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Acute noise stress decreased [3H]5-hydroxytryptamine ([3H]5-HT) uptake in synaptosomes from rat hypothalamus, hippocampus and cerebral cortex. The decrease was due to the maximum rate of [3H]5-HT uptake, which peaked 30 min after stress and partly returned to resting values within 4 h, with no changes in affinity (Km values). No changes in [3H]paroxetine binding and basal [3H]5-HT release were found in stressed rats. Tianeptine, given at the dose of 10 mg/kg 1 h before stress, counteracted the noise-induced decrease of 5-HT uptake, since it increased [3H]5-HT uptake in both resting and stressed animals, but did not prevent the rise in plasma corticosterone of stressed rats. Buspirone pretreatment had no effect on [3H]5-HT uptake in resting rats but prevented the noise-induced decrease in [3H]-HT uptake. Diazepam did not modify either the basal or the noise-induced reduction in [3H]5-HT uptake. The evidence that treatments reducing extrasynaptic 5-HT, by increasing its reuptake (tianeptine) or reducing its release (buspirone) in innervated regions are able to modify the stress-induced decrease in 5-HT uptake, further confirms the importance of serotonin in the mechanisms mediating neurochemical responses to stress.

The importance of d-norfenfluramine in regard to the indole-depleting action of d-fenfluramine has not been well studied in sensitive animal species. The present study therefore examined the intensity and time course of the neurochemical effects of i.p. injected d-fenfluramine (2.5 and 5 mg/kg) and d-norfenfluramine (2.5 mg/kg) in vehicle- and SKF-525A-pretreated rats, relating the effects to the brain concentration-time profiles of the drug and its active metabolite. At the lower dose d-fenfluramine caused only a small, short-lasting decrease in brain serotonin (5-HT) without affecting the 5-hydroxyindoleacetic acid (5-HIAA). Higher doses affected both 5-HT and 5-HIAA (50-60 and 30-40% reductions, respectively), the effect being maximal for at least 8 h. d-Norfenfluramine reduced the brain content of 5-HT and 5-HIAA less (by about 30%) than 5 mg/kg d-fenfluramine did. Brain concentrations of d-norfenfluramine at the time of the maximal depletion of indoles were close to those of the metabolite after 5 mg/kg d-fenfluramine, indicating that the acute indole-depleting effects did not depend solely on the brain concentrations of its nor-metabolite. SKF-525A changed the metabolite-to-parent drug ratios in brain without appreciably influencing the action of d-fenfluramine. However, the maximum decrease in indole content caused by 2.5 mg/kg d-fenfluramine in SKF-525A-pretreated rats was only 12% of the control level, although the brain concentration of unchanged drug was comparable to that after 5 mg/kg d-fenfluramine in vehicle-pretreated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of d-fenfluramine (1.5 mg/kg) and sertraline (10 mg/kg), administered intraperitoneally once daily for seven days were studied on feeding parameters of rats over various periods. On the first day of treatment both drugs markedly reduced meal size and meal duration during the first hour and, to a lesser extent, the first 4 h. No effects were seen later. The size and duration of eating bouts were also markedly reduced by both drugs in the first hour. There was no significant effect of either drug on meal frequency in any period. Only d-fenfluramine significantly reduced the rate of eating within 4 h from the start of testing. Sertraline, but not d-fenfluramine, markedly increased locomotor activity in the first 4 h after the start of testing. The d-fenfluramine effect on eating rate disappeared by the second day whereas total intake and meal size were still reduced on day five. By days six and seven however the d-fenfluramine-treated rats did not differ from the controls. During the seven-day treatment sertraline always reduced total food eaten and meal size but caused only transient changes of locomotor activity and eating rate. Since the effects of d-fenfluramine and sertraline on meal size and food intake could be separated from the effects on eating rate and arousal, it appears that at appropriate doses these drugs specifically increase the satiating effect of food. Tolerance to this effect appears to develop more rapidly for d-fenfluramine than for sertraline.

In one experiment, the effect of d-fenfluramine (DF) on gastric emptying was studied in rats treated i.p. with metergoline, a non-selective serotonin (5-HT) receptor antagonist, ritanserin, a selective 5-HT2 and 5-HT1C receptor antagonist, and xylamidine, a 5-HT antagonist which has poor access to the brain. Metergoline (1 mg/kg) but not ritanserin (0.5 mg/kg) or xylamidine (3 mg/kg) blocked the effect of 2.5 mg/kg DF studied 2 and 4 h after injection. In a second experiment, we studied the ability of metergoline to antagonise the effect of DF, administered after a meal, on runway performance, food intake and gastric emptying assessed 4 h later. Metergoline at a dose of 1 mg/kg did not antagonise the effect of DF (2.5 mg/kg) on runway performance but completely blocked the effect on gastric emptying. The data clearly show that DF delays gastric emptying by indirectly activating 5-HT1 receptors; this effect is not important for the ability of DF to reduce runway performance and food intake when the drug is injected after a pre-feeding period. While there is evidence that DF hastens the termination of the meal by a 5-HT mechanism, the data suggest that DF may prolong the satiating effect of food during the post-absorptive phase by mechanisms other than 5-HT.

In previous work, we reported that chlorpromazine inhibits tumor necrosis factor (TNF) production in endotoxin lipopolysaccharide-treated mice, and protects against lipopolysaccharide toxicity. Chlorpromazine is used as an antipsychotic and has several effects on the central nervous system. It acts on different neurotransmitter receptors and has other biochemical activities some of which, like inhibition of phospholipase A2, might be responsible for the inhibitory effect on TNF production. To investigate the role of these actions in the inhibition of TNF production by chlorpromazine, we have synthesized some chlorpromazine derivatives that do not have central activities. Some of these analogs have lost their affinity for various receptors and their phospholipase A2 inhibitory activity, but still inhibit TNF production. No correlation was found between TNF inhibition and the ability to inhibit nitric oxide (NO) synthase, whereas a good correlation was evident between TNF inhibition and antioxidant activity.

6-Hydroxydopamine, given intraventricularly, did not affect the high concentrations of (+)-amphetamine present in the rat striatum and brainstem 1 h after its administration but considerably reduced the small amounts of (+)-amphetamine remaining after 5 h. In contrast, 5,6-dihydroxytryptamine did not modify the (+)-amphetamine concentrations at the times tested. These findings suggest that (+)-amphetamine might be stored in the catecholaminergic but not in serotonergic central terminals.

The effect of L-cysteine on the depletion of serotonin and 5-hydroxyindoleacetic acid concentrations caused by p-chloroamphetamine and d-fenfluramine was studied in various brain regions one week after drug injection. p-Chloroamphetamine (2.5 and 5 mg/kg i.p.) and d-fenfluramine (13.4 mg/kg i.p.) significantly reduced serotonin and 5-hydroxyindoleacetic acid levels in the striatum, hippocampus and cortex, particularly in the latter areas. L-cysteine (500 mg/kg i.p.), administered 30 min before and 5 h after p-chloroamphetamine or d-fenfluramine, significantly reduced the effect of either drug on the concentrations of both indoles without causing any effect by itself. In another experiment, the rats were treated as above and were killed at various times after p-chloroamphetamine or d-fenfluramine injection to determine, in parallel, the indole levels in the whole brain and concentration of p-chloroamphetamine, d-fenfluramine and its metabolite d-norfenfluramine in the plasma and brain. p-Chloroamphetamine and d-fenfluramine markedly lowered both indoles, particularly 16 and 24 h after injection. L-cysteine had no effect on the indole concentrations but significantly reduced the effect of p-chloroamphetamine and d-fenfluramine 16 and 24 h after injection. At these times, the brain concentrations of p-chloroamphetamine, d-fenfluramine and d-norfenfluramine were markedly lower in the L-cysteine-treated than in the control rats. Analysis of the blood concentration of p-chloroamphetamine, d-fenfluramine and d-norfenfluramine showed that the rats treated with L-cysteine eliminated the drugs studied more rapidly than the control animals. The results show that L-cysteine partially prevents the depletion of the brain content of serotonin and 5-hydroxyindoleacetic acid caused by p-chloroamphetamine and d-fenfluramine one week after drug administration. The fact that the effect of p-chloroamphetamine and d-fenfluramine seen at shorter times was associated with a marked reduction in the blood and brain drug concentration in the L-cysteine-treated animals suggests that the reduced availability of p-chloroamphetamine, d-fenfluramine and its active metabolite may be responsible for the partial prevention by L-cysteine of their neurochemical effects.

The uptake of imipramine- 14 C, desipramine- 14 C, amitriptyline- 14 C and chlorimipramine- 14 C was studied in rat isolated atria incubated in a medium containing concentrations of the drugs ranging from 10 −8 to 10 −5 M: the tissue levels were linearly related to the concentration in the incubation medium, the four lines sharing almost the same equation: accumulation appeared to be a passive unsaturable process for each drug. Desmethyldoxepin, desmethyl-chlorimipramine, nortriptyline were 4–5 times less potent than desipramine in inhibiting l- 3 H-noradrenaline uptake, while the tertiary amines (imipramine, amitriptyline, chlorimipramine and doxepin) were far less potent. Apart from desipramine, which showed some sympathomimetic activity, the main effect of the drugs was a slowing of the spontaneous atrial rate which was more evident for the dimethyl than for the monomethyl compounds. All drugs potentiated l-noradrenaline chronotropic response to varying degrees, but the potentiation of noradrenaline response was not always correlated with the inhibition of its uptake. Thus, inhibition of uptake is not a valid parameter for prediction of noradrenaline potentiation and vice versa. Drug tissue concentrations correlated with l- 3 H-noradrenaline uptake inhibition but not with potentiation of l-noradrenaline chronotropic response.

Various doses of fenfluramine isomers were compared for their ability to affect monoamine levels, metabolism and synthesis in the rat brain. d-Fenfluramine was more potent than 1-fenfluramin in reducing serotonin (5-HT) and 5-hydroxy-indoleacetic acid (5-HIAA) at 4 h after their administration. After decarboxylase inhibition, a low dose of d-fenfluramine (2.5 mg/kg) reduced 5-HT synthesis, assessed as 5-hydroxytryptophan (5-HTP) accumulation, in the hypotalamus and lower brain-stem only, whereas a higher dose (5 mg/kg) reduced 5-HT synthesis in all brain regions examined except the striatum. A higher dose of 1-fenfluramine (10 mg/kg) was required to reduce 5-HT synthesis. Metergoline, a 5-HT antagonist, did not modify the effects of fenfluramine isomers on 5-HT synthesis. One h after its administration 1-fenfluramine 5–20 mg/kg significantly increased brain 3-methoxy-4-hydroxyphenylethylene glycol sulfate (MHPG-SO4), striatal homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) levels, while after 4 h only the highest dose raised HVA levels. No change of striatal HVA and DOPAC levels was seen 1 or 4 h after any dose of d-fenfluramine while the highest dose raised brain MHPG-SO4 levels. Neither 1- nor d-fenfluramine changed striatal 3-methoxytyramine (3-MT) levels. The noradrenaline (NA) and dopamine (DA) levels were decreased 4 h after 10 and 20 mg/kg 1-fenfluramine or 20 mg/kg d-fenfluramine. The results show that the d- and l-isomers of fenfluramine at relatively low doses have a specific action on brain 5-HT and catecholamines, respectively. The effect of d-fenfluramine on brain 5-HT seems to be important for its anorectic activity while the functional outcome of the interaction of l-fenfluramine with catecholamines remains to be clarified.

I.p. administration of d-amphetamine sulphate and fenfluramine · HCl at various doses induced significant modifications of brain noradrenaline (NA) and MOPEG-SO4 (3-methoxy-4-hydrorxyphenylethyleneglycol) in the rat. Both drugs induced a decrease in brain noradrenaline but the two compounds seem to interact with the central noradrenergic system through a different mechanism. The decreased levels of noradrenaline after 1-fenfluramine administration were paralleled by increased MOPEG-SO4 levels. The d-isomer of fenfluramine was less active than the l-isomer. Amphetamine was considerably more effective than 1-fenfluramine in reducing NA concentration. However, in spite of the long lasting effect on noradrenaline levels the i.p. administration of amphetamine did not lead to an increased MOPEG-SO4 concentrations suggesting a more complex interaction with the noradrenergic system.

Nomifensine, at a dose of 10 mg/kg i.p., completely antagonized the decrease of brain dopamine induced by an intraventricular injection of 6-hydroxydopamine. The decrease of brain noradrenaline was also significantly antagonized by nomifensine. Desipramine antagonized the effect of 6-hydroxydopamine on noradrenaline but not on dopamine. The decrease of brain serotonin induced by fenfluramine was antagonized by chlorimipramine but not by nomifensine. The findings indicate that nomifensine specifically blocks the uptake mechanism for catecholamines in the brain without significant effects on serotonin.

Piribedil and its metabolite (pyrimidyl-2′)-1-(dihydroxy-3′,4′-benzyl)-4-piperazine dichlorhydrate (PdHBP), like apomorphine, decrease the level of HVa in the rat striatum. The effect appears rapidly and it lasts for about 2 hr. Piribedil antagonizes the rise of striatal HVA elicited by chlorpromazine, haloperidol and fenfluramine. Piribedil, PdHBP and apomorphine did not counteract the increase of striatal HVA induced by d-amphetamine.

The time course of [3H]spiperone distribution in the three major pools (specifically and non-specifically membrane-bound and soluble) of different brain areas, was studied in rats given a tracer amount of the drug. In addition, the stereospecificity, dissociation kinetics and pharmacological nature of the in vivo bound [3H]spiperone were investigated. The data show that [3H]spiperone binding sites in the striatum, olfactory tubercles and hypophysis differ clearly from those of the cortical regions. In the prevalently dopaminergic areas the amount of ligand bound to membranes is, up to 24 h post-treatment, proportional to the total 3H present. However a more correct analysis of the data was obtained in all the experiments when membrane-bound was measured instead of total radioactivity. Thus assay of the in vivo specifically bound [3H]spiperone appears essential for a correct evaluation of the density, affinity, regional distribution, pharmacological nature and kinetics of the drug-receptor interaction.

The evidence suggests that stimulation of brain noradrenergic neurons plays an inhibitory role in rat mouse-killing (muricidal) aggression. Anxiolytic benzodiazepines inhibit locus coeruleus activity and previous data showed that chlordiazepoxide was capable of antagonizing the locus coeruleus-mediated suppression of muricidal aggression. The present experiments showed that this effect is common to new anxiolytic triazolobenzodiazepines and to other non-benzodiazepine derivatives with anxiolytic activity. In this framework, 10 mg/kg of buspirone, of 1-pyrimidine-piperazine and of MJ-13805 proved to be as active as 2.5 mg/kg of alprazolam and as 5 mg/kg of chlordiazepoxide in inhibiting the locus coeruleus-mediated suppression of muricidal aggression.

Penfluridol is a long-lasting neuroleptic drug which accumulates in the adipose tissue of rats and mice. The concentration in this tissue, depending on the time, may be 50–100 times higher than in blood or in brain. Penfluridol does not selectively distribute in various brain areas of rats including hemispheres, striatum, diencephalon, mesencephalon and cerebellum. The concentration of penfluridol in rat brain necessary to exert significant anti-amphetamine activity is around 7 ng/g.

The effects of optical isomers of fenfluramine and their metabolites, d- and 1-norfenfluramine on the serotonergic system were studied in the nucleus accumbens and hippocampus of freely moving rats by in vivo voltammetry. Both isomers and the metabolites induced a slow, sustained decrease in 5HIAA but only d-fenfluramine and its metabolite, d-norfenfluramine, increased the 5HIAA levels in nucleus accumbens shortly after injection, the increase being greater after the metabolite. No effect could be detected in the hippocampus after the higher dose of d-fenfluramine.

Ipsapirone and gepirone, analogs of buspirone, a newly developed antianxiety agent, form 1-(2-pyrimidinyl)-piperazine (PmP) during their biotransformation in rats. After oral administration (10 mg/kg) of a parent drug, e.g. ipsapirone or gepirone, the metabolite appears in significant amounts in plasma, with maximal concentrations of 0.9 and 1.4 nmol/ml respectively. The metabolite half-life ranged from about 140 to 200 min. Ipsapirone is eliminated more slowly than gepirone, with a half-life of about 100 and 30 min, respectively. The metabolite to parent drug ratios for the areas under the plasma concentration-time curve (AUC) were 1 for ipsapirone and 14 for gepirone. PmP (0.5-2 mg/kg p.o), ipsapirone, gepirone and buspirone (5-20 mg/kg p.o.) dose dependently antagonized the slowing of gastrointestinal transit induced by clonidine 0.1 mg/kg s.c. The doses inhibiting the antitransit effect of clonidine by 50% were 0.8 mg/kg for PmP, 14 mg/kg for ipsapirone and 9 mg/kg for both gepirone and buspirone. Analysis of small intestinal longitudinal muscle of rats given the ED50 of PmP, ipsapirone, gepirone, buspirone showed that PmP concentrations in the longitudinal muscle (with attached myenteric plexus) fell within a relatively narrow range and were consistent with the appropriate transit scores. The plasma was also tested for anticlonidine activity. These data indicate that PmP formation is a pharmacologically significant metabolic process for the buspirone-related drugs, ipsapirone and gepirone, and that this metabolite is responsible for the alpha 2-adrenoceptor blocking activity exerted by these drugs in vivo in the rat.

p-Hydroxy-d-amphetamine (p-OHdA) penetrates the blood—brain barrier poorly, when given acutely or by repeated systemic treatments, or when formed by biotransformation from administered d-amphetamine. However its distribution is relatively selective as it accumulates in the striatum more than in the brainstem. The rate of disappearance also differs in the two areas, being slower in the striatum than in the brainstem. These findings suggest that p-OHdA might be stored in different compartments. To check whether p-OHdA specifically accumulated in nerve terminals, catecholaminergic nerve endings were destroyed with 6-hydroxydopamine (6-OHDA). It has been shown that p-OHdA accumulates much less in the striatum of 6-OHDA-treated rats than of controls. This effect was not present in the brainstem. Accumulation of p-OHdA was similar after repeated d-amphetamine administration. The results are interpreted as showing that p-OHdA tends to accumulate in dopaminergic structures.

Stimulation of the nucleus medianus of the midbrain raphe in rats caused an increase of 5-HT turnover in the forebrain without changes in the 5-HT turnover of the posterior part of the brain and of the spinal cord.

Electrical stimulation of MR in rats induces a marked increase of 5HIAA and a decrease of 5HT in the forebrain. At the same time the onset of electroencephalographic pattern of sleep and behavioral signs of calmness were observed. The most intense biochemical effects were obtained with 10 c/sec stimulation whereas 2 c/sec stimulation produced the clearest behavioral depression. 5HT Midbrain raphe 5HIAA Electroencephalographic changes Behavior Sleep pattern Electrical stimulation

Brain concentrations of acetylcholine and choline were measured within 5–30 min after an i.p. injection of central stimulant or depressant drugs. The acetylcholine concentration in whole mouse brain of controls was 2.35 ± 0.06 μ g/g wet wt. (16.1 nmol/g wet wt.) while the choline concentration was 6.52 ± 0.21 μ g/g wet wt. (62.7 nmol/g). Physostigmine, 0.5 mg/kg, oxotremorine, 2 mg/kg free base, and haloperidol, 4 and 8 mg/kg, increased both acetylcholine and choline 20 min after administration. Pentobarbital, 55 mg/kg, and diazepam, 5–40 mg/kg, increased only acetylcholine without affecting choline. Atropine, 50 mg/kg, lowered acetylcholine without affecting choline. Haloperidol, 1 mg/kg, chlorpromazine, 10 mg/kg, reserpine, 2.5 mg/kg, 20 hr, desmethylimipramine, 20 mg/kg, and amphetamine, 7 and 15 mg/kg, had no effect on either acetylcholine or choline. No drug studied caused a simultaneous decrease in these two quaternary amines. The possible significance of these findings on the mechanism of action of these drugs is discussed.

The typical symptomatology induced by amphetamine in laboratory animals is dependent not only on the species but also on the strain of the animals employed in the experiments. In different strains of mice the hyperthermic response and the lethality to amphetamine showed extreme variations, from more sensitive strains (Albino Swiss) to more resistant strains (C 57 B1/6 and C 3 H). d-Amphetamine toxicity Brain and liver amphetamine Different mice strains

Desipramine increases the sensitivity of the isolated tail artery of the rat to extraluminal noradrenaline much more than to intraluminal noradrenaline. Accumulation of radioactivity after infusions with dl -7- 3 H-noradrenaline is inhibited when noradrenaline is given by the extraluminal route and is unaffected when noradrenaline is given into the lumen.

The metabolic pathways by which diazepam and its metabolites are transformed in vitro by rat and mouse liver microsomes were studied in detail. Using a gas chromatographic technique to measure benzodiazepines, it was demonstrated that the predominant reactions were N-demethylation in rat liver microsomes and C 3 hydroxylation in mouse liver microsomes. When N-demethyldiazepam or N-methyloxazepam was used as a substrate there was a clear formation of oxazepam. No exazepam was found in vitro when diazepam was incubated with liver microsomes. Some preliminary data indicate that the presence of diazepam inhibits the further hydroxylation of N-demethyldiazepam and the N-demethylation of N-methyloxazepam.

The 7-nitro group of nitrazepam (1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one) was reduced to the 7-amino derivative and then acetylated to the 7-acetylamino derivative during perfusion of the isolated rat liver. These compounds were present mainly in perfusion fluid, only small amounts were found in bile or liver tissue, homogenized at the end of the experiment. Other metabolites were not detected with the techniques used. Similar results were found with livers of guinea-pigs and rabbits. In contrast, the 7-amino derivative was the final product of nitrazepam metabolism in perfused mouse livers.

The anticonvulsant activity of diazepam lasts longer in mice than in rats. The brain levels of diazepam are similar in both species but N-demethyl diazepam and oxazepam accumulate in mouse brain while they are practically undetectable in rat brain. This difference occurs also in blood and adipose tissue. N-methyloxazepam was not detected in rats or mice after an intravenous administration of diazepam. It is suggested that the N-methyl diazepam and oxazepam formed in mice may be responsible for the prolonged anticonvulsant action of diazepam in this species.

Diazepam showed an antimetrazol activity which was longer-lasting in mice than in rats. The levels of diazepam in blood and brain were similar in both species but N-desmethyl metabolites ofdiazepam accumulated in mouse brain while they were practically undetectable in rat brain. The three main metabolites of diazepam, namely N-methyloxazepam, N-desmethyldiazepam and oxazepam showed strong anticonvulsant activity in mice.

A comparative study has been made of the action of 3-methyl salicylic acid, a derivative which has a much longer half-life than salicylic acid in man, on free fatty acid mobilisation and plasma cholesterol in the rat, rabbit, baboon and man. 3-Methyl salicylic acid decreased plasma free fatty acids in rats exposed to conditions of increased mobilisation, such as fasting, cold, and treatment with noradrenaline and ACTH. Evidence was obtained that a dose equivalent to salicylic acid given shortly before test was more effective. As for salicylate, 3-methyl salicylate decreased the in vitro production of FFA and glycerol liberated in vitro by the incubated rat epididymal fat pad. Administration of 3-methyl salicylic acid (100 mg/kg, body weight) reduced plasma cholesterol from 7 to 45% in baboons given an atherogenic, cholesterol-containing diet for one month. In acute experiments, the drug caused a marked choleresis in which the volume and excretion of bile acids but not cholesterol was increased. In the rabbit, the drug (100 mg/kg) caused a decrease in fasting FFA for up to four hours, followed by a large elevation. Inclusion of the drug in the diet of animals given a semi-synthetic diet of low cholesterol content did not reduce hypercholesterolaemia or the extent and severity of atherosclerotic lesions in the aorta. Administration of 0.9 g orally to fasting patients caused a 50% reduction in elevated plasma FFA after four hours and even after twelve hours the values were still subnormal. A double-blind control trial of nine hypercholesterolaemic and eight normal patients was conducted over twelve to eighteen months. Subjects in the hypercholesterolaemic group on chronic dosage (0.9–1.8 g per day) showed a fall of 25% in the mean plasma cholesterol, but there was no change in normal patients. Side effects, the chief of which were drowsiness and vomiting precluded the use of 3-methyl salicylate as a therapeutic agent in man.

Peak plasma phenylbutazone levels were reached 1–2 hr after the oral administration of phenylbutazone (40 mg/kg) to rats. Pretreatment with desipramine (DMI, 15 mg/kg) 1 hr before the oral administration of phenylbutazone resulted in a marked decrease in plasma phenylbutazone levels. Phenylbutazone and oxyphenylbutazone levels in 24 hr urine samples of DMI pretreated animals were lower than in controls. The stomach of DMI pretreated rats contained about 4 times more phenylbutazone than controls 4 hr after the oral administration of phenylbutazone while the values were similar after 14 hr. Intestinal contents of phenylbutazone were about 4 times higher in DMI pretreated animals even 14 hr after the oral administration of phenylbutazone. Pretreatment with DMI had no effect on the plasma levels of orally administered amphetamine (15 mg/kg) or pentobarbital (30 mg/kg) while plasma levels of orally administered oxyphenylbutazone (15 mg/kg), hydrocortisone (50 mg/kg) and salicylate (200 mg/kg) were lowered. The possibility that DMI inhibits the absorption of some orally administered drugs by relaxing gastro-intestinal smooth muscle is discussed.

Eucalyptol (1,8-cineole) given by aerosol for 4 days to rats decreases the plasma and/or brain levels of amphetamine, zoxazolamine, pentobarbital and aminopyrine given 24 hr after the last aerosol. However, the levels of plasma phenylbutazone were not affected by previous treatment with eucalyptol (1,8-cineole). Eucalyptol (1,8-cineole) pretreatment increases the rate of disappearance of plasma aminopyrine and the rate of urinary excretion of 4-aminoantipyrine, a metabolite of aminopyrine. This effect may be due to the increased rate of formation of 4-aminoantipyrine. The disappearance of aminopyrine from plasma was enhanced in 4 out of 5 volunteers submitted for 10 days to treatment with eucalyptol (1,8-cineole) aerosol.

The solvents decreased the reduction rate of nitrazepam by rat liver homogenate; the lowest interference was observed with ethanol. High concentrations of nicotinamide used in media for nitroreductase determination lowered enzyme activity. Reduction of nitrazepam to 7-amino derivative decreased during the preservation of liver centrifugal fractions in 1.15% KCl at 0°C. The highest enzyme activity was found in rat liver, followed by the activity of kidney, heart, lung, skeletal muscle and spleen preparations. The substance was not reduced in brain. The Michaelis constants Km of nitrazepam reduction did not differ substantially, being of the same order of 10−4M in preparations from rat, mouse, rabbit and guinea pig liver. The maximal velocities of the reduction Vmax were 10−6moles per hour per 1 g of liver tissue. Chlorpromazine, diazepam and imipramine influenced the reduction only in high concentrations. EDTA, cysteine and ascorbic acid did not change substantially the enzyme activity. KCN was a strong non-competitive inhibitor (Ki = 10−4 M of the nitrazepam reduction.

Rats were treated with a combination of imipramine (IMI) and desipramine (DMI). Tissue concentrations of the drugs were determined at various times and compared with the levels obtained after treatment with either IMI or DMI alone. Brain concentrations of IMI increased when rats were pretreated with DMI. The concentrations of brain and plasma DMI were higher than the sum of the concentrations attained after addition of DMI and IMI separately. However, the rates of removal of IMI from the brain were similar after single or combined treatment. The results are examined in view of the favorable effects obtained in clinical trials with combinations of these antidepressent drugs.

Albino Swiss, C 3 H and C 57 B1/6 mice differ in their sensitivity to the action of dexamphetamine on brain catecholamines. Triiodothyronine pretreatment induces noradrenaline and dopamine decrease in brain of C 3 H and C 57 B1/6 mice otherwise not sensitive to dexamphetamine administration.

The effect of DMI on the absorption of orally administered phenylutazone was studied in human subjects. A single pretreatment with 50 mg of DMI delayed the time to peak absorption of phenylbutazone in 4 volunteer subjects. Peak phenylbutazone plasma levels in untreated subjects were reached 2–6 hr after oral phenylbutazone administration while peaks were not attained even 10 hr after DMI treatment. A seven-day chronic pretreatment with DMI (25 mg, 3 X day) delayed time to peak absorption of phenylbutazone in 4 chronically depressed females from 2 hr (before DMI) to 4–10 hr when phenylbutazone was administered 30 min after the last dose of DMI. When phenylbutazone was given 14 hr after the last dose of a ten-day chronic treatment with DMI (25 mg, 3 X day) to another group of 4 females, no clear effect on the time to peak absorption was observed although plasma levels of phenylbutazone were lower in all 4 patients. The individual differences in phenylbutazone plasma levels may be due to individual variations in the metabolism of DMI.

I.p. administration of piribedil methansulphonate to male Sprague-Dawley rats resulted in a remarkable increase of brain MOPEG-SO4 which was consistent over time. In parallel experiments brain content of NA was found significantly reduced 30 and 60 min after drug administration. The effect seems to be dose dependent. These data cast some doubts on the relative specificity of action of piribedil as a dopaminergic activator.

An intraventricular injection of 6-hydroxydopamine to rats pretreated with pargyline, a procedure which produces a marked decrease of brain catecholamines without significant changes in the serotonin levels, significantly antagonizes the anorectic effect of amphetamine, phentermine, mazindol and diethylpropion, while the reduction of food intake induced by other drugs such as fenfluramine, p-chloroamphetamine, SE 780 and SKF 1-39728 is not significantly affected. The data suggest and involvement of brain catecholamines in the anorectic effect of amphetamine, phentermine, mazindol and diethylpropion whereas other mechanisms appear to be involved in the activity of the other anorectics studied.

A gas chromatographic method for the determination of metrazol in the brain after the administration of this convulsant drug in rats and mice is presented. The peak levels of brain metrazol were reached at the same time in both species, but they were lower and declined faster in mice than in rats, after comparable doses of injected metrazol. The threshold for convulsions was different in the two animal species; in rats it was approximately 45 μg of metrazol per g of brain and in mice approximately 37 μg/g.

The test of aggressiveness in mice caused by prolonged isolation was employed to evaluate the possible anti-aggressive activity of a number of centrally active drugs. A score to evaluate the intensity of aggressive behavior is described.

A single i.v. dose of diazepam, 5 mg/kg, increased mouse whole brain acetylcholine levels. Choline levels, choline acetyltransferase and acetylcholinesterase activities were not affected, which is consistent with the hypothesis that diazepam blocks release of acetylcholine. Diazepam increased acetylcholine levels in the hemispheres and diencephalon but not in the cerebellum or mesencephalon. The effect lasted for 4 hr in the hemispheres and for 30 min in the diencephalon. This short-lastig biochemical action precludes a correlation with the long-lasting action of diazepam against pentylenetetrazole.

Low-molecular weight dialysable peptides, obtained by plasmin degradation of purified bovine fibrinogen preparations, have been shown to increase the chronotropic activity of isolated rat atria. This effect was dose dependent and was inhibited by inhibitors of glycolysis (NaF and 2-deoxy-D-glucose), but not by an inhibitor of oxidative phosphorylation (2, 4-dinitrophenol). Propranolol, a beta-blocking agent, was also ineffective. Fibrinogen-derived peptides increased both cAMP levels and phosphorylase alpha activity in stimulated atria. The increase of these parameters was transitory and appeared to precede the occurrence of the positive chronotropic effect. In the test situation used, the biochemical and functional modifications induced by fibrinogen-derived peptides were similar to those induced by glucagon.

The effect of 1-(2-pyrimidinyl)-piperazine (PmP) and the parent drug, buspirone in counteracting the behavioral and biochemical effects of clonidine were evaluated in the rat. Intraperitoneal or oral administration of PmP, buspirone and yohimbine, but not of prazosin, antagonized the slowing of gastrointestinal motility induced by subcutaneous clonidine (0.1 mg/kg). The does that inhibited the effect of clonidine on the transit time by 50% were 0.5 mg/kg i.p. and 0.7 mg/kg p.o. for PmP, 7 mg/kg i.p. and 9 mg/kg p.o. for buspirone and 0.5 mg/kg i.p. for yohimbine. PmP (0.5 mg/kg) did not block the antitransit effect of clonidine when administered by intracerebroventricular injection. The antitransit effect of a low dose of morphine (0.05 mg/kg i.p.) was not blocked by PmP (2 mg/kg i.p.). The prolongation of the hexobarbital-induced loss of the righting reflex that occurs after clonidine (0.25 mg/kg i.p.) administration was inhibited by pretreatment with PmP (0.1–2 mg/kg p.o.) or yohimbine (1 mg/kg i.p.) but not by pretreatment with prazosin (2 mg/kg i.p.). Buspirone (1–20 mg/kg) also reduced the effect of clonidine after oral administration, with a maximal effect at 5 mg/kg, whereas the same dose administered i.v. had less effect. PmP (2 mg/kg) and buspirone (15 mg/kg) raised the levels of total 3-methoxy-4-hydroxyphenylgycol (MHPG) in rat cerebral cortex, and prevented the decrease in MHPG induced by clonidine. These findings show that buspirone, in doses at which it is active as an anxiolytic, suppresses the central and peripheral effects of clonidine. This action occurs through α 2 -adrenoceptors and is mediated primarily by the metabolite, PmP.

Apomorphine-induced stereotyped behavior and apomorphine levels in plasma, striatum and nucleus accumbens were determined in rats at various intervals after a single i.p. injection of serial doses of apomorphine hydrochloride (0.625, 1.25, 2.5 and 5 mg/kg). Apomorphine disappeared from plasma in a mono-exponential mode with a half-life of about 10 min. In striatum and nucleus accumbens apomorphine concentrations peaked 10 min after administration, declining thereafter with a half-life comparable to that in plasma. Apomorphine was concentrated and distributed similarly in the two brain regions; the brain areas/plasma ratio was approximately seven for all doses tested. The rise of apomorphine levels in brain areas slightly preceded the behavioral response, whereas after the peak effect (20-30 min) the intensity of stereotypy declined almost parallel with the log drug concentrations. Plotting apomorphine levels in the tissues assayed against the drug response at the same interval for individual rats, regardless of dose, indicated a highly significant relation between the degree of behavioral effects and brain apomorphine levels. The threshold apomorphine concentrations for inducing stereotyped behaviour were 108 and 95 ng/g respectively in striatum and nucleus accumbens. These findings show that the time course and magnitude of the behavioral effects of apomorphine corresponded with its brain levels in 'dopaminergic' areas, suggesting that apomorphine-induced stereotyped behavior in rats can be described by a direct mechanism. Reserpine (5 mg/kg s.c.) enhanced the apomorphine stereotypy but did not affect apomorphine's disposition in brain and plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

Nomifensine, at a dose of 40 mg/kg, slightly but significantly increased rat striatal acetylcholine 60 min after i.p. administration without affecting choline levels or choline O-acetyltransferase and cholinesterase activities. This drug had no effect on brainstem acetylcholine. In contrast, d-amphetamine and desipramine both produced a small but significant increase in brainstem acetylcholine. It is suggested that nomifensine increased striatal acetylcholine indirectly through blockade of dopamine uptake.

Experiments were carried out to gain additional evidence that l-fenfluramine reduces the dopamine-mediated effects in intact animals. l-Fenfluramine 5 and 10 mg/kg i.p. dose dependently raised the levels of homovanillic acid in the striatum and nucleus accumbens of rats 1 h after injection. The effect of 5 mg/kg l-fenfluramine disappeared and was actually reversed 4 and 8 h after injection. The effect of 10 mg/kg l-fenfluramine, administered 48 h after the last haloperidol dose, was completely antagonized in both striatum and nucleus accumbens of animals made tolerant to the effect of haloperidol on homovanillic acid levels (through repeated treatment with 1 mg/kg haloperidol i.p. twice daily for 11 days). Unlike haloperidol (0.25 mg/kg), l-fenfluramine in various doses (2.5-20 mg/kg i.p.) did not modify the levels of striatal 3-methoxytyramine or change the decrease induced by a s.c. injection of 0.5 mg/kg apomorphine. The effect of apomorphine was not antagonized by 10 or 20 mg/kg l-norfenfluramine, an active metabolite of l-fenfluramine but 20 mg/kg l-norfenfluramine significantly raised striatal 3-methoxytyramine levels. l-Fenfluramine 20 mg/kg (but not 10 mg/kg) significantly enhanced the output of striatal acetylcholine assessed by trans-striatal microdialysis, for 60 min after injection. Apomorphine 1 mg/kg i.p. completely antagonized the increase of acetylcholine caused by 1 mg/kg haloperidol or 20 mg/kg l-fenfluramine. The results confirm that the l isomer of fenfluramine produces effects on the responses to dopamine and acetylcholine similar to those of neuroleptics by a mechanism not involving direct blockade of receptors.

The interaction of mazindol and d-amphetamine with brain monoamines was studied in rats. At each dose used, both compounds markedly counteracted the decrease of brain noradrenaline induced by 6-hydroxydopamine while only at high doses they did significantly reduce the effect of 6-hydroxydopamine on brain dopamine. Unlike d-amphetamine, mazindol significantly counteracted the decrease of brain serotonin induced by fenfluramine. The anorectic effect of mazindol and of d-amphetamine was markedly reduced by an electrolytic lesion at the level of the ventral noradrenergic bundle but not by an electrolytic lesion of the nucleus raphe medianus. An intrastriatal injection of 6-hydroxydopamine significantly reduced the effect of mazindol but not that of d-amphetamine. The results indicate that both compounds may block noradrenaline uptake in the brain while their effect on dopamine uptake is less evident. Ulike d-amphetamine, mazindol appears to inhibit serotonin uptake also. In addition, the integrity of the noradrenergic neurons in the brain appears to be an important condition for these drugs to exert their anorectic effect.

Fenfluramine decreased plasma triglycerides in fed rats but not in fasted rats. When this compound was administered to rats in a post-absorptive state, a diminution in lymphatic flow and in triglyceride concentration was observed. Moreover, pretreatment with fenfluramine inhibited a rise in plasma and lymph triglycerides, normally found after an olive oil load. No alterations were noted in the flow rate and density of bile. The motility of the small intestine was decreased. These data suggest that the lowering of plasma triglycerides, elicited by fenfluramine, is at least partially due to inhibition of the intestianal absorption of triglycerides.

Lesions of the midbrain raphe in rats produced a marked decrease of 5-HT and 5-HIAA levels in the forebrain. An increase of spontaneous motor activity and an onset of signs of abnormal behaviour were observed. A good correlation has been found between the intensity of behavioural excitation and the decrease of 5-HT and 5-HIAA in the forebrain. Bioelectrical investigations of frontal cortical activity showed a persistent arousal in EEG pattern.

Imipramine, 5 mg/kg, i.p., completely blocked the forebrain 5-HIAA increase in rats that have undergone midbrain raphe stimulation whereas desipramine, 5 mg/kg, i.p., did not. This finding is compatible with the hypothesis that imipramine can block selectively the membrane uptake of serotonin in the central serotoninergic neurons.

Measurements of reserpine in the brain of normal and tetrabenazine-pretreated rats supply direct evidence in favor of the view that these drugs compete at the level of a common target. In addition the results of the present drug interaction study underline the relevance of the long-lasting concentrations of reserpine in the brain for explaining the functional modifications induced by its administration.