Evidence for distinct benzodiazepine receptors for anticonvulsant and sedative actions: Implications for the treatment of temporal lobe epilepsy

1. 1. An imidazobenzodiazepine, Ro15-1788, has anticonvulsant effects in the kindling model for epilepsy.

2. 2. Ro15-1788 reverses the sedative actions of diazepam (3 mg/kg i.p.) but does not reverse the anticonvulsant effects.

3. 3. The anticonvulsant effects of Ro15-1788 are prevented by the pyrazoloquinolinone CGS-8216 which interacts with benzodiazepine receptors but has no anticonvulsant actions itself.

4. 4. It is suggested that Ro15-1788 is a partial agonist at the BZ₂ (anticonvulsant) receptor but is an antagonist at the BZ₁ (sedative, anxiolytic) receptor. CGS-8216 is an antagonist at both receptors.

5. 5. Ro15-1788 or related compounds may be effective anticonvulsants without the sedative side-effects usually found with the benzodiazepines.

A review of recently-developed ligands for neuronal benzodiazepine receptors and their pharmacological activities

Gardner, Colin R: A Review of Recently-developed Ligands for Neuronal Benzodiazepine Receptors and Their Pharmacological Activities. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1992, 16(6): 755–781.

1. 1. There has recently been a large increase in the number of new benzodiazepine receptor ligands, some with benzodiazepine structures, but many with other chemical structures.

2. 2. The pharmacological activities of these ligands have been interpreted on the basis of a continuum of efficacy ranging from full agonist through different degrees of partial agonism to antagonist and through partial to full inverse agonists.

3. 3. Inconsistencies with this hypothesis are considered in terms of alternative hypotheses, particularly the existence of functionally separable receptor subtypes.

4. 4. The potential of partial agonists as non-sedative anxiolytic agents with reduced potential of dependence and of weak partial inverse agonists as pro-cognitive agents is discussed.

5. 5. A pharmacophore for benzodiazepine receptors is proposed and supporting evidence presented.

New concepts in benzodiazepine therapy: Rebound anxiety and new indications for the more potent benzodiazepines

1. 1. Abrupt withdrawal of benzodiazepine treatment in generalized anxiety patients was found to induce a rebound anxiety state in addition to minor physical symptoms.

2. 2. Controlled clinical trials suggest that the newer high potency benzodiazepines (alprazolam, clonazepam and bromazepam) have novel psychiatric indications and greater anxiolytic effect than the classical benzodiazepines.

3. 3. Alprazolam, a triazolobenzodiazepine, was superior to placebo in the treatment of panic disorder, for which medium or low potency benzodiazepines are generally inefficacious.

4. 4. Clonazepam, an anticonvulsant which increases 5HT synthesis, was more efficacious than lithium in reducing manic symptoms.

5. 5. Bromazepam, a new potent benzodiazepine, was superior to diazepam in the treatment of generalized anxiety disorder.

Comparative study in mice of flunitrazepam vs. diazepam on morphine withdrawal syndrome

1. 1. There is some evidence that benzodiazepine may modify the opioid withdrawal syndrome. We have investigated the effect of two different benzodiazepines, diazepam and flunitrazepam, on the morphine withdrawal syndrome experimentaly induced in mice.

2. 2. Opiate dependence has been induced by administration of morphine s.c. over a period of five days. Two hours after last morphine administration withdrawal syndrome was induced by s.c. injection of naloxone (5mg/kg). The number of jumps, wet-dog-shakes and paw tremor, and the presence or absence of ptosis, diarrhea, teeth chatering and body tremor were evaluated after naloxone injection.

3. 3. All the signs of morphine withdrawal syndrome was antagonized by flunitrazepam and diazepam, only wet-dog-shake was strongly increased by flunitrazepam.

CGP 11.952: An experimental benzodiazepine derivative. Effects on cognitive functioning in patients with epilepsy

1. 1. In two open studies using patients with intractable epilepsy, the effects of CGP 11.952, a triazolyl benzophenone, on cognitive functioning were assessed by means of a computerized neuropsychological battery.

2. 2. In the first study CGP 11.952 turned out to have a positive effect on information processing speed, perceptual sensitivity and precisaness of responses.

3. 3. Negative effects were found on reaction time.

4. 4. In the second study this latter effect was less clear.

5. 5. A striking result was the less negative effect on memory consolidation under influence of CGP 11.952 in comparison with other benzodiazepines.

Assessment of agoraphobia and panic disorder

1. 1. Phobia and panic are defined by the measures used.

2. 2. Rating scales, diaries, global measures, physiological measures, behavioural assessment.

3. 3. Three fear systems: physiological, cognitive and behavioral

4. 4. Concordance and discordance.

5. 5. Synchrony and desynchrony

6. 6. The Behavioural Approach Test at the Calgary General Hospital.

Neuroendocrine evaluation of CCK-peptides on dopaminergic function in man

1. 1. CCK-33 (225 Ivy Dog Units iv) antagonized the growth hormone response to the dopamine receptor agonist, apomorphine HCl (0.5 mg sc), and increased basal prolactin secretion in normal male volunteers. A stress mediated prolactin effect could not be excluded.

2. 2. CCK-8 (5 ug iv) antagonized the growth hormone response to apomorphine but had no effect on basal prolactin or plasma homovanillic acid.

3. 3. Ceruletide (0.3 ug/kg im) had no effect on basal prolactin or apomorphine-induced growth hormone secretion.

4. 4. CCK-33, CCK-8 and ceruletide had no effect on basal growth hormone secretion which suggests that they do not inhibit the release of growth hormone.

5. 5. These findings are compatible with an inhibitory effect of CCK-33 and CCK-8 (or fragments) on dopaminergic function in man, at least in the hypothalamic-pituitary axis and point to a simple way to study the effect of peptides on dopaminergic function in man including those which may not cross the blood brain barrier.

Treatment of alcohol organic mental disorder with piracetam

1. 1. The paper presents an investigation of the efficiency of piracetam in alcohol organic mental disorder.

2. 2. A double blind placebo controlled study design was used to compare two dosages of the substance (2 × 3g versus 2 × 12g).

3. 3. The cognitive functions of the patients, especially short term memory and concentration, were assessed on the days 0, 7, 14, 28 and 42 using various psychological instruments.

4. 4. An analysis of 39 patients showed an improvement of cognitive functions in all three groups.

5. 5. Patients receiving drug treatment showed earlier responses than patients receiving placebo; differences between the three investigational groups were not statistically significant.

6. 6. The results achieved make the effect of piracetam appear somewhat questionable.

Regional glucose metabolism in schizophrenic patients before and during neuroleptic treatment

Wiesel, Frits-Axel: Regional glucose metabolism in schizophrenic patients before and during neuroleptic treatment. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1992, 16(6): 871–881.

1. 1. Determination of regional glucose metabolism has been considered to be a tool to elucidate the mechanisms of action of neuroleptics.

2. 2. D₂-dopamine antagonists seem to increase glucose consumption in dopamine innervated areas.

3. 3. Studies in humans do not give results in complete accordance with animal findings.

4. 4. In patients neuroleptic compounds and dopamin agonists probably increase and decrease striatal metabolism respectively.

5. 5. Changes in metabolism, especially in the right hemisphere may be coupled with improvement of the patients.

6. 6. Future research must be based on protocols specially designed for the study of drug effects.

Different effects of antidepressants on dissociation of H-imipramine from solubilized binding sites of rat brain

1. 1. The effects of several antidepressants and 5-hydroxytryptamine on dissociation of ³H-imipramine from solubilized binding sites were investigated.

2. 2. Binding sites were solubilized from rat brain membranes and gelfiltrated on a column of Sephacryl S-300.

3. 3. Most of the agents used allowed biphasic dissociation with 1mM of displacing agent and without using dilution-induced dissociation. This biphasic dissociation without nonspecific effects of membranes may be due to the existence of low-affinity binding sites.

4. 4. Dissociation of up to 40 min followed first-order kinetics. The dissociation half-life of ³H-imipramine with the various displacing agents was calculated at from 15.0 to 25.0 min, and the differences among the agents were not so significant as the attenuation or the acceleration of the dissociation was indicated. The lower concentration of the displacing agents may obscure the modulation of the dissociation.

Time course of physostigmine effects on neuroendocrine responding at varying environmental temperatures

1. 1. Hypothermia was found to be related to both the dose of physostigmine and the environmental temperature.

2. 2. Plasma corticosterone levels were elevated above controls regardless of dose of physostigmine or environmental temperature.

3. 3. Plasma free fatty acid levels appeared to be inversely related to physostigmine-induced hypothermia.

4. 4. A hyperglycemic response was observed under all experimental conditions at 0.5 hours and 1.0 hour post injection.

5. 5. Significant inhibition of brain acetylcholinesterase was observed, whereas, plasma and erythrocyte acetylcholinesterase activity was inconsistent.

A pharmacokinetic/pharmacodynamic/receptor binding model to predict the onset and duration of pharmacological activity of the benzodiazepines

1. 1. Ex vivo receptor binding as a function of time was determined in Charles River rats.

2. 2. The pharmacokinetic and protein binding parameters in man as well as the ex vivo receptor binding parameters in rat brain for three benzodiazepine induction agents, diazepam, lorazepam and midazolam, were used to develop and test a pharmacokinetic/ pharmacodynamic/receptor binding model.

3. 3. The model was subsequently used to predict changes in receptor binding and pharmaco-dynamics as a function of changes in pharmacokinetics.

4. 4. The model was found to be a good predictor of the relative onset and duration of the sedative and amnesic properties in normal subjects as well as in the presence of certain patho-physiological conditions and certain drug interactions.

Unexpected potentializing effect of a tacrine derivative (9-amino-7-methoxy-1,2,3,4 tetrahydroacridine) upon the non-epileptic myoclonus in baboons Papio papio

vejdová Milada, Ivan Raktor, Carmen Silva-Barrat and Christian Menini: Unexpected Potentializinq Effect of a Tacrine Derivative (9-anino- 7 methoxy-1,2,3,4, tetrahydroacridina) upon the Non-Epileptic Myoclonua in Baboons Papio Papio. Prog. Nauro-Psychopharmacol. Biol. Psychiat. 1990, : 961–966.

1. 1. The influence of 7-methoxytacrina (7-MEOTA) on the non epileptic myoclonus of the baboon was studied in 5 animals.

2. 2. This type of myoclonus is thought to depend on a cholinergic system dysfunction since it can be induced by atropine and blocked by physostigmine.

3. 3. 7-MEOTA. a tacrine derivative, is believed to display a conspicuous anticholinesteraee activity but. surprisingly, it here potentiated the non epileptic myoclonus occuring either spontaneously or induced by atropine.

4. 4. In baboons not spontaneously presenting the non epileptic myoclonus. 7-MEOTA induced the myoclonus in a fashion similar to atropine) such a myoclonus was blocked by physostigmine.

5. 5. These data indicate a possible antagonist action of tacrine on the muscarinic acetylcholine receptor. From these data, it is suggested that caution is necessary when introducing a tacrine derivative in clinical practice.

The automated tail suspension test: A computerized device which differentiates psychotropic drugs

1. 1. Mice when suspended by the tail will alternate between active attempts to escape and immobility. Immobility like that measured in the behavioral despair test is reduced by a wide variety of antidepressant agents.

2. 2. The present paper describes a computerized version of this test (ITEMATIC-TST) which in addition to recording immobility measures the power of the movements.

3. 3. Various tricyclic (amitriptyline, desipramine, imipramine), MAOI (clorgyline, moclobemide, nialamide, pargyline, toloxatone) and atypical antidepressants (bupropion, citalopram, indalpine, miansenn, nomifensine, viloxazine) were tested and compared with psychostimulants (d-amphetamine, caffeine), neuroleptics (chlorpromazine, haloperidol, sulpiride), anxiolytics (clobazam, diazepam) and agents acting on the cholinergic system (atropine, oxotremorine).

4. 4. All antidrepressants decreased the duration of immobility and most increased the power of movements.

5. 5. The psychostimulants also decreased immobility but only amphetamine increased the power of movements.

6. 6. Neuroleptics increased immobility without affecting the power of movements, whereas anxiolytics increased immobility but decreased the power of movements.

7. 7. Atropine had a profile similar to antidepressants whereas oxotremorine tended to have opposite effects.

8. 8. The results suggest that the automated test system with its two parameters is not only sensitive to antidepressants but could also be useful for generating activity profiles for different kinds of psychotropic agent.

The future of 5-HT1A receptor agonists. (Aryl-piperazine derivatives).

Mitsukuni Murasaki and Sadanori Miura: The Future of 5-HT_1A Receptor Agonists. (Aryl-Piperazine Derivatives) Prog. Neuro- Psychopharmacol-& Biol Psychiat, 1992, 16(6): 833–845.

1. 1. At present the dominant position among anti-anxiety medications has changed from meprobamate to the benzodiazepine derivatives.

2. 2. In order to avoid benzodiazepine's (BZ) undesirable side effects such as impairment of psycho-motor function, memory impairment, low dose dependence and withdrawal symptoms, a third generation anxiolytic agent, buspirone, the focus of the aryl-piperazine group of anti-anxiety agents, has been introduced recently.

3. 3. Aryl-piperazine derivatives work as 5-HT_1A receptor partial agonists and are known as serotonin normalizers.

4. 4. Therefore, they are expected to have not only an anxiolytic function but also an anti-depressant effect as well.

5. 5. A characteristic of the aryl-piperazine derivatives is that they have no sedative and muscle relaxant effects, and they do not have BZ's undesirable side-effects, especially in regard to withdrawal symptoms. However they have a rather weak anxiolytic action and a slow onset of action.

6. 6. Aryl-piperazine derivatives will not take the place of BZ, but the use of BZ and buspirone as bridge medications, making the most of the strong points of both, can be proposed as a way to compensate for their respective disadvantages.

Determination of plasma haloperidol concentrations by radioreceptor assay in schizophrenia: Clinical utility

1. 1. Haloperidol concentrations were determined by radioreceptor assay (RRA) and prolactin concentrations were measured in 20 patients diagnosed as schizophrenia (DSM-III).

2. 2. The patients were treated with a fixed dose of haloperidol for 21 days.

3. 3. Our results suggest the existence of a curvilinear relationship, in the form of an inverted U, between stable haloperidol levels and clinical improvement assessed by total BPRS score.

4. 4. We also found a curvilinear relationship between the improvement observed in positive symptoms and state steady levels.

5. 5. No relationship was seen between improvement in negative symptoms and state steady levels.

6. 6. An interval of optimal haloperidol concentration was found: 8.1 ng/ml to 19.6 ng/ml.

7. 7. No relation was found between the dose of haloperidol administered and plasmatic concentration, nor between haloperidol and prolactin levels.

8. 8. Our findings suggest that haloperidol concentrations determined by RRA have clinical utility as predictors of response in schizophrenia.

Stereoisomeric tetrahydro-β-carbolines differ in their interaction with rat brain benzodiazepine receptors

1. 1. A series of (+) and (−) tetrahydro-β-carboline-3-carboxamide stereoisomers related to the ethyl ester of β-carboline-3-carboxylate (β-CCE) have been tested for their ability to displace ³H-flunitrazepam from binding sites prepared from rat cerebral cortex (benzodiazepine receptors).

2. 2. The (+) stereoisomers of ethyl and propyl 1,2,3,4-tetrahydro-β-carboline-3-carboxamides were the most potent inhibitors of specific ³H-flunitrazepam binding and had significantly lower IC₅₀s than the corresponding (−) isomers.

3. 3. Although the IC₅₀ values for this series of tetrahydro-β-carboline-3-carboxamides were about 1000 fold higher than the IC₅₀ value for β-CCE, these compounds were as potent as the β-carboline alkaloids harmane and harmine.

4. 4. The title compounds may be useful stereoisomeric probes for the characterization of subtypes of specific benzodiazepine binding sites.

Modulation of NMDA receptors by ACh in the central nervous system

Harata, Nobutoshi, Satoru Ebihara and Norio Akaike: Modulation of NMDA Receptors by ACh in The Central Nervous System. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1992, 16(6): 977–984.

1. 1. The effect of acetylcholine (ACh) on (NMDA)-induced responses in neurons acutely dissociated from the rat nucleus basalis of Meynert (nBM) was investigated with a conventional patch-clamp technique.

2. 2. The whole-cell recording revealed that NMDA-induced inward current (I_NMDA) consisted of transient peak and successive steady-state components.

3. 3. With outside-out recording, these components were shown to have the identical single channel conductance.

4. 4. Pretreating the nBM neurons with the low concentration of ACh suppressed the peak component of (I_NMDA), whear as high concentration potentiated it.

5. 5. The modulatory action of ACh was observed in nBM neurons dissociated from mature rats. The action was deficient, however, in those from immature animals.

6. 6. These results suggest that ACh is either an inhibitory or an excitatory modulator of glutamatergic transmission in the central nervous system.

Effects of haloperidol and SCH 23390 on acoustic startle and prepulse inhibition under basal and stimulated conditions

Schwarzkopf, Steven B., John P. Bruno, and Tanmoy Mitra: Differential Effects of Haloperidol and SCH 23390 on Acoustic Startle and Prepulse Inhibition Under Basal and Stimulated Conditions. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1993, 17(6): 1023–1036.

1. 1. Adult Sprague-Dawley rats underwent startle testing for assessment of baseline startle amplitude and prepulse inhibition (PPI) of the startle reflex.

2. 2. Animals were tested after administration of either: saline, a selective D1 dopamine (DA) receptor antagonist, a relatively selective D2 DA antagonist, or combined low dose D1 and D2 antagonists.

3. 3. Changes due to antagonists were assessed with and without administration of the D1/D2agonist apomorphine.

4. 4. Testing without apomorphine stimulation showed that both D1 and D2 antagonists reduce baseline startle and enhance PPI. Further, the two antagonists exhibited a synergistic interaction.

5. 5. Testing with apomorphine showed that D1 and D2 antagonists reduce apomorphineinduced startle enhancement. Again, the two exhibited a synergistic interaction.

6. 6. For PPI, the D2 but not D1 antagonist reduced the apomorphine effect. However, the D1 antagonist potentiated the effect of the D2 antagonist.

Chronic changes in thyroid hormones do not affect brain adenosine receptors

Stein Murray B., Mike Clark and Suzanne M. Delaney: Chronic changes in thyroid hormones do not affect brain adenosine receptors. Prog Neuro-Psychopharmacol & Biol Psychiat. 1993, 17(6): 1037–1047.

1. 1. In this study, the authors examined the effects of chronic (14 days) changes in thyroid function on a major neuromodulatory receptor system in the brain —the adenosinergic system. While previous investigators have examined the effects of alteration in thyroid function on adenosine receptors in peripheral tissues (adipocytes), this is the first study to examine such effects in brain.

2. 2. Three groups of male Sprague-Dawley rats were treated for 14 days with either a) oral PTU (0.00625%), iodine-free diet, and i.p. saline injections, b) i.p. saline injections, or c) i.p. triiodothyronine (25 μg/100 g) injections.

3. 3. These manipulations reliably resulted in the production of hypothyroidism (TSH 30.2 ± 8.6 ng/ml), euthyroidism (TSH 2.1 ± 0.9), and hyperthyroidism (TSH <0.4).

4. 4. Treatment had no significant effect on the B_max or K_d of [³H]DPCPX (A₁-antagonist) binding to homogenates from cerebral cortex, cerebellum or hippocampus; similarly, no effect on [³H]CGS-21680 (A₂-agonist) binding to striatal homogenates was noted.

5. 5. Similarly, quantitative autoradiographic studies failed to reveal consistent regional alterations unique to either hypo- or hyperthyroidism.

6. 6. Incubation of sections with GppNHp resulted in the expected reduction (≈ 40%) in agonist binding, but there was no differential effect seen for either the hypoor hyperthyroid tissues.

7. 7. These preliminary findings suggest that alterations in brain adenosine receptors or G-protein-receptor coupling are unlikely to be requisite correlates of abnormal thyroid hormone levels.