Effects of SCH23390 and raclopride on anxiety-like behavior in rats tested in the black-white box.

Dopamine (DA) systems are activated by stress, and this response has as a corollary the induction of stress-related behaviors such as anxiety. In mice, D2 receptor blockade produces an apparent anxiogenic effect, although locomotor impairments might have been present. We investigated the effects of D1 and D2 antagonists on a variety of anxiety-like behaviors induced by the black-white box in rats and carefully screened for any locomotor deficits. Adult male Lister hooded rats were injected with either the D1 antagonist SCH23390 (0. 0.1. or 0.25 mg/kg i.p.) or the D2 antagonist raclopride (0, 0.05, or 0.10 mg/kg i.p.) 20 min prior to being placed into the white chamber of the black-white box (n = 8-10/group). Rats were videotaped and the tapes were scored for latency to exit the white chamber, latency to reenter the white chamber, time spent in the white chamber, intercompartmental crossing, and locomotor activity. ANOVA revealed no effect of the D1 antagonist SCH23390 on any behavioral measure. However, the raclopride-treated rats left the white area sooner than control rats (p < 0.01). Raclopride-treated rats also exhibited delayed reentry times to the white chamber compared to control rats (p < 0.01) and spent significantly less time in the white chamber (p < 0.05). Neither SCH23390 nor raclopride affected locomotor activity in a manner that confounded these behaviors. These results confirm that D2 receptor blockade enhances anxiety in rats tested in the black-white box.

Regulation of hippocampal theta activity by corticosterone: opposing functions of mineralocorticoid and glucocorticoid receptors.

Recently, we reported that intrahippocampal cholinergic blockade increased corticosterone (CORT) and adrenocorticotrophin (ACTH) secretion induced by restraint stress. These data suggested to us that CORT may modify hippocampal cholinergic function as part of the negative-feedback control of hypothalamic-pituitary-adrenal (HPA) axis activity. Hippocampal cholinergic theta is a rhythmic, sinusoidal waveform that occurs in alert, immobile rats presented with threatening stimuli and is reliably expressed in urethanized rats. We reasoned that if hippocampal cholinergic systems regulate HPA axis activity, perhaps CORT acts to modulate theta activity. In the present study we have examined the effects of blocking mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) on theta activity in urethane-anesthetized rats. Adult male, Lister hooded rats (n=15) were anesthetized with urethane, and a theta recording electrode was positioned in the hippocampus adjacent to an infusion cannula. A bipolar stimulating electrode was placed in the dorsomedial posterior hypothalamus (DMPH) to activate theta. Baseline recordings of DMPH-stimulated activity (0.1-0.5 mA) were obtained. Rats were then administered either the MR antagonist spironolactone or the GR antagonist RU 38486 (150 ng), and DMPH-stimulated activities were monitored for 45 min. Changes in theta frequency (Hz) and amplitude (mV; energy at peak theta frequency) were analyzed using analysis of variance (ANOVA) followed by Bonferroni t-tests. Neither drug affected hippocampal theta frequencies elicited by DMPH stimulation. However, GR blockade produced marked increases in theta amplitudes of approximately 100% above predrug levels. Alternatively, MR blockade produced exactly the opposite response, as amplitude values fell to approximately 50% of predrug levels. Hippocampal cholinergic theta activity is modulated by CORT acting through MR and GR, and the rapidity of the response suggests a nongenomic mechanism. These data raise the possibility that hippocampal cholinergic systems, and theta activity, are involved in CORT-mediated negative-feedback control of the HPA axis.

The effects of intrahippocampal scopolamine infusions on anxiety in rats as measured by the black-white box test.

Hippocampal cholinergic projections mediate attention to arousing stimuli as demonstrated by behavioral, electrophysiological, and endocrine studies. We recently reported that peripheral injections of the cholinergic antagonist scopolamine (SCOP) increased anxiety-like behaviour (ALB) in rats and we sought to investigate if this response might be hippocampally mediated. Adult male, Lister Hooded rats were implanted bilaterally with hippocampal cannulae 3 weeks prior to testing. On the test day, rats were injected with vehicle (VEH; artificial CSF at 3 microl), 15 or 30 microg SCOP, 20 min prior to being placed into the white chamber of the black-white box (n = 10/group). Rats were scored for latencies to exit and reenter the white chamber, total time spent in the white chamber, intercompartmental crossings, and activity. SCOP at 30 microg significantly reduced time to exit the white arena, while both doses of SCOP elevated latencies to reenter the white chamber. There were no effects of SCOP on intercompartmental crossing, time spent in the white chamber, or on activity levels. Loss of hippocampal cholinergic function impairs processing of threatening stimuli that manifests itself as increased ALB.

Hippocampal cholinergic blockade enhances hypothalamic-pituitary-adrenal responses to stress.

We examined the role of the hippocampal cholinergic system, which is known to mediate processes related to fear and anxiety, in the regulation of stress-induced hypothalamic-pituitary-adrenal (HPA) activity. Bilateral intra-hippocampal injections (30 microg per side) of the muscarinic antagonist Scopolamine augmented adrenocorticotropin and corticosterone responses to restraint without altering basal HPA activity compared to vehicle-treated animals. These results suggest that the hippocampal cholinergic system regulates stress-induced HPA activity and may serve to coordinate behavioral and neuroendocrine responses to stress.

Cognitive dysfunctions induced by scopolamine are reduced by systemic or intrahippocampal mineralocorticoid receptor blockade.

Central cholinergic blockade with scopolamine (SCOP) produces profound cognitive impairments in human and animal subjects. We hypothesized that cognitive deficits induced by cholinergic blockade originate partly from its ability to enhance reactivity to the environment, an effect that would be ameliorated by prior mineralocorticoid receptor (MR) blockade, because MR antagonists reduce reactivity to novelty. In the present study, we investigated whether or not systemic or intrahippocampal infusions of the MR antagonist spironolactone (SPIRO) would affect SCOP-induced cognitive impairments in a water maze task. Adult male Lister hooded rats (350-450 g) served as subjects. In Experiment 1, rats were administered SPIRO (0 or 100 mg/kg i.p.) followed 10 min later by SCOP (0, 0.5, or 2.0 mg/kg i.p.; n = 10/group). In Experiment 2, groups of rats implanted with hippocampal cannulae received central infusions of SPIRO (50 ng/microliter; 3 microliters in total) 10 min prior to SCOP injection (2.0 mg/kg i.p.; n = 6/group). Behavioural testing started 15 min after SCOP administration and consisted of a simple water maze task in which animals were required to locate a submerged platform using spatial cues. The testing regime consisted of two phases: a) acquisition, and b) retention, 24 h later. Peripheral, but not central, injections of SPIRO enhanced water maze performance during acquisition in SCOP-treated rats, as shown by shorter latencies and shorter distances travelled to locate the hidden platform. Both peripheral and central SPIRO administration reduced the long-term retention deficits in performance in the SCOP-treated animals. These data are in general agreement with a growing body of research suggesting that corticosteroid hormones interact with central cholinergic systems to affect both physiological and behavioural responses. MR blockade may reduce an animal's reactivity to the environment and enable it to selectively filter out extraneous stimuli that it would otherwise react to, thus impairing performance.

Hippocampal mineralocorticoid, but not glucocorticoid, receptors modulate anxiety-like behavior in rats.

Stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis is regulated by negative-feedback mechanisms in the form of cytosolic and nuclear steroid receptors, sensitive to levels of circulating corticosterone (CORT). There are two types of steroid binding sites found in the brain: (i) mineralocorticoid receptors (MR); and (ii) glucocorticoid receptors (GR). The hippocampus expresses the highest density of both MR and GR relative to other brain regions, and has long been recognized as a principal component controlling HPA axis inhibition. Because hippocampal cholinergic blockade produced anxiety-like behaviour, and affected HPA axis function, we explored if the induction of anxiety might be attributable to changes in CORT. CORT also produced anxiety, although in a qualitatively unique manner than that produced by cholinergic blockade. In the present study, we have examined if CORT-induced anxiety occurs through an interaction with hippocampal MR or GR. Adult, male Lister Hooded rats were implanted bilaterally with hippocampal cannulae, and received infusions of either the MR antagonist, spironolactone (150 ng), or the GR antagonist, RU38486 (150 ng), either 10 min or 3 h prior to being tested in the Black-White box. MR blockade, 10 min prior to testing, led to a pronounced anxiolytic effect as revealed by the increased amount of time spent in the white compartment, and increased amount of intercompartmental exploration. There was no effect of MR blockade 3 h prior to testing, and GR antagonism produced no effects at either pretreatment time. These data are the first to show that hippocampal MR are directly involved in anxiety; moreover, the time course of the effect demonstrates that a non-genomic mechanism probably underlies this response. Stress may be an important predisposing factor in the development and expression of anxiety.

Muscarinic antagonists are anxiogenic in rats tested in the black-white box.

Central cholinergic (ACh) projections have been shown to modulate stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis and are integral to the expression of electrophysiological correlates of arousal, namely hippocampal theta rhythm. The degree to which these actions of ACh are behaviorally relevant has received comparatively less attention, and we sought to investigate if manipulations of ACh systems might also affect behaviors related to stress and arousal. We chose to examine indices of anxiety as revealed by changes in behavior elicited by the black-white box test, a relatively novel and recently validated model of rodent anxiety. Groups of rats were injected with either scopolamine hydrobromide (SCOP; 0, 0.05, and 0.10 mg/kg i.p.) or the peripherally acting scopolamine methyl bromide (methyl-SCOP; 0, 0.05, and 0.10 mg/kg i.p.) to compare and contrast the effects of central and peripheral ACh blockade on measures of anxiety. SCOP pretreatment significantly lowered latencies for rats to escape from the white to black compartment, while methyl-SCOP elevated latencies to reenter the white chamber from the black. Both drugs increased the amount of time rats spent in the black compartment and also suppressed exploration as revealed by decreased episodes of intercompartmental locomotion. Neither drug deleteriously affected locomotor activity, however; in fact, SCOP significantly increased locomotion in the white chamber. In the absence of motor disturbances to account for any group differences, we contend that both central and peripheral ACh blockade may affect measures of anxiety, perhaps by directly or indirectly affecting HPA activity. Central ACh systems may underlie sensory filtering whereby irrelevant stimuli are excluded from sensory processing. Antagonism of ACh transmission may render an animal incapable of correctly processing sensory information leading to hyperresponsiveness, which can manifest itself as enhanced anxiety and fear.

Median eminence corticotrophin-releasing hormone content following prenatal stress and neonatal handling.

Neonatal handling produces enduring changes in hypothalamic-pituitary-adrenal (HPA) axis activation in response to acute stress presentation. Handled rats display reduced HPA activity in response to stress, which is associated with increased hippocampal glucocorticoid receptor densities and decreased median eminence corticotrophin-releasing hormone (CRH) content. Prenatal stress (PS) also has long-term consequences on HPA responsivity to stress and related behavioral profiles. On the basis of earlier behavioral data suggesting that PS contributed to the expression of handled responses, we investigated how PS and handling might interact to affect median eminence CRH content. Groups of prenatally stressed rats and controls were subjected to a handling procedure or left undisturbed. Adult rats were killed and median eminence CRH levels were assayed as well as plasma corticosterone (CORT). PS and handling did not affect CRH content; however, handled plus PS rats exhibited significantly reduced CRH levels. Handling decreased plasma CORT concentrations, an effect that was absent in the PS rats. We contend that PS can modulate an animal's sensitivity to later environmental manipulations while producing minimal effects on its own. Researchers interested in early environmental conditions and later physiologic and behavioral responses should monitor their subjects' gestational history.

Benzodiazepine receptor stimulation blocks scopolamine-induced learning impairments in a water maze task.

Central cholinergic (ACh) blockade produces profound cognitive impairments in human and animal subjects. Our previous research demonstrated that ACh blockade exacerbates stress-induced adrenocorticotrophin (ACTH) and corticosterone (CORT) secretion, and increases anxiety-like behavior (ALB) in rats. The fact that all these responses occur following the same manipulation led us to question whether or not increases in ALB might play a part in the cognitive deficits. This issue was all the more intriguing given that anxiolytic agents such as benzodiazepines are reported to produce learning and memory impairments on their own. We reasoned that a low dose of diazepam (DZP) with no apparent cognitive effects itself, might be able to antagonize an impairment induced by scopolamine (SCOP). Adult male Lister rats (n = 6/group) were administered IP either vehicle (VEH), 0.5 mg/kg DZP, 0.25 mg/kg SCOP, or 0.5 mg/kg DZP, followed 20 min later by 0.25 mg/kg SCOP, and tested 20 min later in a water maze for latency to locate a hidden platform and for path length taken to the platform. Rats were tested in an acquisition phase (Day 1) and a retention phase (Day 2), as well as on a visually guided task. On Day 1, SCOP produced a marked acquisition deficit that was unaffected by DZP. DZP by itself had no obvious effect. However, whereas SCOP resulted in a persistent deficit on the retention task (Day 2), pretreatment with DZP prior to SCOP on Day 1 completely abolished the impairment. There were no group differences on the visually cued task. We contend that SCOP-induced cognitive deficits may, in part, be due to increases in ALB. Stimulation of benzodiazepine receptors may offset the loss of cholinergic systems underlying consolidation mechanisms, but not those mediating immediate task performance. Whether this effect of DZP relates to an action on ALB remains to be elucidated.

Sex-specific effects of prenatal stress on hypothalamic-pituitary-adrenal responses to stress and brain glucocorticoid receptor density in adult rats.

Previous research indicates that the offspring of dams exposed to stress during late gestation show altered hypothalamic-pituitary-adrenal (HPA) responses to stress. However, the results are inconsistent and a review of the literature suggests that the effects may differ depending upon the gender of the offspring. In the present study, we measured plasma adrenocorticotropin (ACTH) and corticosterone (B) levels prior to, and at 0, 20, 40 and 70 min following restraint stress in catheterized adult male and female offspring of dams stressed in the last week of gestation (i.e. days 15-19 of gestation). Prenatal stress significantly increased both plasma ACTH and B levels in response to restraint, but only in females; male offspring were largely unaffected. In addition, plasma corticosteroid-binding globulin (CBG) levels were significantly increased in prenatally-stressed females, but not in males. Despite these differences in plasma CBG, estimated free B levels following restraint were also significantly elevated in prenatally-stressed females. We then examined glucocorticoid receptor binding in a variety of forebrain structures. Prenatal stress had no effect on glucocorticoid receptor density in the hypothalamus or hippocampus in either males or females. Differences in glucocorticoid receptor density across groups were observed in the septum, frontal cortex, and amygdala. However, the pattern of observed differences across the groups was not consistent with the pattern of hormonal differences. In summary, the effect of prenatal stress on HPA function is substantially more marked in females than in males. Interestingly, a similar pattern of effects on HPA activity has been reported for prenatal alcohol exposure.

Neonatal handling alters serotonin (5-HT) turnover and 5-HT2 receptor binding in selected brain regions: relationship to the handling effect on glucocorticoid receptor expression.

Neonatal handling permanently alters hypothalamic-pituitary-adrenal responses to stress. This effect is, in part, mediated by a handling-induced increase in forebrain glucocorticoid receptor gene expression. The effect of postnatal handling on glucocorticoid receptor expression appears to be mediated by an increase in serotonin (5-HT) activity, acting via a 5-HT2 receptor with a high affinity for 5-HT (i.e. the 5-HT2H receptor). In the present study we examined the nature of the effects of handling on the relevant 5-HT systems. We found that: (1) handling increases 5-HT turnover in regions of the neonatal rat brain where glucocorticoid receptor expression is altered (i.e. the hippocampus and frontal cortex), but not in regions where glucocorticoid receptor expression in unaffected (e.g. hypothalamus and amygdala); (2) handling has no long-term effects on hippocampal or frontal cortex 5-HT turnover, and is actually associated with a decrease in 5-HT concentrations; and (3) handling does not alter 5-HT2 receptor density in the hippocampus or frontal cortex in neonates (although there are surprising effects on 5-HT2 receptor density in the frontal cortex of adult animals). Taken together these data provide further evidence for the importance of 5-HT in mediating the effects of handling on the development of glucocorticoid receptor expression, but suggest that the role of 5-HT is unique to early development; differences in glucocorticoid receptor expression in adult handled and non-handled animals are not associated with long-term differences in either 5-HT levels or 5-HT2 receptors.

The interaction between prenatal stress and neonatal handling on nociceptive response latencies in male and female rats.

Neonatal handling produces physiological and behavioral changes that persist into adulthood. These effects are opposite to those resulting from prenatal stress (PS). We examined the interaction between PS and handling on nociception in adult male and female rats. Randomly selected pregnant rats were subjected to restraint stress on days 13-17 of gestation for 25 min each day, or left undisturbed. At birth, selected stressed/nonstressed litters were assigned to be handled. handling consisted of 15 min of separation from the dam, once per day, from postnatal days 1-14. At 4 months of age, rats were placed on a 50 degrees C hot plate, and their latencies to paw lick were recorded. Prenatal stress and handling interacted to affect latencies in male rats. Handled (H)/PS rats had significantly lower paw lick latencies than nonhandled (NH)/PS rats (p < 0.05). However, handling had no effect on the male offspring of control dams. Handling elevated paw lick latencies in the female offspring of control dams, an effect that was most pronounced in diestrous vs. estrous rats. The NH/PS rats showed significantly elevated latencies compared to NH/NS rats (p < 0.05). These results suggest that handling effects on nociception are most apparent in rats subjected to PS; in males at least, these effects would otherwise not be present.

The extrinsic modulation of hippocampal theta depends on the coactivation of cholinergic and GABA-ergic medial septal inputs.

The long trains of theta field activity recorded from the hippocampal formation of urethane-anesthetized rats are thought to be primarily dependent on cholinergic afferents originating in the medial septum/vertical limb of the diagonal band of Broca (MS/vDBB). Recent anatomical studies have revealed the existence of a septal GABA-ergic input to the hippocampal formation which synapses mainly on intrinsic GABA-ergic interneurons. The present work investigated the possibility that some form of interaction between cholinergic and GABA-ergic MS/vDBB inputs might be required for the generation of hippocampal theta field and cellular activities in urethane-anesthetized rats. Reversible inactivation of the MS/vDBB completely abolished theta field and theta-on cell activities, but "released" theta-off cells. The theta field and theta-on cell activities induced by direct intrahippocampal microinfusions of carbachol were also abolished by MS/vDBB inactivation. We speculated that septal suppression was producing two effects: 1) removing excitatory, cholinergic input; and 2) removing inhibitory control of hippocampal GABA-ergic interneurons, thereby increasing the overall level of hippocampal inhibition. Sequential administration of both carbachol and the GABA-A antagonist, bicuculline, resulted in theta-like oscillations similar to those seen in hippocampal slices bath perfused with carbachol alone. Thus, following MS/vDBB inactivation hippocampal GABA-ergic systems are overactive; this enhances intrinsic inhibition and blocks carbachol theta. By reducing the overall level of inhibition in the hippocampus with bicuculline, it is possible to reinstate its oscillatory properties. Conversely, increasing the level of inhibition in the hippocampus (with muscimol) results in the abolishment of theta field activity and the discharges of both theta-on and theta-off cells. Based on these findings we are proposing that cholinergic and GABA-ergic systems originating in the MS/vDBB act synergistically to modulate hippocampal theta. Cholinergic projections provide the afferent excitatory drive for hippocampal theta-on cells and septal GABA-ergic projections act to reduce the overall level of inhibition by inhibiting hippocampal GABA-ergic interneurons (hippocampal theta-off cells). Both activities must be present for the generation of hippocampal theta field and cellular activities. The balance between the cholinergic and GABA-ergic systems may determine whether hippocampal synchrony (theta) or asynchrony (LIA) occurs.

In vivo intrahippocampal microinfusion of carbachol and bicuculline induces theta-like oscillations in the septally deafferented hippocampus.

In their laboratory the authors have previously demonstrated that hippocampal slices could be induced to generate trains of "theta-like" oscillations by whole-bath perfusions of carbachol. Until recently, it has not been possible to generate similar activity in the septally deafferented hippocampus of an otherwise intact brain by microinfusions of carbachol. This study presents a full report of the first demonstration of a theta-like oscillation in the in vivo, septally deafferented hippocampal formation. Rats were anesthetized with urethane and implanted with microinfusion cannulae in the region of the medial septum/vertical limb of the diagonal band of Broca (MS/vDBB) and at single or multiple sites in the stratum moleculare of the fascia dentata. The MS/vDBB was microinfused with procaine hydrochloride to produce a reversible suppression lasting for approximately 20 minutes. Intrahippocampal microinfusions of carbachol or bicuculline alone (in the postprocaine condition of the MS/vDBB) failed to produce any theta-like oscillations. The combination of carbachol and bicuculline produced trains of theta-like oscillations during suppression of the MS/vDBB very similar to those seen in the slice preparations. The oscillations were blocked by intravenous administration of atropine sulfate, and they had the same depth profile as that of theta. Theta-on cells were shown to discharge in rhythmic bursts in synchrony with the oscillations. Thus, it would appear that the essential nature of the medial septal input to the hippocampal formation, for the generation of theta field activity in the intact brain, consists of a critical balance between cholinergic and GABAergic circuitry.

Hippocampal theta field activity and theta-on/theta-off cell discharges are controlled by an ascending hypothalamo-septal pathway.

The nature of the control of hippocampal formation field activity [theta (theta) and large-amplitude irregular activity (LIA)] and theta-on/theta-off cell discharges by an ascending hypothalamo-septal pathway was investigated in urethane-anesthetized rats. Electrical stimulation of the dorsomedial-posterior hypothalamus in the range of 0.1-1.0 mA in 0.1-mA steps produced theta in the hippocampal formation, with a linear positive relation between stimulus intensity, theta frequency, and theta amplitude. Reversible blockade of the medial septal (MS)/vertical limb of the diagonal band of Broca (vDBB) region by microinjection of procaine hydrochloride abolished spontaneous and hypothalamically elicited theta, resulting in a field activity at 1-min post-procaine that had a lower power than pre-procaine LIA levels. The efficacy and recovery of the MS/vDBB suppression was tested at 1, 10, 20, 30, 40, 50, and 60 min post-procaine using 0.5, 0.8, and 1.0 mA of hypothalamic stimulation. All three of the dependent measures of hippocampal field activity (frequency, amplitude, and power) showed a progressive recovery during the 60-min post-procaine period. Frequency exhibited a rapid recovery with a shallow slope between 20 and 60 min post-procaine. In contrast, the amplitude and power of theta exhibited a gradual recovery with a steeper slope between 20 and 60 min post-procaine. During the time of maximal MS/vDBB suppression, theta-on cell discharges were reduced to 0 in most cases. The initial recovery of theta-on cells in the post-procaine condition was correlated with the first appearance of theta and was characterized by low discharge rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal demedullation blocks and brain norepinephrine depletion potentiates the hyperglycemic response to a variety of stressors.

The role of adrenal hormones in mediating the increase in blood glucose levels following several stressful stimuli (environmental and pharmacological) was studied. The role for brain norepinephrine systems in the initiation of the BG response to these challenges was investigated as well. There is disagreement as to whether stress-induced increases in blood glucose levels are mediated primarily by hormonal or neural stimulation of the liver. A stressful stimulus probably causes increases in blood glucose levels by activating neural connections from the brain to both the liver and the adrenal medulla. The relative contribution that each of these pathways makes to the overall blood glucose response may be dependent on certain factors, such as the type of preparation used (awake or anesthetized, fasted or fed) and the intensity of the stimulus used to induce hyperglycemia. In the experiments reported here, which were performed in awake male rats, we found that increases in blood glucose levels following brief footshock stress, injection of 2-deoxy-D-glucose, exposure to the odor of a predator, and electrical stimulation of the hypothalamus were almost entirely eliminated by removal of the adrenal medullae, a procedure that does not damage hypothalamic norepinephrine systems or the multi-synaptic neural pathways from the hypothalamus to the liver. Furthermore, rather than having impaired blood glucose responses, rats that were depleted of brain norepinephrine showed normal responses to the injection of adrenergic agonists (including epinephrine), and potentiated responses to stressful stimuli compared to non-depleted controls. We conclude that: (1) rapid changes in blood glucose levels that occur following the stressful stimuli used here are mediated mainly by the release of epinephrine from the adrenal medullae and (2) intact brain norepinephrine systems are not required for these increases in blood glucose to occur.