Binding characteristics of [3H]quinupramine to rat brain membrane fractions.
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The binding characteristics of [3H]quinupramine to rat brain membrane fractions were studied. The specific binding of [3H]quinupramine to rat brain membrane fractions was stable, reversible and saturable. Scatchard analysis of the data from saturation experiments indicated that the specific binding was a single population with an affinity (KD) of 3.04 nM, a maximal binding site number (Bmax) of 714 fmol/mg protein, and a Hill coefficient (nH) of 1.08. Compounds known to inhibit muscarinic cholinergic receptors such as atropine and quinuclidinyl benzilate were the most potent competitors of [3H]quinupramine binding. When the drug potencies in inhibiting [3H]quinupramine binding were tested in the presence of 10 nM atropine, mianserin was the most potent competitor. Studies of the subcellular fractions showed that there was an enrichment of [3H]quinupramine binding sites in the synaptosome fraction. The regional distribution study revealed the highest densities of binding sites in the cerebral cortex and the lowest in the cerebellum. Thus, the specific binding of [3H]quinupramine observed here can be accounted for by both muscarinic cholinergic and serotonin S2 receptors. (+info)
Toxic "ictal" confusion in middle age: treatment with benzodiazepines.
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In adult and elderly non-epileptic subjects psychoactive drugs may cause an altered state of consciousness and repetitive irritative EEG discharges. The neurotoxic pathogenesis of this drug-induced confusion and the differentiation from absence status are discussed. Dramatic relief by intravenous benzodiazepines is detailed. Recovery is complete and prognosis is excellent on withdrawal of the offending drug. (+info)
Possible mechanisms by which repeated clozapine administration differentially affects the activity of two subpopulations of midbrain dopamine neurons.
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Extracellular single-cell recording techniques were employed to study the mechanism of action of repeated oral clozapine administration on the in vivo spontaneous activity of substantia nigra (A9) and ventral tegmental area (A10) dopamine (DA)-containing neurons in the rat. Clozapine was observed to affect DA neurons differentially within these two regions when compared to haloperidol. Acute treatment (1 hr) with both drugs increased the number of spontaneously firing neurons in both A9 and A10. Chronic (21 day) treatment with haloperidol decreased the number of cells encountered in both regions, whereas repeated treatment with clozapine reduced the number of DA cells per track only in A10. In all cases, the silent DA neurons were inferred to be in a state of depolarization inactivation since they could be induced to discharge normally by the microiontophoretic application of the inhibitory neurotransmitter gamma-aminobutyric acid. These effects were not due to an effect of chloral hydrate anesthesia since they were also observed in gallamine-paralyzed, artificially respired animals. Chronic co-administration with haloperidol of either an anticholinergic (trihexyphenidyl) or the alpha 1-norepinephrine (NE) receptor antagonist, prazosin, but not an alpha 2-NE antagonist, RX781094, resulted in a differential effect on A9 and A10 DA neurons identical to that observed with repeated clozapine administration alone. Thus, chronic treatment with these combinations of drugs resulted in the depolarization inactivation of only A10 cells. These data suggest that anticholinergic and/or alpha 1-NE-blocking properties of clozapine may, in part, mediate its differential effects on A9 and A10 midbrain DA neurons. (+info)
Effects of chronic administration of amitriptyline or mianserin on rat cardiac and central adrenoceptors.
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Rats were administered either amitriptyline (20 mg kg-1, i.p.) or mianserin (10 mg kg-1, i.p.) for 21 consecutive days and the alpha- and beta-adrenoceptor characteristics of cardiac ventricles, cerebral cortex and hippocampus examined by ligand-binding procedure. Chronic administration of amitriptyline significantly reduced the maximum density of beta-receptors in the cerebral cortex without significantly altering cardiac alpha- or beta-receptors; mianserin treatment had no significant effect on any of the receptors studied. (+info)
Down-regulation of central serotonin S2 receptors after repeated treatment with quinupramine in rats.
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The present studies were undertaken to determine whether the repeated administration of quinupramine caused down- or up-regulation of beta-, alpha 2-adrenergic, serotonin S2, imipramine and muscarinic cholinergic receptors, as had been demonstrated for tricyclic and atypical antidepressant drugs. Quinupramine administered at 10 mg/kg (p.o.) twice daily for 10 days caused a down-regulation of serotonin S2 receptors in the frontal cortex of the rat as determined by [3H]ketanserin binding. However, quinupramine did not alter the binding populations of beta-adrenergic, muscarinic cholinergic and alpha 2-adrenergic receptors in the rat brain as determined by the Scatchard analysis of the [3H]ligand binding data. Differing from quinupramine, imipramine caused down-regulation of beta-adrenergic and serotonin S2 receptor bindings, and it caused slight but significant up-regulation of muscarinic cholinergic receptor bindings. These results show that the antidepressant activity of quinupramine is associated with the central serotonin system, but not with the beta-adrenergic system. Accordingly, quinupramine, chemically one of the typical tricyclic antidepressant drugs, seems to be pharmacologically one of the atypical antidepressant drugs, and it was suggested that the central serotonin system plays an important role in the antidepressant activity of quinupramine. (+info)
Uptake and release of 5-hydroxytryptamine by enteric 5-hydroxytryptaminergic neurones: effects of fluoxetine (Lilly 110140) and chlorimipramine.
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The effect of fluoxetine on uptake of 5-hydroxytryptamine (5-HT) by enteric 5-hydroxytryptaminergic neurones has been analyzed in order to compare further these neurones with 5-HT neurones of the CNS. In addition, the effects of fluoxetine and chlorimipramine on efflux of [3H]-5-HT from the myenteric plexus were also evaluated. Fluoxetine was found to be a competitive inhibitor of 5-HT uptake by the myenteric plexus and was a more potent inhibitor of 5-HT uptake than was chlorimipramine. However, chlorimipramine enhanced the efflux of [3H]-5-HT more than could be explained by inhibition of 5-HT uptake and, therefore, appears to have the additional action of releasing the amine. These observations, similar to those of others studying central neurones, support the view that enteric 5-HT neurones resemble those of the CNS and are a useful model for the evaluation of drugs. (+info)
The abnormal open-field behavior of SART-stressed rats and effects of some drugs on it.
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As part of an investigation on the behavioral characteristics of SART-stressed animals, an animal model of autonomic imbalance, the open-field behavior of SART-stressed (repeated cold-stressed) rats was studied and compared with that of rats exposed to other types of stress. In addition, the effects of several drugs on it were also studied. As compared with normal rats, SART-stressed rats exhibited increased locomotor activity, rearing and center-field penetration, together with decreased grooming and increased defecation, whereas they showed no significant changes in spontaneous movements in the daytime as measured by an Animex activity meter. These behavioral abnormalities were remarkably different from those due to 1-hr cold, 48-hr cold and repeated restraint stresses. These abnormal forms of open-field behavior due to SART stress were considerably inhibited by chlorpromazine, imipramine and neurotropin at doses having no corresponding influence on normal rats; and they were partially inhibited by alprazolam, diazepam and carpipramine at doses exerting considerable influence on normal rats. The above results show that SART-stressed rats exhibit open-field behavioral abnormalities that are different from those of rats exposed to other types of stress. Such abnormalities include excessive activity, which is considered to be caused by excessive emotionality. (+info)
Controlled study comparing nomifensine and clomipramine in unipolar depression, using the probenecid technique.
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1. Central dopamine turnover may be lowered in patients with unipolar endogenous depression particularly when associated with retardation. 2. Nomifensine selectively activates the central dopaminergic system and may be of special therapeutic value in patients with motor inhibition. 3. A double-blind comparison of clomipramine and nomifensine was carried out in patients with recurrent unipolar depression. Biochemical and clinical assessments were carried out weekly for 4 weeks. 4. The mean homovanillic acid level in cisternal liquor of those patients who responded to nomifensine, was significantly lower than the mean level of the total group. 5. The factor "retardation" on the Hamilton Depression Scale was improved more with nomifensine than with clomipramine. (+info)