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A comparison of the acute effects of a tricyclic and a MAOI antidepressant on septal driving of hippocampal rhythmical slow activity

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Abstract

In free-moving male rats, the function relating frequency to the threshold current required to drive hippocampal rhythmical slow activity (RSA) with septal stimulation has a minimum at 130 ms. Both classical anxiolytics (e.g. benzodiazepines) and the novel anxiolytic buspirone show similar effects on septal driving of RSA. The tricyclic antidepressant imipramine may be as effective as anxiolytic drugs in treatment of generalized anxiety disorder. The antidepressant monoamine oxidase inhibitor phenelzine has also been reported to be effective in treating anxiety, but this may reflect an action on "atypical depression" rather than "anxiety". The present study therefore compared the effects of acute administration of imipramine and phenelzine on septal driving of RSA to determine whether either would mimic anxiolytics in this test. Rats were chronically implanted with septal stimulating electrodes and subicular recording electrodes. Three groups of rats received IP injection of either imipramine (5.9-13.3 mg/kg or 13.3-30 mg/kg) or phenelzine (0.2-5.4 mg/kg). The effects produced by imipramine were very similar to the effects produced by anxiolytic drugs. In contrast, the effects produced by phenelzine were essentially opposite to those of both anxiolytic drugs and imipramine. The present experiment suggests that imipramine may act as a true anxiolytic, in addition to its conventional antidepressant properties. In contrast, phenelzine may be effective in cases where the etiology is essentially that of depression even when the symptomatology appears to be that of anxiety.

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... Equally important for the 1982 theory was the fact that anxiolytic drugs produce characteristic changes in hippocampal electrical activity. By 2000 this was shown to be true of all classes of anxiolytic drug, including those (like anti-depressants) that have no overlapping sideeffects with classical anxiolytics Coop, McNaughton, Warnock and Laverty 1990;Coop, McNaughton and Scott 1992;McNaughton and Coop 1991;Zhu and McNaughton 1991a, 1991b, 1994a, 1994b, 1994c, 1995a), 1995b A further link with memory is forged by the fact that all these drugs have immediate neural effects that change little with time and have immediate actions in tests of animal learning -while the truly anxiolytic (as opposed to euphoriant and muscle relaxant) clinical actions of even the classical anxiolytics take time to develop (Wheatley 1990). The drugs appear, then, to reduce the formation of new threatening memories leaving old ones intact. ...
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All anxiolytics so far tested show a common reduction in the frequency of reticular-elicited hippocampal rhythmical slow activity (RSA). The present experiments tested whether imipramine, an antidepressant drug which has also been used to treat generalized anxiety disorders, shares the common characteristics of anxiolytics on hippocampal RSA. Rats implanted with reticular stimulating electrodes and subicular recording electrodes received both acute and chronic injection of different doses of imipramine. Only relatively high doses (20 and 30 mg/kg, IP) of imipramine produced a reduction in RSA frequency after a single administration. Long-term administration of 20 mg/kg (but not 10 mg/kg, IP) imipramine induced an increase in baseline RSA frequency but there was no change in the acute frequency-reducing effect of the drug. These results suggest that changes in hippocampal RSA reflect different mechanisms of action for chronic versus acute treatment with antidepressant. It is possible that, at high doses, apparently anxiolytic effects of imipramine may be mediated by similar mechanisms to conventional anxiolytic drugs.
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In the free-moving male rat in which the hippocampal theta rhythm is driven by low-frequency stimulation of the medial septal area driving threshold is related to stimulation frequency: over the range 6–10 Hz the minimum threshold is at 7.7 Hz. A number of drugs with common behavioural properties (antagonism of the effects of nonreward and punishment) abolished this minimum by selectively raising the threshold at 7.7 Hz: three minor tranquillizers (sodium amylobarbitone, ethanol and chlodiazepoxide) and Δ9-tetrahydrocannabinol. This effect was mimicked by blockade of noradrenaline but not by cholinomimetic, anti-cholinergic, anti-serotonergic or anti-dopaminergic drugs. Blockade of serotonin synthesis also abolished the 7.7 Hz minimum. but by lowering thresholds at frequencies other than 7.7 Hz. It is suggested that the minor tranquillizers affect septa) driving of the hippocampal theta by imparing activity in the dorsal noradrenergic bundle: and that this pathway and a serotonergic mechanism are responsible for the function relating septal stimulation frequency to theta-driving threshold.
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In free-moving male rats chronically implanted with electrodes in the septal area and hippocampal formation it was possible to drive the hippocampal theta rhythm by low-frequency septal stimulation. Measurements of the function relating the threshold driving current to stimulation frequency demonstrated a minimum at an inter-pulse interval of 130 ms (7.7 Hz) over the range 100–170 ms. The observed function was reliably obtained in single animals, showed good inter-observer agreement and good stability over time. and was little affected by the exact stimulation site (medial or lateral septum), recording site (dorsomedial subiculum or hippocampus) or stimulation parameters (pulses or interrupted high-frequency trains) When thresholds for septal elicitation of evoked potentials were similarly estimated there was no minimum at 7.7 Hz. There was also no deviation from linearity at 7.7 Hz when the frequency of the hippocampal theta rhythm was plotted as a function of the intensity of reticular stimulation. Movement accompanied theta rhythm elicited from the reticular formation. but not theta rhythm elicited by septal stimulation.
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draw attention to a number of researchable issues in the neuropsychology of anxiety / [present] an outline of a theory of the neuropsychology of anxiety that has been developed in detail elsewhere a theory of anxiety: the role of the limbic system [the antianxiety drugs, the brain and anxiety, a theory of anxiety] / the issues [the role of GABA [gamma-aminobutyric acid], the opiate connection, anxiety and depression] (PsycINFO Database Record (c) 2012 APA, all rights reserved)
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Article
THERE are similarities between the behavioural effects of minor tranquillising drugs and those of lesions to the septal area and hippocampus1. Since the septal area contains the pacemaker cells for the hippocampal theta rhythm2, a parsimonious hypothesis to account for these common effects is that tranquillisers affect behaviour by altering septal control of this rhythm. Sodium amylobarbitone (SA) has been shown to block the behavioural effects of frustrative non-reward1, as do septal3 and hippocampal4 lesions. Rats exposed to non-reward in the runway show a characteristic hippocampal theta response at 7.7 Hz (ref. 1) (the theta frequency range in the rat is about 6-12 Hz). Higher and lower frequencies occur during forms of behaviour which are unaffected by the drug. It has therefore been proposed1 that the behavioural effects of SA arise by virtue of an impairment of septal control of the hippocampal theta rhythm specifically in a frequency band centred on 7.7 Hz. In support of this, it has been demonstrated5 that this drug raises the threshold for septal driving of the hippocampal theta rhythm selectively at 7.7 Hz, frequencies both above and below this value being minimally affected. Here we show that this kind of frequency-specific effect on septal driving of the hippocampal theta rhythm is also produced by other drugs with similar effects on behaviour1 (ethanol, chlordiazepoxide and Delta9-tetrahydro-cannabinol (Delta9-THC)), by drugs which impair noradrenergic neural transmission, and by destruction of the dorsal ascending noradrenergic bundle by intracerebral injection of 6-hydroxydopamine (6-OHDA)6.
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A double-blind clinical trial of phenelzine and diazepam against placebo and diazepam in neurotic patients over a four-week period showed phenelzine to be superior to placebo on three rating scales in some groups of patients who completed the trial. The findings suggest that phenelzine may exert a beneficial effect on some as yet undefined features of anxiety and depression which were not revealed by a multiple regression analysis of clinical symptomatology or premorbid personality.
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There is renewed interest in the clinical pharmacology of phenelzine sulfate and other monoamine oxidase (MAO) inhibitors. Newer clinical and analytic techniques recently have been applied to investigations of this class of drugs in man. The results show that drugs such as phenelzine are effective in nonendogenous depression and phobic disorders. Clinical response to phenelzine is related to platelet MAO inhibition and dosage per unit body weight. High percent MAO inhibition in platelets at two weeks is associated with greater improvement after a six-week course of treatment. Our data show that a safe, effective phenelzine dose in 1 mg/kg body weight per day. These results have delineated the pharmacologic and therapeutic effects of phenelzine and support a continuing role for MAO inhibitors in psychopharmacology.
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The effect of drugs on hippocampal theta rhythm induced by high frequency stimulation of the midbrain reticular formation was investigated in free-moving rats. The linearity of the relationship between the frequency of theta produced and the intensity of the stimulating current was unchanged by injections of sodium amylobarbitone; however, the frequency itself was reduced. Cholinergic blockade or depletion of noradrenaline, dopamine or serotonin levels in brain did not produce such a reduction in frequency, nor did they change the linearity of the function.These results contrast with the nonlinear effects which have been found with sodium amylobarbitone when septal stimulation is used to evoke theta rhythm; and with the fact that such nonlinear effects can be reproduced by depletion of forebrain noradrenaline levels. Sodium amylobarbitone appears, therefore, to affect control of hippocampal theta rhythm by actions on two systems, only one of which is dependent on noradrenaline. The duplication of behavioural effects of the drug by lesions of the dorsal ascending noradrenergic bundle may imply that the frequency at which theta occurs is less important for the control of such behaviours than other aspects of this electrical activity.
Article
In a double-blind, controlled experiment, 62 outpatients with symptoms of depression with anxiety were selected for treatment with phenelzine sulfate, 60 mg daily, phenelzine sulfate, 30 mg daily, or placebo for six weeks. Forty-nine patients (79%) completed the experiment. Phenelzine sulfate, 60 mg daily, was significantly more effective than placebo in relieving symptoms of both depression and anxiety. Phenelzine sulfate, 30 mg daily, did not differ from the placebo. Only phenelzine sulfate, 60 mg daily, resulted in a median inhibition of platelet monoamine oxidase that exceded 80%. The results confirm a previous study that found phenelzine to be effective in the treatment of outpatients with depressive-anxiety states. Drug dosage is an important variable influencing clinical outcome in this patient group.
Article
Hippocampal rhythmical slow activity (RSA) can be elicited by stimulation of the midbrain reticular formation. All classes of anxiolytic drug so far tested reduce the frequency of this RSA. Anxiolytic barbiturates and benzodiazepines, as opposed to compounds such as buspirone, are thought to act as receptor agonists of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). In the present study muscimol (a GABAA receptor agonist) and baclofen (a GABAB receptor agonist) were injected into freely moving rats. Baclofen produced a dose-related decrease in frequency of RSA in the range 1 to 9 mg/kg i.p. and abolished RSA at 27 mg/kg. Muscimol produced an increase in RSA frequency with an inverted U-shaped dose response curve in the range 0.0001 to 1.0 mg/kg with maximal effect at 0.001 mg/kg. The effects of classical anxiolytic drugs in the present test resemble those of the GABAB receptor agonist baclofen more than they resemble those of the GABAA receptor agonist muscimol but it is possible that they are acting via GABA systems which employ low rather than high affinity GABAA receptors or through some transmitter system other than GABA.
Article
Buspirone is effective in treating clinical anxiety but, unlike classical anxiolytics, does not have anti-convulsant, sedative or muscle relaxant side-effects and does not interact with GABA. Buspirone may also differ from classical anxiolytics in requiring a period of 2 weeks or more to achieve its full therapeutic action. It has previously been shown that all anxiolytic drugs, including buspirone, reduce the frequency of reticular-elicited hippocampal rhythmical slow activity (RSA). The present experiments tested whether the time course of the effect of buspirone on rhythmical slow activity differed from that of the anxiolytic benzodiazepine chlordiazepoxide. Rats, implanted with reticular stimulation electrodes and subicular recording electrodes, received three intraperitoneal injections per day of buspirone (2.5 mg/kg), chlordizepoxide (5 mg/kg) or saline for 45 days. Both buspirone and chlordiazepoxide reduced the frequency of rhythmical slow activity on the first day of testing and Ro15-1788 (10 mg/kg) blocked the effects of chlordiazepoxide but not buspirone. There was no increase in the effect of buspirone with time. These results showed that, if the effect of anxiolytic drugs on rhythmical slow activity provides any basis for their clinical action, then some additional factors are required to explain both the delayed action of buspirone and the immediate action of classical anxiolytic drugs.
Article
Previous experiments have shown that anxiolytic drugs reduce the frequency of hippocampal rhythmic slow activity, induced by high frequency stimulation of the reticular formation and flatten the function relating threshold septal stimulation to the frequency of driven rhythmic slow activity. All of the drugs involved are known to augment GABAergic transmission. The present experiments investigated the effects of the novel anxiolytic compound buspirone which, unlike conventional anxiolytics, does not interact with GABA, yet is a clinically effective anxiolytic. Buspirone (0.156-40 mg/kg, i.p.) was found to reduce the frequency of reticular-elicited rhythmic slow activity, in a similar manner to chlordiazepoxide (0.019-20 mg/kg, i.p.). Buspirone did not change the linearity of the voltage-frequency function. Buspirone (10 mg/kg, i.p.) also altered the threshold for septal driving of rhythmic slow activity, in a similar manner to classical anxiolytics. The combination of chlordiazepoxide (5 mg/kg, i.p.) with corticosterone (0.2 mg, s.c.) removed the minor differences between buspirone and chlordiazepoxide in both the septal and reticular tests. These results show that buspirone altered the control of rhythmic slow activity in the hippocampus, in a manner which appeared functionally equivalent to other anxiolytics but which depends on mechanisms which are likely to be neurally and pharmacologically distinct from those of other anxiolytic drugs.
Article
Pigeons were trained to discriminate the tricyclic antidepressant imipramine (3.0 or 5.6 mg/kg) from saline. The selective 5-HT1A agonist 8-OH-DPAT (0.03-1.0 mg/kg) resulted in dose-dependent increases in responding on the key correlated with imipramine administration. Doses of 8-OH-DPAT from 0.3 to 1.0 mg/kg substituted completely for imipramine. NAN-190 (0.3-3.0 mg/kg), a putative 5-HT1A antagonist with affinity for both 5-HT1A and alpha 1 receptors, blocked the discriminative stimulus effects of imipramine and resulted in saline-key responding. The discriminative stimulus effects of imipramine were also blocked by administration of the alpha 1-adrenoceptor antagonist prazosin, suggesting a dual mediation of imipramine through both 5-HT1A and alpha 1-adrenoreceptor systems. Although antidepressants have not been used frequently as stimuli in drug discrimination studies, it may be possible to arrive at a more complete understanding of their neurochemical and behavioral effects using this procedure.
Article
In free-moving male rats, when the hippocampal theta rhythm is artificially driven by stimulation in the septum at frequencies between 5 and 10 Hz, the function relating frequency to the threshold current required to drive the theta rhythm has a minimum at 7.7 Hz. This minimum is eliminated by anxiolytic drugs. Dose-response curves for this effect are reported for chlordiazepoxide, diazepam and meprobamate. The effect of meprobamate was reversed by two gamma-aminobutyrateA antagonists, picrotoxin and bicuculline, which have previously been shown to be without effects of their own. The gamma-aminobutyrateB agonist, baclofen, also without effect on its own, blocked the elimination of the 7.7-Hz minimum caused by the gamma-aminobutyrateA agonist, muscimol. The beta-carboline, ethyl-beta-carboline-3-carboxylate, had mixed agonist/antagonist properties, blocking the effects of chlordiazepoxide, diazepam and muscimol (though not sodium amylobarbitone) but itself acting like a benzodiazepine. Coupled with earlier data, these findings support a role for gamma-aminobutyrate receptors in mediating the effects of anxiolytic drugs.
Article
Anxiolytic drugs share many of the common behavioural effects of septal and hippocampal lesions in animals. Gray attributes this to changes which the anxiolytics produce in septal generation of hippocampal rhythmical slow activity. However, lesions of the dorsal ascending noradrenergic bundle reproduce this electrophysiological effect of the anxiolytics while only reproducing part of the behavioural profile of the anxiolytics. The present paper reports what appears to be a second common effect of anxiolytic drugs on the generation of hippocampal slow waves which could underlie their behavioural effects. Freely moving rats, previously implanted with electrodes, received high frequency electrical stimulation of the midbrain reticular formation to elicit hippocampal rhythmic slow activity. The frequency of the slow waves produced increased linearly with increasing stimulation intensity as has been reported previously. A barbiturate (amylobarbitone, 15 mg/kg, i.p.) and three benzodiazepines (chlordiazepoxide, 5 mg/kg; diazepam, 5 mg/kg; alprazolam, 1 mg/kg) all decreased the slope of the voltage-frequency function and decreased overall frequency of slow waves produced. Two antipsychotic drugs (haloperidol, 0.2 mg/kg; chlorpromazine, 2 mg/kg) produced similar behavioural sedation to the anxiolytics but did not decrease either the slope of the voltage-frequency function nor the overall frequency of slow waves. The results show that these barbiturates and benzodiazepines produce a common reduction in the frequency of hippocampal rhythmical slow activity. Given the importance attached to slow waves in current theories of hippocampal function, it is possible that this electrophysiological effect could have some relation to the behavioural effects of these anxiolytic drugs. If the effect can be shown to generalize to other classes of anxiolytic drug it could reflect changes in the substrate for the common effects of anxiolytic drugs on behaviour.
Article
Sixty patients with probable atypical depression--defined as meeting Research Diagnostic Criteria for depressive illness, having reactive mood, and having one of four associated symptoms (hyperphagia, hypersomnolence, leaden feeling, and sensitivity to rejection)--took part in a study contrasting phenelzine, imipramine, and placebo. Phenelzine was found to be superior to imipramine and placebo. These results were compared to results from a sample of 120 patients with identical characteristics, except that they had more than one associated atypical symptom (full atypical syndrome). The size of the drug effect was comparable in patients with full atypical and partial atypical syndromes.
Article
A double-blind, placebo-controlled comparison at three collaborating university sites included 242 patients diagnosed as having anxiety disorders. A two-week placebo washout period preceded random assignment to eight weeks of imipramine hydrochloride, chlordiazepoxide hydrochloride, or placebo treatment. Antianxiety effects of imipramine were superior to those of the other two agents by the second treatment week; these effects became more clearly significant thereafter and were independent of degree of both baseline depression and anxiety. Excluding patients with possible panic-phobic syndromes from the analyses removed most significant antiphobic and antidepressant effects of imipramine but left intact imipramine's significantly superior antianxiety effects.
Article
We randomly assigned 425 outpatients, independently classified as primarily depressed by two trained psychiatrists, to double-blind treatment with Imipramine hydrochloride, chlordiazepoxide hydrochloride, or placebo. Those patients who remained at least moderately depressed (following a two-week placebo washout period) were treated for an additional eight weeks. An endpoint analysis of 387 patients who completed two or more weeks of medication disclosed early therapeutic advantages of chlordiazepoxide. By week 4 of treatment, however, imipramine produced more improvement than did placebo and chlordiazepoxide. By six and eight weeks a general, marked therapeutic advantage was found for imipramine relative to placebo and to chlordiazepoxide on measures of depression, anxiety, anger-hostility, interpersonal sensitivity, and global improvement. Chlordiazepoxide-treated patients generally did significantly better on sleep difficulty but significantly worse on anger-hostility and interpersonal sensitivity than did imipramine- or placebo-treated patients.
Article
To the Editor.— I would like to comment on two articles in the Archives.1,2 These two articles from some of the world's most famous and reputable universities must be received by European psychiatrists with the utmost attention.The article by Lipman et al1 deals with a sample of primarily depressed outpatients (recruited by advertisement), who are not very ill but considered to be at least moderately depressed. The mean score on the Hamilton Depression Scale (on 21-item modification) was 22.1±6, telling us that a part of the sample hardly meets Hamilton's criteria for clinical depression (>15 on a 17-item scale). This is unjust to the outcome of treatment, probably more so to treatment with imipramine hydrochloride than to the other treatments, and might explain why patients at week 8 did not rate appreciable improvement very often; only 31% rated "very much better" or "quite a bit better." That
Article
The frequency of the hippocampal theta rhythm in freely moving rats varies predictably in relation to behavior in a simple learning situation. The theta rhythm may be driven by electrical stimulation of the medial septal area at frequencies within the theta range. The threshold for septal driving is lowest at that frequency which the rat displays in response to frustrative nonreward; the driving threshold is selectively raised at this frequency by sodium amobarbital. It is suggested that the behavioral effects of amobarbital are due to a disruption of the theta frequency normally displayed in response to nonreward.
Article
Biochemically, buspirone is unlike the benzodiazepines in that it neither stimulates nor inhibits 3H-benzodiazepine binding, does not affect the influence of GABA or halide anion on 3H-benzodiazepine binding, and does not interfere with GABA binding or uptake. Buspirone lacks anticonvulsant activity, interacts minimally with CNS depressants, and does not cause muscle relaxation. Its tranquilizing activity is characterized by the ability to (1) tame aggressive rhesus monkeys, (2) block conditioned avoidance responding in the rat, (3) inhibit shock-induced fighting in the mouse, and (4) attenuate shock-induced suppression of drinking in the rat. In vitro binding experiments indicate that buspirone lacks significant activity at several binding sites. It appears to interact only with the dopaminergic system and possesses properties that are similar to both dopamine agonists and dopamine antagonists.
Article
The safety and antianxiety and antidepressive effects of buspirone (average 16.5 mg/day) were compared in a double-blind trial with those of diazepam (15 mg/day). The two drugs were nearly equivalent in relieving symptoms of both anxiety and depression in 100 patients. Scores on the impaired cognition factor of the SCL-56 and confusion factor of the POMS showed significantly greater improvement with buspirone than with diazepam. Side effects, such as sedation and drowsiness, were significantly more frequent and severe with diazepam. Buspirone may be particularly indicated for anxious patients with associated depression.
Article
Sixty patients meeting specific criteria for atypical depression completed six weeks of double-blind, randomly assigned treatment with phenelzine sulfate, imipramine hydrochloride, or placebo. The overall response rates were 67% with phenelzine, 43% with imipramine, and 29% with placebo. At week 6, phenelzine was superior to placebo on many measures, while the superiority of imipramine to placebo was confined to several variables. Phenelzine was superior to imipramine on the interpersonal sensitivity and paranoia factors of the 90-item Hopkins Symptom Checklist, with trends toward superiority on several other measures, while imipramine was not differentially superior on any measure. Atypical depressive patients with a history of spontaneous panic attacks and hysteroid dysphoric patients both showed extremely low rates of response to placebo and high rates of response to phenelzine. Conversely, those without panic or hysteroid dysphoric features responded equally to all three treatments. Responders to pheneizine also had greater platelet monoamine oxidase inhibition while receiving drug therapy than did nonresponders. Completion of the 120-patient sample will allow more detailed analyses.
Article
Unilateral blockade of the dorsal ascending noradrenergic bundle was produced by injections of procaine or of 6-hydroxydopamine. The threshold current of septal stimulation required to drive the hippocampal theta rhythm was then investigated at frequencies between 5.9 and 10.0 Hz. With both types of blockade the threshold-frequency function showed a normal 7.7 Hz minimum ipsilaterally and an abolition of the minimum contralaterally. Ventral noradrenergic bundle lesions had no effect. Septal elicitation of hippocampal theta rhythm may, therefore, be dependent on a noradrenergic mechanism controlling aspects of the theta rhythm, e.g. interhemispheric balance, which would not be obvious in ordinary spontaneous records.
Article
The selectivity of benserazide and phenelzine toward inhibition of benzylamine oxidase (BzAO) and monoamine oxidases (MAO-A and MAO-B) was studied in homogenates of rat skull and lung. In addition, the kinetic interaction and reversibility of BzAO inhibition were assessed. Both drugs inhibited BzAO but only phenelzine inhibited MAO, whether tested in vitro or in vivo. Neither compound acted as an irreversible inhibitor of BzAO. Benserazide was found to be a noncompetitive inhibitor. Phenelzine acted as a substrate for BzAO followed by product-induced noncompetitive inhibition which was labile at 37 degrees but not at 4 degrees. A reversible component in phenelzine-induced inhibition of MAO-A and -B is also suggested from in vivo studies.
The neuropsychology of anxiety The psychology of fear and stress Frequency specific relation between hip-pocampal theta rhythm, behaviour and amobarbital action
  • Gray
  • Ja
Gray JA (1982) The neuropsychology of anxiety. Oxford University Press, Oxford Gray JA (1987) The psychology of fear and stress. Cambridge University, Press, Cambridge Gray JA, Ball GG (1970) Frequency specific relation between hip-pocampal theta rhythm, behaviour and amobarbital action. Science 168:1246-1248
Characteristics and specificity of phenelzine and benserazide as inhibitors of benzylamine oxidase and monoamine oxidase Involvement of 5HT1A activity in the discriminative stimulus effects of imipramine
  • Andree Th Clarke
  • De
Andree TH, Clarke DE (1982) Characteristics and specificity of phenelzine and benserazide as inhibitors of benzylamine oxidase and monoamine oxidase. Biochem Pharmacol 31:825-830 Barrett JE, Zhang L (1991) Involvement of 5HT1A activity in the discriminative stimulus effects of imipramine. Pharmacol Bio-chem Behav 38:407-410
Statistical methods Effects of long-term administration of anxiolytics and antidepressants on hippocampal rhythmical slow activity Effects of long-term administra-tion of anxiolytics on reticular-elicited hippocampal rhythmical slow activity
  • Snedecor Gw
  • Cochran
Snedecor GW, Cochran WG (1967) Statistical methods. Iowa State University Press: Iowa Zhu XO (1992) Effects of long-term administration of anxiolytics and antidepressants on hippocampal rhythmical slow activity. PhD thesis, Department of psychology, University of Otago, Dunedin, New Zealand Zhu XO, McNaughton N (1991a) Effects of long-term administra-tion of anxiolytics on reticular-elicited hippocampal rhythmical slow activity. Neuropharmacology 30:1095-1099
The pharmacology of reticular-elicited hippocampal rhythmical slow activity
  • C F Coop
  • CF Coop
Effects of long-term administration of anxiolytics and antidepressants on hippocampal rhythmical slow activity
  • X O Zhu
  • XO Zhu