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The effects of centrally administered galanin (10 and 20 mcg) on the EEG, somatic behaviour and some autonomic parameters have been studied in unanesthetized rabbits. In this species the peptide induced a dose related increase in electrocortical power spectrum density and behavioural sedation. Autonomic changes, consisting in moderate hyperthermia and bradypnea, were seen only after the highest dose of the peptide. These data support a central action of the peptide and suggest a role for galanin as sedative neuropeptide.

We have studied the rat under chronic treatment with lithium carbonate and rubidium chloride both given ip. For a four week period we have recorded, once a week, weight, rectal temperature, tail-flick, motor co-ordination and general activity in a one-arm radial maze and in a Boissier-Simon table. At the end of the fourth week surface (SEEG) and deep EEGrams (DEEG: hippocampus, amygdala) were recorded from treated and control animals. FFT (Hanning window) was performed both for SEEG and DEEG. The findings are: 1) No changes in weight, rectal temperature, tail-flick and motor coordination (rotarod). 2) In the one-arm maze and in the Boissier-Simon table rubidium is in contrast to the effects of lithium, it causes increased activity and aggression 3) the EEGrams were analyzed by means of FFT as power in preselected bands of frequency. The results, on the whole, suggest, since these two ions have opposite effects on brain norepinephrine metabolism, that they may be useful in the treatment of PMD.

A[Sar1, Ile7] AngIII, an angiotensin III analogue apparently devoid of any affinity for vascular angiotensin II (AngII) receptors, inhibits AngII-induced drinking but neither affects cellular dehydration-induced drinking nor produces any intake of water in water replete rats, suggesting that the dipsogenic effect of AngII is not of vascular origin. Thus, [Sar1, Ile7] AngIII is an interesting tool to study the central effects of AngII.

In this paper we have studied the rat under chronic treatment with Lobeline sulphate ip. For a three week period we have recorded, once a week, weight, rectal temperature, tail-flick, motor coordination and general activity in a one-arm radial maze and in a Boissier-Simon table. At the end of the third week surface (SEEG) and deep (DEEG) EEG were recorded both from treated and control animals. The findings are: 1) no changes was observed in weight, rectal temperature, tail-flick and motor coordination; 2) the treated rats showed an increased general activity both in a one-arm radial maze and in the Boissier-Simon table; 3) the EEG effects were analyzed and quantified, by means of Fast Fourier transform, as total power and as power in preselected bands of frequency. The lobeline sulphate seems to produce both in SEEG and hippocampus a shift toward low frequencies and in amygdala a drift toward high frequencies.

Some 5-[(dialkylamino)alkyl]-8-chloro-3,5-dihydro-2-methyl/phenyl-4H- pyrido[2,3-b] [1,4]-diazepin-4-ones previously prepared, were subjected to pharmacological experimentation in order to verify variation in biological activity induced by introduction of chlorine on the pyridine nucleus and by replacement of pyridinic with a benzenic ring. The effect upon mice with regard to exploratory activity, motor coordination, spontaneous activity, analgesic activity was tested and their anti-stricnine, anti-cardiazole, anti-amphetamine and anti-reserpine activities were also evaluated. The activities of the texted compounds were compared with those already showed by the analogues unchlorinated derivatives (B) and by isosters benzodiazepinones (D).

The authors review the latest data found in the literature on the various effects of yohimbine, especially the behavioral and anxiogenic ones. They also report experimental findings on the potentiation of yohimbine mortality by stress.

In this paper we have studied the rat under chronic treatment with Passiflora oral. For a three week period we have recorded, once a week, weight, rectal temperature, tail flick, motor coordination and general activity in a one-arm radial maze. At the end of the third week surface (SEEG) and deep (DEEG) EEG were recorded from treated animals. The findings are: 1) no change was observed in weight, rectal temperature, tail-flick and motor coordination. 2) The treated rats, when in a one-arm radial maze showed a diminished general activity. 3) SEEG and DEEG recordings showed "normal" electric activity.

Ethanol causes behavioral effects in rats and mice similar to those observed in humans. Moreover, by selective breeding, lines of rats or mice have been obtained that prefer ethanol solution to water and vice versa (ethanol-preferring and ethanol-avoiding animals). Recent studies suggest that ethanol stimulates GABA receptor-mediated opening of the chloride channels in neuronal membranes, and that some behavioral responses to ethanol, such as its sedative and anxiolytic effects, are mediated by central GABA receptors. Recently, we have shown that ethanol suppresses the firing of neurons in the pars reticulata of the substantia nigra, which exert an inhibitory control over dopaminergic neurons. Escaping from inhibitory control, the latter neurons are stimulated by ethanol. Dopaminergic neurons especially sensitive to ethanol are those of the meso-cortico-limbic system, belonging to the "pleasure centers" of the brain. In addiction, it has been shown that ethanol stimulates dopamine metabolism in different brain areas, but more effectively so in ethanol-preferring than in ethanol-avoiding rats. Finally, voluntary ethanol intake modifies dopamine metabolism in different brain areas.

5,11-Dioxo-1,2,3,5,6,11,12,12a-octahydropyrrolo [2,1-c] [1,4]benzodiazepine and the corresponding 2-hydroxyderivative were prepared by the intramolecular cyclization of 1-(2-aminophenylacetyl)pyrrolidin-2-carboxylic acid and 1-(2-aminophenylacetyl)-4-hydroxypyrrolidin-2-carboxylic acid; some of the tricyclic compounds were tested for neuropsychopharmacological effects.

The reaction of 4-(dialkylamino)-1,3-dihydro-2H-1,5-benzodiazepin-2-ones (I a-c) with N,N-dimethylformamide in the presence of phosphorus pentachloride at room temperature gave rise to the formation of 4-(dialkylamino)-3-[(dimethylamino)methylene]-1,3-dihydro-2H-1,5-benzodiazepin- 2-ones (IX a-c) which were useful starting materials to achieve the synthesis of tricyclic 1,5-benzodiazepine derivatives. Actually (IX a), selected for the smallest steric hindrance of the 4-dialkylamino substituent, by reaction with hydrazines afforded pyrazolo[3,4-b][1,5]benzodiazepine derivatives whereas reaction with guanidine or amidines gave 5H-pyrimido-[4,5-b][1,5]benzodiazepine derivatives. The structure of isomeric N-methyl-pyrazoles (X c) and (XI a) and of N-phenylpyrazole (X b) were elucidated by comparison with compounds prepared by unequivocal chemical methods. Pharmacological evaluation of some of the products showed only generic CNS depressant activity.

Several new derivatives of trans-1-(4-phenylcyclohexyl)-ethylamine (M.G. 6669) have been synthesized with various substituents at the alpha-carbon and/or at the amine nitrogen atom. All compounds were evaluated for a potential antidepressant activity taking M.G. 6669 as reference. They turned out to be less active than the reference substance. Pharmacological evaluation of M.G. 6669 itself was broadened during this work. The good antidepressant properties of this compound were confirmed, accompanied however by some toxic phenomena.

A compound formerly obtained through the reduction of cyclohexanone o-nitrophenylhydrazone has been defined as cyclohexane-3-spiro-3,4-dihydro-1,2,4-benzotriazine, and its formation has been interpreted via air oxidation of a cyclic form of o-aminophenylhydrazone formed first. The extension of such a reaction to several o-nitrophenylhydrazones of aliphatic, alicyclic and arylaliphatic ketones has been investigated. Formation of 3,4-dihydro-1,2,4-benzotriazines disubstituted in position 3 happens as a general rule; yields are good so long as bulky groups or aromatic nuclei are not close to the hydrazone double bond, hindering the amino group addition either sterically or by charge dispersion. Pharmacological screening has not shown any unusual activity for these new compounds; it is suggested that the formation of dihydrobenzotriazine derivatives be used to latentiate biologically active ketones.

Numerous derivatives of 2-phenyl-2H-indazole were prepared. The compounds were of general formula I: where R is an acid, neutral or basic radical and R1, R2, R3 represent various functional groups, hydrogen atom or chlorine. The compounds were examined for analgesic-antiinflammatory properties and in some cases as inhibitors of platelets aggregation. Among the compounds where R is an alkanoic acid residue, the only compound showing interesting activity was M.G. 18755 [R = CH(CH3) COOH; R1, R2, R3 = H] and its lysine salt (M.G. 18334), which in various tests showed activity greater than that of ibuprofen. The homologous butyric derivative (M.G. 18860) showed a good anti-aggregatin activity.

It has been found that TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), in rats, endoperitoneally or orally administered at dose of 1-10 mcg/kg, provokes irritability, aggressivity and restlessness (increase of spontaneous crossings in the shuttle box). The TCDD does not modify the conditioned avoidance (C.A.) or the conflictual situation. In "vitro" the TCDD stimulates directly the striatal and hypothalamic adenylate cyclase of rat. The TCDD increases the stimulation produced by dopamine on striatal adenylate cyclase. Haloperidol (dopamine antagonist) inhibits the stimulation produced by TCDD. TCDD does not significantly modify the stimulation by hystamine on hypothalamic adenylate cyclase. Cimetidine (H2) antagonist) causes a remarkable increase of the TCDD stimulating effect.

The authors, after going carefully over the specific bibliography on the matter, report their results relating to exploratory behaviour in mice after simultaneous administration with morphine (1 mg/kg i.p.) and naloxone (0,05 mg/kg i.p.). Exploratory behaviour was evaluated using an automatic recording hole-board, that simultaneously registered the locomotor activity. Morphine and naloxone simultaneously administered produced, at the used doses, a significant statistic decrease in exploratory behaviour, while locomotor activity was unchanged, in comparison with drug-naive subjects. At the end, some possible interpretations are proposed about obtained results.

Compounds with potential activity on the Central Nervous System were prepared starting either from 2,5-diethoxycarbonylpyrrolidine or from N-benzyloxycarbonyl-2,5-pyrrolidinedicarboxylic acid anhydride. By the Arndt-Eistert reaction it was possible to obtain chain lengthening at position 6. The carboxy group was also successfully reduced to a hydroxymethyl group. The synthetic work was completed with the synthesis of some derivatives having a phenyl ring condensed at position 7 and 8. Some pharmacological data on the Central Nervous System depressant activity of the prepared compounds are also reported.

Lactating female albino rats have been treated with coumatetralyl rodenticide, having anticoagulant activity. The letal effect on mothers was of 40% (using a maximum concentration of toxic substance) while it was of 54% in offsprings. Among the probable causes of death in offsprings, the authors suggest the hypothesis that an interference in the relationship mother-offsprings is due to the influence of coumatetralyl on parental behavior.

The authors examined pharmacological actions of Yohimbine, an indolic alkaloid alpha-2-adrenoceptor antagonist. Several specific functions have been attributed to the alpha-2-adrenoceptor such as reduction of sympathetic outflow and pre-synaptic inhibition of noradrenergic neurons. Particularly the following are discussed: behavioural, antidepressant and anxiogenic effects: aphrodisiac effect; cardiovascular effects and metabolic effects.

The authors after going carefully over the specific bibliography on the matter, report their results relating to exploratory behaviour in mice after administration of naloxone (0, 05 mg/Kg i.p.). Exploratory behaviour was evaluated using an automatic recording hole-board, that simultaneously registered the locomotor activity. At the utilized doses, naloxone produced a significant decrease of exploring activity and a significant increase of motility, in comparison with drug-naive subjects. At the end, some possible interpretations are proposed about obtained results.

Treatment of 2,3-dihydro-2-oxo-4-dialkylamino-1H-1,5-benzodiazepines with phosphorus pentasulfide afforded 2-thio derivatives which in turn gave the corresponding methylmercapto derivatives by reaction with sodium hydride and methyl iodide. By treating these compounds with dialkylamines the formation of 2,4-bisdialkylamino-3H-1,5-benzodiazepines was achieved. Pharmacological screening of some of the products indicated that the introduction of a second dialkylamino substituent into the 1,5-benzodiazepine molecule gave the compounds CNS excitant properties, while the initial monodialkylamino derivatives containing sulfur showed a CNS depressant activity.

The synthesis and activity on the central nervous system of a series of 2-aryl or 2-alkyl-7-phenylhexahydroimidazo[1,5-a] pyrazin-3(2H)-ones (II a-f) are reported. The intermediate 3-carbomethoxy-1-phenylpiperazine (X) was prepared in six steps from aniline and methyl-2-chloroacrylate. Compared with that of derivatives of Zetidoline, the depressant activity of (II a-f) is markedly reduced.

In order to investigate the effects of the overlapping of cinchophene and phenothiazine structures, connected with antiinflammatory and analgesic activities, several derivatives of 2-phenothiazin-2'-yl-cinchoninic acid were prepared through the condensation of isatin or 5-substituted isatins with 2-acetylphenothiazine or its 10-ter-aminoalkyl derivatives. Most of these compounds exhibit analgesic activity, but only a few, of those so far tested, show antiinflammatory activity. Compound (G) with R' = H, R" = C2H5 and R"' = dimethylaminoethyl shows analgesic activity corresponding to 88% of that of phenylbutazone. Moreover some compounds show signs of sympatholytic and vasodilatatory activities and also bactericidal and amebicidal properties in vitro, while some others demonstrate a modest neuroplegic activity.

The synthesis of new derivatives of 6H-pyrrolo[1,2-a] [1,4]benzodiazepine is described. These compounds were tested for activity on the C.N.S. by several screening tests on mice.

The following compounds have been synthesized according to a previously tested route, of the 9-chloro-, 9-trifluoromethyl- and 9-methoxy-5-phenylpyrrolo[2,1-d][1,5]benzothiazepin-6,6-dioxide (II a-c), 9-chloro- and 9-trifluoromethyl-5-p-nitrophenylpyrrolo[2,1-d][1,5]benzothiazepin-6,6-dioxide (II d, e), 5-(4-pyridyl)pyrrolo[2,1-d][1,5]benzothiazepin-6,6-dioxide (III) and 5-(3-pyridyl)pyrrolo[2,1-d][1,5]benzothiazepin-6,6-dioxide (IVa) with the 9-chloro- and 9-trifluoromethyl- derivatives (IV b, c) are reported. The sedative action in the rat was tested against the motor activity induced by amphetamine. The 9-chloro-5(3-pyridyl)pyrrolo[2,1-d][1,5]benzothiazepin-6,6-dioxide was particularly active and showed sedative action superior to that of diazepam. Marked sedative activity was observed with 9-methoxy-5-phenylpyrrolo[2,1-d][1,5]benzothiazepin-6,6-dioxide (NF19) and 9-chloro-5-p-nitrophenylpyrrolo[2,1-d][1,5]benzothiazepin-6,6-dioxide (NF20).

The pharmacological activity of hematoporphyrin has been studied on two experimental models which are able to monitor the motor coordination in the rat, namely the natatory exhaustion and the Rota-Rod tests. A dose related effect of hematoporphyrin in increasing resistane to motor fatigue has been observed in the Rota-Rod between 2-8 mg/kg i.p. Higher doses of hematoporphyrin seem to be less effective (difasic effect). In both tests hematoporphyrin was able to potentiate the stimulating effect of d-amphetamine (6 mg/kg s.c.). The potentiation appeared to be dose related between 2 and 8 mg/kg in the Rota Rod and between 2 and 16 mg/kg in the natatory test.

Reaction of N,N-dialkylethoxycarbonylacetamides with 1-methyl-2-naphthol, in the presence of phosphorus oxychloride, gave rise to the formation of 2-dialkylamino-4-oxo-10-methyl-4H-naphtho[2,3-b] pyrans through the preliminary attack of the amide-phosphorus oxychloride reactant at the phenolic hydroxyl and cyclization at position 3 of the naphthalene moiety. However when (N-alkyl,N-phenyl)ethoxycarbonylacetamides were used in the reaction an ortho position of the N-phenyl group was involved in the cyclization and 1-alkyl-2(1'-methyl-2'-naphthoxy)-4-quinolones were achieved. Pharmacological investigation showed that some naphtho[2,3-b]pyran derivatives have neurotropic activity of the sedative, anticonvulsant and antidepressant type very similar to that shown by previously studied 1-oxo-3-dialkylamino-1H-naphtho[2,1-b]pyrans (5).

The synthesis of 5H-imidazo [2,1-c] [1,4] benzodiazepine derivatives is described. Hydroxymethylation of 1-(2-nitrobenzyl)imidazoles by reaction with formaldehyde in a sealed tube and subsequent oxidation of hydroxymethylimidazoles with activated manganese dioxide afforded 1-(2-nitrobenzyl)imidazole-2-carboxaldehydes. The latter compounds were treated with iron(II) sulphate to yield directly the expected tricyclic imidazobenzodiazepines by intramolecular cyclization of the intermediates aminoaldehydes. The tricyclic derivatives were subjected to pharmacological screening to evaluate the effects on the behavior of the animals and the interaction with some biogenic amines. Some of the tested compounds were comparable to chlordiazepoxide in sedative and muscle-relaxant activities. None of them showed antiserotonin, anticholinergic or adrenolytic activities.

The locomotor activity of rats subcutaneously treated with apomorphine HCl (300 microgram/kg, 30 sec before emmission into actometers) was evaluated every 60 sec for 1 hour. An inhibitory phase appeared in the first 6 min of recording in comparison to the more elevated values of the control group. From 18th to 44th min a more sustained activity was easily recognizable in treated rats in comparison to the decline of control values. The results were discussed by supposing that the first amounts of drug entering CNS stimulated pre-synaptic dopamine receptors and the full dose activated post-synaptic dopamine neurons. The study of time-course of a single dose of apomorphine could be a useful model for evaluating pre- and post-synaptic effects of antidopaminergic drugs.

The authors, after going carefully over the specific bibliography on the matter, report their results relating to exploratory behaviour in mice after administration of morphine (1 mg/kg i.p.). Exploratory behaviour was evaluated using an automatic recording hole-board, that simultaneously registered the locomotor activity. At the used doses, morphine did not produce variations either in exploratory behaviour or in locomotor activity of utilized mice, in comparison with drug-naive subjects. At the end, some possible interpretations are proposed about obtained results.

The synthesis of a series of dialkylaminoalkylic amides of 1-chloro-3-carboxy-4-methylisoquinoline (VIII), of 1-methoxy-3-carboxy-4-methylisoquinoline (VI) and of 3-carboxy-2,4-dimethyl-1-oxoisoquinoline (XIII) is described. In addition a series of 1-amino-substituted 3-carboxymethyl-4-methylisoquinolines (II) was synthesized. The pharmacological activity of some of these compounds was studied. The compounds (XIIIa), (VIa) and (VIIIa) showed a clear local anaesthetic activity, a little lower than that of lidocaine; the same compounds also showed fairly good antispasmodic properties.

As a part of a research on analgesic compounds 0-(4-methoxyphenyl)carbamoyl-3-aminopropiophenone oximes, 0-(4-methoxyphenyl)-carbamoyl-3-aminomethylcamphor oximes and 4-(4-methoxyphenyl)semicarbazones of 3-aminopropiophenones were prepared. The analgesic activity of these compounds was tested and the results of pharmacological screening are discussed.

The synthesis and the results of pharmacological screening of 4H-benzo[b][1,4]thiazine derivatives are described. These substances were prepared by reacting 2,2'-dithiodianiline with ethyl-2-oxocycloalkanecarboxylates followed by NaBH4 reduction. The pharmacological results indicate remarkable depressive activity [see (IV b) (n = 3)] shown by 100% potentiation of barbituric-induced sleeping time.

The synthesis of imidazo [2,1-b]-1,3,4-thiadiazole derivatives and preliminary pharmacological screening are reported. The compounds studied showed mainly antiphlogistic, antipyretic and analgesic activity. From the results it appears that analgesic activity is peripheral.

The synthesis of two new series of 3,8-diazabicyclo [3.2.1] octane derivatives is described. The first series includes some 3-(or 8)-allyl and 3-(or 8)-(3,3-dimethylallyl) derivatives of 3,8-diazabicyclo [3.2.1] octane and 3,8-diazabicyclo [3.2.1] octane-2-one. The second series includes some esters and carbamates of 3-(3-hydroxy-3-methyl)butyl-3,8-diazabicyclo [3.2.1] octane. Two new 3,8-diazabicyclo [3.2.1] octane derivatives structurally related to propoxyphene are also described. Some pharmacological data of these compounds are reported.

In this research the Authors have studied the action of scopolamine on the memorization of the explorative behavior of the mice. They gave scopolamine before each of the 2 explorations made at an interval of 24 h one from the other. The results obtained show that in these experimental conditions, scopolamine cancels the short-time memory in a more complete fashion compared to the only administration before the second exploration. The Authors advance the hypothesis that this effect of scopolamine can be in relationship to its action on the cholinergic system.

PHLIP-7 and PHLIP-8, two peptides reproducing at least in part the N-terminal aminoacid sequence of physalaemin, have been identified in mammalian tissues. These peptides produce alterations of fighting behaviour in the mouse, but are devoid of any behavioural activity in the rat. This suggests that PHLIP-7 and PHLIP-8 have no affinity for brain receptors involved in the behavioural effects evoked by tachykinins in the rat, and that the brain of this animal is lacking in receptors for the N-terminal sequence of tachykinins.