Preproenkephalin knockout mice show no depression-related phenotype.

Clinical, preclinical, and pharmacological studies have suggested that decreased enkephalin tone is associated with depression-like symptoms and increase in enkephalin signaling could have a therapeutic value in the treatment of depression. In this study we demonstrate that, surprisingly, animals lacking enkephalin (preproenkephalin, Penk1(-/-)) showed no depression-related phenotype in the Porsolt forced swimming or tail suspension tests. Moreover, Penk1(-/-) mice had a lower frequency of depression-related behavior in stress-induced hypoactivity and ultrasonic vocalization models of depression, similar to animals treated with antidepressant drugs, although this effect was specific to the genetic background. In addition, there was no significant difference in the efficacy of antidepressant reference compounds in wild-type and knockout animals. Nialamide and amitriptyline were even slightly more effective in animals with genetic deletion of Penk1, whereas the minimal effective dose of imipramine and fluoxetine was the same in the two genotypes. The dual peptidase inhibitor RB-101 was also effective in Penk1(-/-) as well as in Penk1(-/-)/Pdyn(-/-) animals, although its efficacy was somewhat reduced compared with wild-type animals. This result was also surprising because the antidepressant effects of RB-101 were thought to be due to the elevation of enkephalin levels.

Effects of antidepressant drugs on a quickly-learned conditioned-suppression response in mice.

Mice experienced to electric shock, exhibited a marked suppression of motor activity when placed in the same cage 24 hr after administration of shocks. Acute administration of imipramine-HCl (10 mg/kg, i.p.), desipramine-HCl (5 and 10 mg/kg, i.p.) and amitriptyline-HCl (5 and 10 mg/kg, i.p.) caused marked reduction of the conditioned suppression of shocked mice, but reduced the motor activity of the non-shocked mice. Maprotiline, mianserin and dimetacrine did not cause reduction of the conditioned suppression. Nialamide (100 mg/kg, i.p.) and pargyline-HCl (100 and 200 mg/kg, i.p.) caused marked reduction of the conditioned suppression but did not increase the motor activity of the non-shocked mice, and tranylcypromine-HCl (10 and 20 mg/kg, i.p.) did not cause reduction of the conditioned suppression. Diphenhydramine-HCl (10 and 20 mg/kg, i.p.) reduced the conditioned suppression of shocked mice in a dose-related manner. Chronic administration of imipramine-HCl (1 and 5 mg/kg, i.p.) for 14 days significantly reduced the conditioned suppression but did not influence the motility rate of the non-shocked mice. Also, chronic administration of amitriptyline (1 mg/kg, i.p.), desipramine (5 mg/kg, i.p.) and dimetacrine (10 mg/kg, i.p.), for 10 days, significantly reduced the conditioned suppression, but did not influence the motility rate of the non-shocked mice. Chronic administration of maprotiline reduced the conditioned suppression. On the other hand, chronic administration of mianserin (5 mg/kg, i.p.) and diphenhydramine (10 mg/kg, i.p.) did not cause a reduction of the conditioned suppression.

Clinical investigation of the menstrual cycle. II. Neuroendocrine investigation and therapy of the inadequate luteal phase.

Nonhormonal drugs--diphenylhydantoin and nialamide, which act on the central nervous system and have no known endocrine activity--were given to two groups of women with distinct types of electroencephalographic patterns in an effort to regulate menstrual disorders. Equalization of the lengths of both the follicular phase and the luteal phase to the normal range was observed during the drug therapy. Forty-five per cent of the pregnancy rate was achieved in 36 of the 80 infecund patients within 4 months of treatment. The mode of action of these drugs is still unknown.

A comparative study of antidepressants in the treatment of depressive states.

The effect of six antidepressants has been investigated in six groups of twenty patients suffering from depressive states. The over-all response of the six groups, as well as the response of the individual target symptoms of depression according to the Hamilton Rating Scale are reported.

[Cases of enuresis nocturna treated with single reflexotherapy. Clinical and therapeutic evaluation]. / Casi di enuresi notturna idiopatica trattati con la sola riflessoterapia. Valutazioni clinich e terapeutiche

Treatment of children with nocturnal enuresis by means of acupuncture, auriculotherapy, etc. is reported. The aetiopathogenetic background, the results of treatment, and the neurophysiological mechanisms through which the action of reflexotherapy can be explained are discussed.

Heart-transplant and mono-amine oxidase inhibitors.

A case of anesthesia for a heart-transplant operation on a patient on mono-amine oxidase inhibitors (M.A.O.I.) is reported. This 63-year-old farmer was in end-stage cardiac failure due to familial cardiomyopathy. For 24 hours before surgery, he was on a dobutamine infusion (3 mcg/kg/min). He had been taking nialamide (100 mg/day) for 8 years for reactional depression and had not stopped it, despite advice. Anesthesia was induced with etomidate and succinylcholine, and maintained with fentanyl (25 mcg/kg/min) and pancuronium. Cardio-vascular stability was maintained during induction and first stage of surgery, up to cardectomy. Graft ischemia was 188 minutes. Successful defibrillation occurred after verapamil 3 mg. Weaning from C.P.B. was easy with dopamine (5 mcg/kg/min) and isoprenaline (0.01 mcg/kg/min). Post-operatively, on day 1, hypertension appeared and needed a nitroprusside infusion. On day 3, the patient needed another anesthetic for removal of pericardial clots, without problems. He remained very confused and disorientated during all his stay in hospital, but improved greatly with a neuroleptic. He left the hospital on day 28 in a good shape, with an anxiolytic, captopril and immunosuppressors. One month later, he was back on nialamide. The pharmacology of the M.A.O.I. is reviewed and their interactions with anesthesia are discussed as well as the use of inotropes. In this case, the denervated heart-graft, free from M.A.O. inhibition, behaved normally when transplanted in a chronically M.A.O.I. treated recipient.

[Neuroendocrine investigation and therapy of the menstrual cycle disorders (author's transl)(proceedings)]. / Investigation et thérapeutique neuro-endocriniennes de certains désordres du cycle menstruel

PIP: A group of patients with irregular menstrual cycles and who could not become pregnant underwent electroencephalography (EEG). 2 distinct types of EEG tracings were noted; therapy was based on these tracings, with administration of diphenyldantoin to one group of patients, nialamid to the other. Moreover, to be able to compare normal cycles to pathological ones, and to be able to appreciate an eventual therapeutic improvement, normograms were taken of 46 regular menstrual cycles. After 4 months of treatment 36, i.e. 68% of patients, were pregnant, and fertilization was obtained mostly during the 2nd and 3rd cycles of treatment.^ieng

[Plea for monoamine oxidase inhibitors. Retrospective study of 350 cases]. / Plaidoyer pour les inhibiteurs de la monoamine-oxydase. Etude rétrospective de 350 observations.

The case-records of 350 outpatients treated with monoamine oxidase inhibitors have been reviewed. All patients presented with depression, obsessions or phobias. About two-thirds benefited from the drugs, particularly after other treatments (including psychotropic drugs, seismotherapy, psychotherapy and internment) had failed. With the moderate doses administered (iproniazide: 50 mg/day; nialamide: 100 mg/day) side-effects were uncommon and mild and no incident was noted in 32 general anaesthesias given for surgical operations. These findings should help in lifting the ban on this category of drugs. Monoamine oxidase inhibitors are effective, useful and sometimes indispensable after failure of other antidepressants.

[Inhibitory effects of L-threo-DOPS on electroshock seizure in mice].

Effects of L-threo-3,4-dihydroxyphenylserine (L-DOPS), a synthetic norepinephrine (NE) precursor, on electroshock seizure were studied in mice. All substances were administered intraperitoneally. Minimal electroshock seizure threshold (EST) was not significantly altered by L-DOPS at a dose of 200 or 400 mg/kg. L-DOPS was unable to abolish tonic extensions of hind legs in maximal electroshock seizure (MES) test at doses from 100 to 400 mg/kg. However, it significantly reduced extension/flexion (E/F) ratio in a dose-dependent manner. Furthermore, L-DOPS dose-dependently blocked maximal electroconvulsions in a combined use with nialamide (30 mg/kg), desipramine (20 mg/kg) or maprotiline (40 mg/kg) at so small doses as not to show any anticonvulsant effect when they were used alone. ED50 (with 95% confidence limit) of L-DOPS in the combination treatments were 210 (145-305), 160 (100-256) and 95 (50-181) mg/kg respectively. Those results indicate that L-DOPS has an anticonvulsant property, which is potentiated by a MAO inhibitor or NE uptake blockers. It was presumed that the effect of L-DOPS was caused by the inhibition of spreading of seizure discharges. It was suggested that L-DOPS would be a useful substance for the investigation on a role of NE in experimental epilepsy and could be used clinically as an adjunct drug for generalized tonic-clonic convulsions.

[Pathogenetic therapy of cobalt-induced cardiomyopathies]. / Patogeneticheskaia terapiia kobal'tovykh kardiomiopatii.

The pathogenesis of damage to the heart muscle caused by exposure to the effect of cobalt compounds is demonstrated. Agents with various mechanisms of action were tested in the experiment. The most effective pharmacological agents (beta-adrenergic blocking agents, anabolic steroids) are recommended for testing in the clinic. A positive effect was registered in the treatment of cobalt cardiomyopathy in the clinic. The mechanisms of the favourable effect of beta-adrenergic blocking agents and anabolic steroids are discussed.