Reduced P3 amplitudes are associated with both a family history of alcoholism and antisocial personality disorder

1. 1. Previous research has demonstrated that the amplitude of the P3 component of the event-related electroencephalographic potential (ERP) is influenced by the presence/absence of a family history of alcoholism (FHA). The present study extended this line of research by examining the P3 effects of both FHA and antisocial personality disorder (ASP) in a 2 × 2 factorial design.

2. 2. The task required subjects to judge the orientation of an infrequently-occurring outline drawing, representing an aerial view of a human head.

3. 3. Analyses of P3 amplitudes elicited by this drawing revealed reductions attributable to the effects of both FHA and ASP, but not their interaction. These effects were most apparent at frontal electrode sites. Analyses of P3 latency revealed no consistent pattern of findings. However, the interval between P3 and manual reaction time was shorter in the ASP+ group relative to the ASP- group.

Biphasic actions of pentobarbital on synaptic transmission

1. 1. The effects of pentobarbital were studied on synaptic transmission in the rat hippocampal slice preparation.

2. 2. Low concentrations of pentobarbital (0.04–0.1 mM) produced an increase in the Schaffer collateral to CA 1 evoked EPSP and population field potential amplitudes.

3. 3. Higher concentrations of pentobarbital (0.2–1.0 mM) produced depression of field potential amplitudes.

4. 4. Pentobarbital altered synaptic transmission by affecting both pre- and post-synaptic functions.

5. 5. Analysis of input/output curves suggest the presynaptic site is most sensitive.

Topographic evoked potentials during backward masking in schizophrenics, patient controls and normal controls

1. 1. A backward masking task with simultaneous measurement of topographically mapped evoked potentials was performed by normal, schizophrenic, and patient control subjects.

2. 2. Behavioral results replicated previous studies demonstrating schizophrenic deficit and to a lesser extent patient control deficit in this task.

3. 3. Two competing theories of (A) defects in “gating” mechanisms or (B) failure in early stimulus “registration” processes were tested.

4. 4. Topographical evoked response maps Indicated a significant absence of a negative going wave in the 70–100 msec epoch in the schizophrenic group relative to both control groups.

5. 5. As the 70–100 msec negativitity attenuation occurred during target presentation, and well before mask onset, it was concluded that schizophrenic deficit in this task consists of a failure in Initial stimulus “registration” processes within the time allowed for stimulus availability.

6. 6. Such defective mechanisms may be significant in the pathogenesis of schizophrenia.

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.

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.

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.

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.

Introduction to the pharmacokinetics and pharmacodynamics of benzodiazepines

1. 1. The contributions of pharmacokinetics and pharmacodynamics to the generation and maintenance of drug responses are reviewed from the literature.

2. 2. Potential pharmacokinetic determinants of duration of drug action are dose, lipid solubility and elimination half-life.

3. 3. Certain paradoxes are inherent in the view that clinical differences among benzodiazepines are due primarily to their elimination half-lives.

4. 4. It is concluded that the respective roles of pharmacokinetics and pharmacodynamics in the generation and maintenance of clinical responses to benzodiazepines require clarification.

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.

Membrane glycoconjugates as potential mediators of alcohol effects

1. 1. Membrane glycoconjugates include glycoproteins and glycolipids that have many important functions in a wide variety of tissues, especially brain.

2. 2. Alcohol's ability to fluidize and swell plasma membranes could be expected to alter the orientation and conformation of the embedded glycoconjugates.

3. 3. Both kinds of glycoconjugates can contain terminal moieties of sialic acid, which has been shown to be decreased by single doses of alcohol. Chronic exposure to alcohol may have no effect on sialic acid, except in very young animals.

4. 4. Glycolipids containing sialic acid (gangliosides) are also decreased by acute doses of alcohol, but chronic alcohol has little effect. Thus, gangliosides may have a role in the development and expression of tolerance.

5. 5. Glycoproteins containing sialic acid may also be involved in alcohol action, but there has been less research in this area.

6. 6. Alcohol-induced disruptions in membrane glycoconjugates could affect the important cellular functions that glycoconjugates have, and thus research on alcohol effects on glycoconjugates could lead to important discoveries of diagnostic and therapeutic value for alcohol abuse and alcoholism.

Neuropharmacological and physiological validation of a computer-controlled two-compartment black and white box for the assessment of anxiety

1. 1. The two-compartment black and white box first described by Crawley and Goodwin (1980) has been used to study anti-anxiety properties of drugs but has not been validated.

2. 2. An automated test system and validation of the protocol for the evaluation of compounds with anxiolytic or anxiogenic potential is described.

3. 3. The box is partitioned into black and white sections with an interconnecting opening and is equipped with micro-switch photoelectric controls (light source and photorecciver) and an interface connected to the menudriven computer during anxiety testing.

4. 4. Plasma corticosterone levels in naive mice maintained on a reversed L:D cycle was significantly reduced following restricted exposure to the brightly lit white section but not in the red-illuminated black section.

5. 5. The optimal structural configuration in different test situations was found to be a square rather than a round box.

6. 6. Under normal conditions, mice spend about 60% of the time in the dark compartment so that the exploratory activities and time spent in the white section are taken as a measure of anxiety.

7. 7. Compounds examined included the reference anxiolytic diazepam, nicotine, naloxone, MDL 72222, ICS 205 930 and buspirone, all of which increased mouse exploratory activities in the white section. PTZ, β-CCP, morphine and amphetamine increased exploration in the black compartment and reduced exploration in the white area.

8. 8. Fluphenazine and imipramine had no specific effects on anxiety responding, although the cataleptogenic effect of fluphenarinc was apparent.

9. 9. Daily repeated testing was possible with a maximum of up to four trials a week using naive animals during the 5-min test session.

10. 10. The results suggest that the rapid and automated test system for the assessment of changes in measures of anxiety is not only valid for large scale evaluation of compounds but could be used to elucidate mechanisms of drug action and the CNS pathways linked with anxiolysis and/or anxiogenesis.

Are all benzodiazepines clinically equivalent?

Since the introduction of chlordiazepoxide in the late 1950's and then diazepam shortly thereafter, the use of benzodiazepines in medicine has proliferated, reaching a peak and then plateauing a few years ago. The number of available benzodiazepines has continued to proliferate for a number of reasons. Thus, the so-called short-acting or short half-life compounds have been promoted commercially as advantageous over the compounds producing a number of metabolites and thus having a longer half-life.

1. 1. Clinical observations are not always consistent with laboratory findings where half-life or pharmacokinetics do not always correlate with pharmacodynamics, ie. clinically effective duration of action.

2. 2. The parent compound, chlordiazepoxide, was observed to have anticonvulsant, anxiolytic, muscle relaxant properties to varying degrees. Subsequently, diazepam seemed to exert a greater potency in these three areas.

3. 3. The final metabolite, oxazepam, has been observed to have a different therapeutic profile. The advent of the triazolo compounds brought a new dimension to benzodiazepine treatment both in primary and side effects.

4. 4. The relationship between blood levels and clinical efficacy is considered in the light of clinical observations as well as in the perspective of clinical management. Problems of tolerance and escalation of dosage must be addressed in the administration of these drugs where the confluence of pharmacokinetic and pharmacodynamic findings may serve as a guide in he management of anxious patients.

Electroconvulsive therapy and plasma prostaglandin E2 metabolite in major depressive disorder

1. 1. Animal experiments show that PGE₂ affects the release of ACTH and corticosteroids. In depressed subjects, plasma concentrations of the same hormones are increased immediately following ECT. Consequently we explored passible effects of ECT on PGE₂.

2. 2. The major plasma PGE₂ metabolite (PGEM), ACTH, and cortisol were determined by RIA.

3. 3. PGEM did not change with time alone and anesthesia without ECT also did not have a consistent effect. PGEM was significantly elevated at all post ECT sampling times. The maximum increase, about fifty percent, was attained at 15 and 30 minutes. Similar changes were observed following ECT-I and ECT-VI.

4. 4. Positive correlations between PGEM, ACTH and cortisol were obtained.

5. 5. The results demonstrate that following ECT stimulus there is a robust increase in circulating PGEM. The increased release of PGE₂ may, in part, account for the elevated plasma ACTH and cortisol.

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.

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.

Increments in plasma homovanillic acid concentrations after neuroleptic discontinuation are associated with worsening of schizophrenic symptoms

Khan, René s., Farooq Amin, Peter Powchik, Peter Knott, Marvin Goldstein, Seth Apter, Ben Kerman, Stacey Jaff and Michael Davidson: Increments in Plasma Homovanillic Acid Concentrations after Neuroleptic Discontinuation are Associated with Worsening of Schizophrenic Symptoms. Prog. NeuroPsychopharmacol. & Biol. Psychiat. 1990, : 879–884.

1. 1. Thirty-two male schizophrenic patients participated in this study.

2. 2. Plasma concentrations of the dopamine metabolite, homovanillic acid (pHVA) were assessed once on neuroleptic medication and twice a week for a maximum of six weeks after its discontinuation.

3. 3. Psychiatric symptomatology was assessed once on neuroleptic medication and once a week for a maximum of six weeks after its discontinuation, using the brief psychiatric rating scale (BPRS).

4. 4. pHVA and total BPRS score increased significantly after discontinuation of neuroleptic as compared to baseline.

5. 5. The magnitude of pHVA and BPRS increments after discontinuation of neuroleptic correlated significantly.

6. 6. Results of this study suggest that worsening of schizophrenic symptoms after discontinuation of neuroleptic treatment is associated with increased pHVA concentrations.

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.

Variation in evoked potential measures over the menstrual cycle: A pilot study

Nancy Kluck, Scan J. O'Connor, Victor M. Hesselbrock, Allan Tasman and Donald Maier, Lance Bauer: Variation in Evoked Potential Measures Over the Menstrual Cycle: A Pilot Study. Prog. Neuro. Psychopharmacol. Biol. Psychiat. 1992. 16(6): 901–911.

1. 1. The P3 component of a visual event related potential (ERP) was studied for five consecutive weeks in six women with normal menstrual cycles. Serum concentrations of luteinizing hormone (LH), estradiol (E2) and progesterone were studied during the same period.

2. 2. Increases in P3 amplitude, although nonsignificant, were noted in the week preceding onset of menses.

3. 3. No significant changes in reaction times to target/nontarget stimuli were noted over the same time period.

The emergence test: effects of psychotropic drugs on neophobic disposition in Wistar Kyoto (WKY) and Sprague Dawley rats

1. The Emergence Test (ET), a variation of the open field test in which the rat is not handled, and is purported to measure neophobia, was applied to Wistar Kyoto (WKY) and Sprague Dawley (S-D) rats.

2. While no-stress control WKY rats were less active in the ET, pre-treatment with shock stress exacerbated strain differences. WKY rats, previously exposed to shock, did not emerge from the home cage start box during repeated testing, whereas previously stressed S-D rats vacated the home cage quickly and revealed increasing behavioral agitation.

3. Diazepam reduced emergence latency only in S-D rats, whereas nomifensine significantly increased head poke responses in WKY rats.

4. WKY rats responded to the ET with characteristically depressive behavior, whereas S-D rats responded to the same ET with behavioral agitation and anxiety. The implications of these behavior patterns for discriminating between anxiety and depressive behavior are presented.

Selective inhibition by alcohol and cortisol of natural killer cell activity of lymphocytes from cord blood

1. 1. The immunosuppressive effects of drugs such as alcohol or hormones such as cortisol may be age-related. To test this hypothesis, the authors investigated the in vitro effects of ethanol (EtOH) and cortisol on Natural Killer (NK) cell activity of lymphocytes from normal cord blood in comparison with that of lymphocytes from normal adult peripheral blood.

2. 2. K562, an erythroleukemia cell line, was used as a target in a 4 hr ⁵¹Cr release assay.

3. 3. Ethanol at 0.3% (V/V) and cortisol at 0.05, 0.1 and 0.2 μg/ml concentrations, added directly to a mixture of effector and target cells significantly suppressed the NK activity of cord blood lymphocytes in a dose dependent fashion, whereas similar concentrations of either EtOH or cortisol did not manifest significant immunoregulatory effects on NK cell activity of normal adult lymphocytes.

4. 4. Pre-treatment of the target with either EtOH or cortisol for 4 hours did not affect cytotoxicity. Inhibition of cytotoxicity was also not due to direct toxicity of effector cells because lymphocytes treated with either EtOH or cortisol showed normal ⁵¹Cr release and their viability was comparable to that of untreated control cells.

5. 5. This suggests a selective inhibitory effect of EtOH and cortisol on NK activity of neonatal lymphocytes that may be of clinical significance.