Involvement of noradrenergic and corticoid receptors in the consolidation of the lasting anxiogenic effects of predator stress.

The roles of beta-NER (beta-noradrenergic receptor), GR (glucocorticoid) and mineral corticoid receptors (MR) in the consolidation of anxiogenic effects of predator stress were studied. One minute after predator stress, different groups of rats were injected (ip) with vehicle, propranolol (beta-NER blocker, 5 and 10 mg/kg), mifepristone (RU486, GR blocker, 20 mg/kg), spironolactone (MR blocker, 50 mg/kg), propranolol (5 mg/kg) plus RU486 (20 mg/kg) or the anxiolytic, chloradiazepoxide (CPZ, 10 mg/kg). One week later, rodent anxiety was assessed in elevated plus maze, hole board, light/dark box, social interaction and acoustic startle. Considering all tests except startle, propranolol dose dependently blocked consolidation of lasting anxiogenic effects of predator stress in all tests. GR receptor block alone was ineffective. However, GR block in combination with an ineffective dose of propranolol did blocked consolidation of predator stress effects in all tests, suggesting a synergism between beta-NER and GR. Surprisingly, MR block prevented consolidation of anxiogenic effects in all tests except the light/dark box. CPZ post stress was ineffective against the anxiogenic impact of predator stress. Study of startle was complicated by the fact that anxiogenic effects of stress on startle amplitude manifested as both an increase and a decrease in startle amplitude. Suppression of startle occurred in stressed plus vehicle injected groups handled three times prior to predator stress. In contrast, stressed plus vehicle rats handled five times prior to predator stress showed increases in startle, as did all predator stressed only groups. Mechanisms of consolidation of the different startle responses appear to differ. CPZ post stress blocked startle suppression but not enhancement of startle. Propranolol post stress had no effect on either suppression or enhancement of startle. GR block alone post stress prevented suppression of startle, but not enhancement. In contrast blocking GR and beta-NER together prevented startle enhancement. MR block also prevented startle enhancement. Effects of MR block on startle suppression were not tested. Delay of habituation to startle was found in all stressed rats. Consolidation of delay of habituation was blocked or attenuated by post stress MR block, GR plus beta-NER block and CPZ but not by post stress GR or beta-NER block alone. Taken together, present findings suggest consolidation of lasting anxiogenic effects of predator stress may share some of the same neurochemical mechanisms implicated in some forms of fear memory consolidation. Implications of these findings for the study of stress-induced changes in affect including posttraumatic stress disorder (PTSD) are discussed.

Does long term potentiation in periacqueductal gray (PAG) mediate lasting changes in rodent anxiety-like behavior (ALB) produced by predator stress?--Effects of low frequency stimulation (LFS) of PAG on place preference and changes in ALB produced by predator stress.

The effects on rodent behavior of low frequency bilateral stimulation (LFS, 900 pulses at 1 Hz) of periacqueducatal gray (PAG) was investigated. The first experiment examined aversive qualities of LFS in a place preference paradigm. There was no evidence of a place preference after 1 or 7 applications of LFS. After the first LFS, rats showed longer latencies to leave the conditioned chamber, suggesting a positively reinforcing effect of LFS. Latency differences were not accounted for by freezing or immobility prior to leaving. Rats with electrodes outside the PAG did not show these effects. After repeated LFS, stimulated rats did not differ from controls in place preference or in anxiety-like behavior (ALB). Experiment 2 studied the effects of predator stress in unimplanted rats on an extended battery of measures of ALB in hole board, plus maze and light/dark box tests of rodent anxiety. Effects of electrode damage in the PAG on ALB was also examined. In addition, the effect of 7 applications of bilateral LFS of PAG on ALB following a 5 min unprotected exposure of rats to a cat (predator stress) was examined. Predator stress lastingly changed a wide variety of behaviors in the plus maze, [Rodgers, Behav. Pharmacol. 8 (1997) 477] replicating and extending previous reports. A new finding is an increase in light avoidance in the light/dark box test. Moreover, factor analysis revealed open arm avoidance, risk assessment, light avoidance and cautious exploration loaded on independent factors, replicating and extending previous findings. Bilateral, but not unilateral, damage specific to PAG was also found to be anxiolytic in plus maze measures of ALB. Bilateral implants in the PAG seemed to prevent many of the effects of predator stress on ALB measured 8 days later. Nevertheless, predator stress did decrease head dips in the open arm and LFS reversed this effect. Light avoidance also increased following predator stress and LFS reversed this increase. These findings suggest the PAG occupies an important position in the final common path of substrate changes mediating effects of predator stress on a range of behaviors in the rodent. The fact that LFS in the PAG can reverse stress induced changes in behavior supports the idea that LTP in PAG mediates stress induced increases in anxiety in rodents, as it does in the cat [Adamec, Neurosci. Biobevav. Rev. 21(6) (1997) 755; Adamec, J. Psychopharmacol. 2000 (in press); Adamec, J. Psychopharmacol. 2000 (in press); Adamec, J. Psychopharmacol. 12(2) (1998) 129; Adamec, J. Psychopharmacol. 12(13) (1998) 227].

Neural plasticity and stress induced changes in defense in the rat.

We investigated the effects of predator stress on behavior and amygdala afferent and efferent neural transmission in rats. Pathways studied were: ventral angular bundle input to the basolateral amygdala; central and basolateral amygdala output to the periaqueductal gray (PAG). Predator stress was 'anxiogenic' in elevated plus maze, light/dark box and acoustic startle tests one week after stress. Lasting changes were also observed in neural transmission. Predator stress appeared to potentiate right and depotentiate left hemisphere afferent amygdala transmission. In contrast, predator stress potentiated amygdala efferent transmission to right and left PAG, depending on the amygdala nucleus stimulated. Paired pulse and intensity series analysis suggests that transmission changes may be postsynaptic or presynaptic, depending on the pathway. Path analysis relating brain and behavioral changes suggests that potentiation and depotentiation in both hemispheres participate jointly in effecting some, but not all, of the behavioral changes produced by predator stress. Potentiation in left hemisphere amygdala afferents and efferents predicts anxiolytic-like effects, while potentiation in the right hemisphere amygdala afferents predicts anxiogenic-like effects. Path analysis also supports the view that changes in different neural systems mediate changes in different behaviors. These findings have their parallel in studies in the cat, but there are species differences.

Amiodarone therapy for sustained ventricular tachycardia after myocardial infarction: long-term follow-up, risk assessment and predictive value of programmed ventricular stimulation.

We determine the value of the programmed ventricular stimulation (PVS) and of clinical, angiographic and electrophysiologic variables in assessing the long-term risk of arrhythmia recurrence in a group of coronary artery diseased patients presenting with a first episode of monomorphic sustained ventricular tachycardia (VT) treated with amiodarone. Mortality and arrhythmia recurrence rates were retrospectively assessed in 55 consecutive patients with previous myocardial infarction presenting with a first VT episode. Results of left heart catheterization, echocardiography and time-domain signal-averaging were collected. Patients underwent PVS after amiodarone oral loading and were classified according to inducibility before being all discharged on amiodarone (200 mg daily). The mean follow-up was 42+/-31 months. Total and cardiac mortality rates were 29% (16 patients) and 23% (13 patients) respectively. Sudden death (SD) occurred in nine patients (16%). VT recurred in 13 patients (23%). Sustained monomorphic VT was inducible in 40 patients (72%) after amiodarone loading. Neither total mortality (10/40 vs. 6/15) nor cardiac mortality (3/40 vs. 1/15) were significantly different between inducible and non-inducible patients. Recurrent VT rate was 27% (11/40 patients) for the inducible group and 13% (2/15 patients) for the non-inducible group (NS). SD occurred in 6/40 inducible patients (15%) and in 2/15 non-inducible patients (13%) (NS). Arrhythmic events occurred in 42% (17/40) inducible patients vs. 26% (4/15) non-inducible patients (P=0.07). Parameters correlated with outcome were ejection fraction (EF) (5 SD/11 patients with EF <0.3 vs. 4/44 with EF >0.3, P=0.003), mitral insufficiency (MI) (4 SD/10 patients with MI vs. 4/44 patients without MI, P=0.004) and age (65+/-9 years for patients with VT recurrence vs. 58+/-9, P=0.02). Although the risk stratification can be improved, reliable and safe long-term prediction of recurrence of malignant ventricular arrhythmia in individual patients cannot be made. Consequently, the systematic implantation of a cardioverter-defibrillator in case of a first episode of sustained VT occurring in coronary artery disease patients should be further debated.

Intravenous amiodarone or magnesium sulphate is not cost-beneficial prophylaxis for atrial fibrillation after coronary artery bypass surgery.

Our aims were to examine whether the administration of amiodarone or magnesium sulphate after coronary artery bypass graft surgery (CABG) could reduce the occurrence of atrial fibrillation, and to identify the risk factors associated with atrial fibrillation after CABG. Patients scheduled for elective CABG (n = 155) were allocated randomly, in a controlled double-blind study, to receive immediately after surgery a 72-h infusion of amiodarone (900 mg per 24 h), magnesium (4 g per 24 h) or placebo (0.9% NaCl; 50 ml per 24 h) intravenously. A 72-h Holter ECG was recorded concomitantly. The primary end-point was the prevention of atrial fibrillation; its onset was considered as prophylactic failure. An interim safety analysis was performed in 147 patients. The cumulative occurrence of atrial fibrillation was 27% in the placebo group, 14% in the amiodarone group (P = 0.14) and 23% in the magnesium group (P = 0.82). Although amiodarone delayed the onset of the first tachyarrhythmic episode (P = 0.02), it was associated with the need for longer periods of vasoactive drug infusion and invasive monitoring and a longer stay in the intensive care unit. Variables associated with the onset of atrial fibrillation were older age (odds ratio 1.9) and a plasma magnesium concentration at 24 h of less than 0.95 mmol litre-1 (odds ratio 6.7). Postoperative administration of amiodarone reduced the occurrence of atrial fibrillation after elective CABG surgery, but was associated with a longer duration of cardiovascular instability and longer need for intensive care; magnesium prophylaxis had no effect. Advanced age and a low plasma magnesium concentration are risk factors for postoperative atrial fibrillation.

Neuroplasticity in specific limbic system circuits may mediate specific kindling induced changes in animal affect-implications for understanding anxiety associated with epilepsy.

In two complementary experiments, we studied the effects of low frequency stimulation (LFS) of the amygdala on behavioral effects of kindling in rats and cats. These studies tested the hypothesis that kindling induced long term potentiation (KLTP) in amygdala circuits underlies interictal behavioral change. Since LFS can depotentiate LTP, it was predicted that LFS should both depotentiate KLTP and reverse behavioral effects of kindling. In cats, the effects of LFS on KLTP of amygdala efferents was studied, and related to behavioral effects. Partial ventral hippocampal kindling in cats and right amygdala kindling in rodents lastingly increased defensive response to rats in cats, and anxiety-like behavior (ALB) in the elevated plus-maze in rats. In addition, partial kindling reduced predatory attack behavior in cats independent of its effects on defensive response. Partial kindling also induced KLTP of amygdala efferent transmission to ventromedial hypothalamus (VMH) and periaqueductal gray (PAG) in left and right hemispheres. Depotentiation of amygdala efferent KLTP by bilateral amygdala LFS selectively reduced KLTP in right amygdala efferents. At the same time, defensive behavior, but not attack behavior, was returned to levels seen prior to partial kindling. Defensiveness returned to post kindling levels between 44 and 76days after LFS. At the same time, LTP was restored in the right Amygdalo-PAG pathway only. These findings suggest that lasting change in affect produced by kindling depends on LTP of right amygdala efferent transmission to PAG, replicating studies of the effects of FG-7142 on brain and behavior in the cat. The findings suggest further that the spectrum of behavioral changes produced by partial kindling are dependent on changes in a variety of neural circuits, and that amygdala efferent transmission changes are responsible for changes in defensive behavior, but not attack behavior. Effects of LFS were not due to damage, as thresholds to evoke amygdala efferent response were unchanged. Other data suggest KLTP and depotentiation in right Amygdalo-PAG may reflect changes in glutamate receptor density/synapse number. Kindling effects on rat ALB persisted for at least 1month. Bilateral but not unilateral amygdala LFS reversed the effects of kindling on risk assessment in the plus maze for at least 3weeks. Bilateral LFS also reversed the effects of kindling on open arm exploration, but effects were shorter lived, appearing at 1day but not 3weeks after kindling and LFS. These findings are consistent with other studies which suggest that amygdala neuroplasticity in separable amygdala circuits mediates lasting changes in open arm avoidance and risk assessment. Taken together, the findings of both studies support the hypothesis that a form of LTP of specific amygdala circuits underlies lasting changes in affect produced by limbic kindling. Clinical implications of these findings are discussed.

Effects of baseline anxiety on response to kindling of the right medial amygdala.

The effects of kindling of the right anterior medial amygdala of Wistar rats was studied. Kindling lastingly increased anxiety (decreased open-arm exploration) in the elevated plus-maze 1 week after the last kindled seizure, replicating previous findings. Changes in anxiety were independent of changes in exploration or activity in either the plus-maze or hole board. A new finding is the dependence on baseline behavior of kindling induced behavioral changes. Using a novel-retest paradigm, it was possible to retest rats in the plus-maze without changes in their open arm explorations. This permitted pretesting rats to determine their baseline levels of plus-maze anxiety. Controls proved to be stable in their plus-maze behavior over a retest interval of 3 weeks. Rats below the median level of Test 1 open-arm exploration were unaffected by kindling. Those above the Test 1 median level of open-arm exploration showed reduced exploration following kindling. Kindling did not affect closed-arm entries in the plus-maze in this analysis. However, it was discovered that rats with arm entries below a critical level on Test 1 showed an increase in closed-arm entries following kindling. These findings point out how baseline behaviors can interact with kindling to influence behavioral outcome. Risk assessment was unchanged by kindling in this study, unlike previous reports. Subtle changes in focus location within the medial amygdala may have altered the effects of kindling on risk assessment. The electrodes in this study were in a slightly but significantly different location in the medial amygdala than in previous studies. As in previous studies, risk assessment was measured as frequency and duration of stretch attend postures toward the open arm of the plus maze when the hind quarters were in the closed arms. Risk assessment was taken as a ratio of time spent in the closed arms of the maze. This study, along with others reviewed elsewhere, suggest that a complex set of factors contributes to the effects of kindling on behavior. The fact that previous studies have not taken them into account perhaps explains inconsistencies in the reported behavioral effects of kindling on behavior in rodents.

Rodent anxiety and kindling of the central amygdala and nucleus basalis.

We studied lasting behavioral effects of kindling of three parts of the central nucleus of the amygdala and the anterior nucleus basalis in the right hemisphere of male Wistar rats. Kindling lastingly changed two measures of anxiety in the elevated plus-maze. The nature of the change depended on the location of the kindled focus. Kindling of the posterior central nucleus decreased both open-arm exploration and frequency of risk assessment in the elevated plus-maze 1 week after the fourth stage 5 seizure. Kindling of the middle parts of the central nucleus was without behavioral effects. Kindling of the anterior central nucleus and the anterior nucleus basalis increased risk assessment, which was interpreted as an anxiolytic effect. Changes in risk assessment produced by kindling of the central nucleus were dependent on open-arm avoidance, whereas the effects of nucleus basalis kindling were independent of open-arm avoidance. Analysis of covariance and factor analysis support the view that control of risk assessment is by circuitry, which is independent of that which controls open-arm avoidance. Moreover, part of this circuitry appears to involve the anterior nucleus basalis. Changes in plus-maze behavior were independent of changes in exploration or activity in either the plus-maze or hole board. These findings add to a growing body of evidence that suggests that subtle differences in location of a kindled focus within the rat amygdala lead to different behavioral outcomes.

Evidence that long-lasting potentiation in limbic circuits mediating defensive behaviour in the right hemisphere underlies pharmacological stressor (FG-7142) induced lasting increases in anxiety-like behaviour: role of benzodiazepine receptors.

The hypothesis that benzodiazepine receptors mediate initiation of lasting behavioural changes induced by FG-7142 was supported in this study. Behavioural changes normally induced by FG-7142 were blocked by prior administration of the competitive benzodiazepine receptor blocker, Flumazenil. When cats were subsequently given FG-7142 alone, the drug produced lasting behavioural changes in species characteristic defensive responses to rodent and cat vocal threat. FG-7142 also induced long-lasting potentiation (LLP) of evoked potentials in a number of efferent pathways from the amygdala in both hemispheres. Flumazenil given prior to FG-7142 blocked LLP in all but one of the amygdala efferent pathways, suggesting benzodiazepine receptor dependence of initiation of LLP. Three physiological changes were most closely correlated with behavioural changes. LLP in the right amygdalo-ventromedial hypothalamic (VMH) and amygdalo-periacqueductal gray (PAG) pathways coincided closely with behavioural changes, as did a reduced threshold for the right amygdalo-VMH evoked potential. Administration of Flumazenil after FG-7142 returned defensive behaviour to pre FG-7142 baseline levels in a drug-dependent manner. At the same time LLP only in the right amygdalo-PAG pathway was reduced by Flumazenil. LLP in other pathways and amygdalo-VMH threshold were unaltered by Flumazenil. Moreover, covariance analyses indicated that increased defensiveness depended solely on LLP in the right amygdalo-PAG. These findings support the view that maintenance of lasting increases in defensive behaviour depend upon LLP of excitatory neural transmission between amygdala and lateral column of the PAG in the right hemisphere. Moreover, FG-7142 may be a useful model of the effects of traumatic stressors on limbic system function in anxiety, especially in view of the recent data in humans implicating right hemispheric function in persisting negative affective states in post-traumatic stress disorder.

Evidence that long-lasting potentiation of amygdala efferents in the right hemisphere underlies pharmacological stressor (FG-7142) induced lasting increases in anxiety-like behaviour: role of GABA tone in initiation of brain and behavioural changes.

The hypothesis that long-lasting potentiation (LLP) in amygdala efferents to the periacqueductal gray (PAG) of the right hemisphere mediates initiation of lasting increases in defensive response to rats induced by FG-7142 was supported in this study. GABA transmission was potentiated with Vigabatrin (gamma vinyl GABA, GVG), a suicide inhibitor of GABA transaminase. It was predicted that increasing GABA transmission would interfere with LLP and behavioural changes. The hypothesis was confirmed, for the most part. GVG given 1 day prior to FG-7142 prevented increased defensive response to rats as well as LLP in right amygdala efferent transmission to the PAG. It did not prevent LLP in the left amygdalo-PAG pathway, although LLP duration was shortened. Nor did it prevent LLP in the right amygdalo-ventromedial hypothalamic (VMH) pathway, and LLP in this pathway was associated with a slightly increased response to vocal threat, but not to rats. GVG given without FG-7142 had no behavioural effects, although it did potentiate transmission in the left amygdalo-PAG pathway. The effects of increasing GABA transmission are consistent with the hypothesis that FG-7142 changes behaviour by inducing a failure of GABA transmission, which in turn facilitates NMDA transmission and NMDA dependent limbic LLP. Finally, the hypothesis that altering GABA tone would change the efficacy of Flumazenil from a neutral antagonist to an inverse agonist was tested on limbic transmission. The hypothesis was confirmed in the left amygdalo-VMH pathway, but no other. It was concluded that mechanisms other than a change in GABA tone account for the drug-dependent reversal of LLP in the right amygdalo-PAG by Flumazenil. The findings of the present study suggest that response to FG-7142 may be a useful model of the effects of traumatic stressors on limbic system function in anxiety.

Atrial overdriving is beneficial in patients with atrial arrhythmias: first results of the PROVE Study.

The AF Prevention by Overdriving (PROVE) trial is an ongoing prospective study of the effectiveness of atrial overdrive pacing combined with an Automatic Rest Rate function in the prevention of atrial arrhythmias. All patients who have received a Talent DR 213 pacemaker are eligible for enrollment into the study. After a 1-month monitoring period, the patients are divided into two groups. Group I includes patients with > or = 2 appropriate mode-switch (MS) episodes, or 1 MS episode of > or = 10 minutes, and/or > 300 atrial runs of > 5 beats/month. Group II includes all other patients. The number and duration of atrial arrhythmias are measured the pacemaker's Automatic Interpretation and Data Analysis software (AIDA). Patients' quality-of-life is measured by a validated functional status questionnaire. After having been grouped, the patients are randomly assigned, in a crossover design, to standard DDDR or overdrive pacing + Rest Rate, each programmed for a 3-month period. Preliminary results in 78 patients show a 34% reduction in the mean number of MS, and a mean 48% shortening of the overall duration of the episodes by overdrive pacing + Rest Rate, achieved by a mean 84% prevalence of atrial pacing. Overdrive pacing + Rest Rate was well tolerated and associated with a slight improvement in quality-of-life.

Association between nonreentrant supraventricular tachycardia and atrioventricular node reentrant tachycardia: a presentation of dual AV node physiology.

Persistent simultaneous conduction of P waves over a fast and a slow nodal pathway defines the nonreentrant type of supraventricular tachycardia, usually not associated with reciprocating movements. We report a unique association between this uncommon tachycardia and a usual AV nodal reentrant tachycardia, made possible by the existence of three different nodal pathways.

Evidence that limbic neural plasticity in the right hemisphere mediates partial kindling induced lasting increases in anxiety-like behavior: effects of low frequency stimulation (quenching?) on long term potentiation of amygdala efferents and behavior following kindling.

Behavioral and physiological effects of partial kindling of the right ventral hippocampus by perforant path (PP) stimulation were investigated in the cat. Partial kindling produced lasting changes in affect (increased defensive response to rats) and predatory attack (decreased pawing and biting attack). Partial kindling also induced long term potentiation (LTP) of amygdala efferent transmission to ventromedial hypothalamus (VMH) and periaqueductal gray (PAG) in left and right hemispheres. LTP of field population spikes evoked in area CA3 by PP stimulation was also observed. LTP was detected using evoked potential methods. These findings parallel previous studies of left PP-CA3 partial kindling. Analysis of covariance removing effects of LTP from behavioral changes suggests that initiation of increased defensiveness at 2 days after completion of partial kindling depended on LTP of left and right amygdalo-VMH and right amygdalo-PAG transmission. From 6 days after kindling onward, increased defensiveness depended on LTP of right amygdalo-PAG transmission. Depotentiation of amygdala efferent LTP by bilateral low frequency amygdala stimulation (LFS) (900 pulses at 1 Hz, once daily for 7 days) selectively reduced LTP in right amygdala efferents. At the same time, defensive, but not predatory attack behavior, was returned to levels seen prior to partial kindling. Both depotentiation and reduction of defensiveness were transient. Defensiveness increased to post-kindling levels by 76 days after LFS. At the same time, LTP was restored in the right amygdalo-PAG pathway. In contrast LTP in the right amygdalo-VMH pathway remained depotentiated. Effects of LFS were not due to damage, as thresholds to evoke amygdala efferent response were unchanged. These findings suggest that lasting change in affect following partial hippocampal kindling depends on LTP of right amygdala efferent transmission to PAG. The findings parallel studies of non-convulsant pharmacological induction of lasting increases in defensiveness and amygdalo-PAG LTP with FG-7142. The parallel between the present findings and the FG-7142 experiments suggests that lasting changes in defensive response are dependent on LTP of right amygdala efferents to the PAG, however produced. The findings suggest further that the spectrum of behavioral changes produced by partial kindling are dependent on changes in a variety of neural circuits, and that amygdala efferent transmission changes are responsible for changes in defensive behavior, but not predatory attack behavior. Clinical implications are discussed.

Unilateral block of NMDA receptors in the amygdala prevents predator stress-induced lasting increases in anxiety-like behavior and unconditioned startle--effective hemisphere depends on the behavior.

Lasting increases in anxiety-like behavior (ALB) in the elevated plus-maze are produced by a single 5-min exposure of a rat to a cat. Rats become more anxious in the plus-maze for up to 3 weeks after the exposure. The first study in this series demonstrated that blockade of NMDA receptors in rats with MK-801, AP7, or CPP, given systemically 30 min prior to exposure to a cat prevents the increase in ALB assessed 1 week later in the elevated plus-maze. To localize the site of action of systemic MK-801, MK-801 was injected in the amygdala 30 min prior to predator stress. Injections were given either unilaterally in either hemisphere, or bilaterally in both hemispheres. The target of the injection was the basolateral amygdala. The effects of injection depended on both the type of behavior and the hemisphere of injection. Injections of MK-801 in a variety of sites in the basolateral amygdala had no effect on the suppression of open-arm exploration produced by predator stress. Other amygdala nuclei or other limbic sites likely mediate the effects of systemically administered MK-801 on this behavior. In contrast, NMDA receptors in the left lateral amygdala mediate lasting suppression of risk assessment. MK-801, in a variety of sites in the left but not right lateral amygdala, blocked the effects of predator stress on risk assessment. This is clear evidence of separability of neural mechanisms controlling open-arm exploration and risk assessment. Different NMDA-dependent amygdala circuitry mediated effects of predator stress on unconditioned acoustic startle 1 week after cat exposure. The data indicate that integrity of the left lateral amygdala is necessary for potentiation of startle amplitude by predator stress, though NMDA receptors are not involved in this function. Nevertheless, NMDA receptors in the right, but not the left lateral amygdala, mediate initiation of changes in startle. The data also suggest that the right amygdala action is "downstream" from the left amygdala contribution. These findings are consistent with the view that NMDA receptors are involved in initiation, but not maintenance, of neural changes mediating lasting increases in anxiety following severe stress. Finally, the findings of the importance of the right amygdala in stress-induced enhancement of the startle response provides neurobiological face validity to predator stress as a model of aspects of posttraumatic stress disorder.

NMDA receptors mediate lasting increases in anxiety-like behavior produced by the stress of predator exposure--implications for anxiety associated with posttraumatic stress disorder.

It has been proposed that NMDA-dependent long-term potentiation (LTP) of limbic system circuits controlling defensive behavior underlies stressor-induced lasting increases in anxiety-like behavior (ALB). Findings in cats given the stress-inducing beta-carboline, FG-7142, support this hypothesis. An animal model of lasting affective change following traumatic stress has recently been developed. In this model, lasting increases in anxiety-like behavior (ALB) assessed in the elevated plus maze are produced by a single 5-min exposure of a rat to a cat. Rats become more anxious in the plus maze for up to 3 weeks after the exposure. The present study demonstrates that blockade of NMDA receptors in rats with MK-801, AP7, or CPP, given 30 min prior to exposure to a cat, prevents the increase in ALB assessed 1 week later. MK-801 or AP7, given 30 min after exposure to a cat, do not prevent the increase in ALB seen 1 week later, however. MK-801, but not CPP or AP7, promotes approaches to cats during exposure. This "fearlessness" may reflect some anxiolytic action of MK-801. Approach to cats following injection of MK-801 was eliminated by prior injection of Prazosin. Prazosin did not interfere with the block of increases in ALB following cat exposure, however. These findings are consistent with the view that NMDA receptors are involved in initiation, but not maintenance of neural changes mediating lasting increases in anxiety following severe stress. The significance of these findings for PTSD are discussed.

Atrial vulnerability in patients with paroxysmal "lone" atrial fibrillation.

Little is known about the electrophysiological properties of the atrium predisposing to paroxysmal atrial fibrillation (AF), especially in patients without structural heart disease. This study was conducted to analyze intraatrial conduction, atrial refractoriness, and arrhythmia inducibility in patients with lone paroxysmal AF. An electrophysiological study was performed in 24 patients with a documented history of lone paroxysmal AF but in sinus rhythm at the time of the electrophysiological study. Twelve patients without any history of atrial arrhythmias served as controls. The patients with lone paroxysmal AF showed a significant prolonged local conduction time S1A1 (70 +/- 21 ms vs 36 +/- 12 ms, P < 0.0001), a lack of rate adaptation of the functional refractory period (FRP changes/cycle length changes < 10% in 15 of 24 patients with lone paroxysmal AF vs 1/12 controls, P = 0.002) and a higher incidence of inducible AF with only one extrastimulus (13/24 vs 0/12, P = 0.0014). The total P wave duration in the surface ECG (89 +/- 14 ms vs 83 +/- 8 ms, P = 0.15), the intraatrial conduction time (36 +/- 14 ms vs 28 +/- 8 ms, P = 0.07), the presence of a fragmented atrial electrogram (16/24 vs 7/12, P = 0.62), the absolute value of the effective refractory period (204 +/- 28 ms vs 212 +/- 23 ms, P = 0.42), and the vulnerability index (3.0 +/- 1.5 vs 3.6 +/- 1.5, P = 0.26) were not statistically different between the two groups. The presence of a prolonged (> 50 ms) S1A1 and/or the presence of a lack of rate adaptation of the FRP and/or the presence of inducible AF identified patients with spontaneous lone paroxysmal AF with a sensitivity of 96%, a specificity of 67%, a positive predictive value of 85%, and a negative predictive value of 89%. In patients with lone paroxysmal AF, the electrophysiological study using conventional techniques allows not only to detect AF inducibility using a nonaggressive protocol, but also to reveal several electrophysiological abnormalities related to the atrial substrate itself. This atrial vulnerability may explain the high incidence of recurrences in patients with lone paroxysmal AF.

Evidence that NMDA-dependent limbic neural plasticity in the right hemisphere mediates pharmacological stressor (FG-7142)-induced lasting increases in anxiety-like behavior. Study 1--Role of NMDA receptors in efferent transmission from the cat amygdala.

The anxiogenic beta-carboline, FG-7142, produces intense anxiety in humans and anxiety-like behavior in animals. FG-7142 also mimics the effects of exogenous stressors. In cats, FG-7142 lastingly changes defensive and aggressive behavior. Long-term potentiation (LTP) of neural transmission between limbic structures known to modulate feline defensive response to threat accompany behavioral changes. A series of three reports describes experiments designed to test the hypothesis that behavioral changes depend upon an N-methyl-D-aspartate (NMDA) receptor-based LTP of efferent transmission from the amygdala. This first study characterizes the dose and time effects of injection of the NMDA receptor blocker 7-amino-phosphono-heptanoic acid (AP7) on efferent transmission from the cat amygdala to the ventromedial hypothalamus (VMH). Effects of doses of 0.5-10mg/kg (i.v.) of AP7 on potentials evoked in the VMH by single pulse stimulation of the basal amygdala were examined. In order to localize the action of the drug, concurrent measurements were taken of potentials evoked in the VMH by stimulation of the efferent fibers from the amygdala to the VMH (ventral amygdalofugal pathway, VAF). There was a dose-dependent reduction in the amygdalo-VMH evoked potential. The greatest reduction occurred at 5 mg/kg. Effects peaked at 10 min, and persisted for at least 1 h after injection. In contrast, AP7 increased the VAF-VMH-evoked potential at 10 min after injection, with a maximal increase at 5mg/kg. The data suggest that NMDA receptors intrinsic to the amygdala modulate excitatory efferent transmission from amygdala to VMH in the cat. It is speculated that a glutamatergic projection to gamma-aminobutyric acid tonic inhibitory systems in the VMH accounts for the VAF-VMH results.

Evidence that NMDA-dependent limbic neural plasticity in the right hemisphere mediates pharmacological stressor (FG-7142)-induced lasting increases in anxiety-like behavior. Study 2--The effects on behavior of block of NMDA receptors prior to injection of FG-7142.

The hypothesis that N-methyl-D-aspartate (NMDA) receptors mediate initiation of lasting behavioral changes induced by the anxiogenic beta-carboline, FG-7142, was supported in this study. Behavioral changes normally induced by FG-7142 were blocked when the competitive NMDA receptor blocker, 7-amino-phosphono-heptanoic acid, was given prior to administration of FG-7142. When cats were subsequently given FG-7142 alone, the drug produced lasting behavioral changes like those reported previously. Flumazenil, a benzodiazepine receptor antagonist, reversed an increase in defensiveness produced by FG-7142 alone, replicating previous findings. The data are consistent with the hypothesis that NMDA-dependent long-term potentiation in limbic pathways subserving defensive response to threat mediates lasting increases in defensiveness produced by FG-7142.