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At least 145 records · Page 8Linked to original sources
PubMed1996

Additive effects of glyburide and antidepressants in the forced swimming test: evidence for the involvement of potassium channel blockade.

Evidence in the literature suggests that the modulatory effects of antidepressant drugs (ADS) on neuronal excitability, via the inhibition of K+ channels, may be the final common pathway of pharmacological action. Therefore, we tested the hypothesis that combining the ATP-sensitive K+ channel blocker glyburide with a variety of ADS would produce an additive effect and decrease the immobility time of mice in the forced swimming test (FST). Glyburide (GLY, IP, 30 and 50 mg/kg) and subactive doses of ADS were administered 45 and 30 min, respectively, prior to behavioral testing. Results showed that when combined with GLY, ADS whose main pharmacological effect is one of 5-HT uptake blockade (imipramine, amitriptyline, citalopram, paroxetine, fluoxetine, and fluvoxamine) were more effective in decreasing the amount of time mice were immobile, than when these drugs were administered alone. Some noradrenaline uptake inhibiting ADS (desipramine and viloxazine, but not maprotiline) were also significantly more effective in decreasing immobility time when combined with GLY than when administered alone. Pretreatment with GLY was found to have no effect on the dopamine uptake inhibitor bupropion, and out of the atypical ADS tested (trazodone, mianserine and iprindole), only coadministration with iprindole decreased the immobility time. Only the specific MAO-A inhibitor moclobemide was observed to have an antiimmobility effect when combined with GLY. Neither MAO-B specific (RO 16 6491) nor mixed MAO inhibitors (nialamide and pargyline) interacted with GLY to produce antiimmobility effects. These results corroborate and extend our previous report of the ADS enhancing effects of quinine in the same behavioral model, and suggest that the additive effects of quinine and GLY on ADS in FST are a result of K+ channel blockade.

Animals↗
PubMed1988

The influence of brain catecholamines on 'drug taking behaviour' relative to oral self-administration of d-amphetamine by rats.

Oral administration of 5 mg/kg of d-amphetamine to adult Wistar rats caused brain NE to decrease to approx. 80% of the control level during 4-24 h after acute treatment and slowly further to 65% after 24 days of self-administration via drinking water. The norepinephrine (NE)-reducing effect was first recognized at 1 mg/kg and appeared to peak at 5 mg/kg of d-amphetamine. Brain dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were only shortly affected. Neither iprindole nor desipramine altered the effect of amphetamine on brain NE. DA was decreased by both inhibitors depending on the duration of pre-treatment. Iproniazid and alpha-methyl-p-tyrosine antagonized and potentiated respectively the amphetamine effect on NE- and DA-concentration after 4 days of simultaneous treatment. In the free choice experiment (water vs. 0.005% d-amphetamine solution) rats developed an aversion to amphetamine. The number of rats taking the drug and the consumption by rats still drinking it declined gradually from 100% and approx. 3 mg/kg/day to 50% and approx. 1.5 mg/kg/day, respectively, during 18 days. The time course of the developing aversive reaction to oral amphetamine ran approximately parallel to that of NE-depletion. Iprindole and desipramine intensified, iproniazid and propranolol weakened, while alpha-methyl-p-tyrosine and haloperidol hardly influenced the aversive effect of amphetamine. It is concluded that the development of aversive behaviour in response to oral d-amphetamine is mediated not only through the depleting effect of amphetamine on NE stores but also by its direct stimulation at beta-adrenergic receptors in the CNS.

Administration, Oral↗
PubMed1984

Presynaptic alpha 2- and postsynaptic beta-adrenoceptor sensitivity in slices of rat neocortex after chronic treatment with various antidepressant drugs.

The effect of chronic (4 weeks) treatment of rats with the antidepressant drugs desipramine, maprotiline, chlorimipramine, zimelidine or iprindol on the sensitivity of presynaptic alpha 2- and postsynaptic beta-adrenoceptors in neocortical slices was investigated. Acute (1 day) treatment with the antidepressants did not affect the efflux of cyclic-AMP induced by isoprenaline (1 microM) from neocortical slices, while after chronic treatment the efflux of cyclic AMP was consistently reduced. Following acute administration the electrically-evoked release of [3H]noradrenaline (NA) from radiolabelled cortical slices remained unchanged. Upon chronic treatment with desipramine the release of [3H]NA was enhanced by about 45%. In contrast, after chronic treatment with maprotiline or chlorimipramine the electrically-evoked release of [3H]NA was not affected, whereas release was even slightly reduced after chronic administration of zimelidine or iprindol. In all cases, however, a similar inhibitory effect of exogenous NA (0.1 microM) on the release of [3H]NA was found. These data indicate that the desensitization of postsynaptic beta-adrenoceptors in rat brain after chronic treatment with antidepressant drugs is not paralleled by a reduction of presynaptic alpha 2-adrenoceptor sensitivity.

Adrenergic alpha-Antagonists↗
PubMed1997

Effects of pretreatment with clonidine, lithium and quinine on the activities of antidepressant drugs in the mouse tail suspension test.

The aim of the present study was the investigation of pretreatment effects with clonidine (0.06 mg/kg, intraperitoneal [i.p.]), lithium (1 mEq, i.p.) or quinine (0.5 mg/kg, i.p.) on the activities of various drugs acting on noradrenergic and/or serotonergic systems in the mouse tail suspension test. Drugs used in the present study included: the tricyclic antidepressants imipramine and dothiepin, the heterocyclic antidepressant trazodone, the 5-HT reuptake inhibitor (SSRI) fluoxetine, the atypical antidepressants mianserin and iprindole, the 5-HT1A receptor agonist ipsapirone, the 5-HT2A/2C receptor antagonist ritanserin, and the 5-HT3 receptor antagonist ondansetron. Clonidine, lithium and quinine differentially enhanced the effects of several psychotropic/drugs administered at sub-active doses. The activity of iprindole (32 mg/kg, i.p.) was not potentiated by pretreatment with clonidine, lithium or quinine. Our results suggest that lithium exerted additive effects via postsynaptic 5-HT1A receptor activation, quinine via potassium ion channel blockade of 5-HT3 receptors, while clonidine did so primarily via action at 5-HT2 receptors.

Animals↗
PubMed1973

Effect of centrally acting drugs on the uptake of gamma-aminobutyric acid (GABA) by slices of rat cerebral cortex.

1. The effects of centrally acting drugs on the uptake of (3)H-gamma-aminobutyric acid (GABA) by slices of rat cerebral cortex have been studied.2. Many centrally acting drugs at concentrations of 0.1-1.0 mM significantly inhibited the uptake of (3)H-GABA by cortical slices, but the only classes of drugs in which all members consistently produced inhibition of uptake were the phenothiazines, tricyclic antidepressants, and butyrophenones.3. The receptor blocking drugs; phentolamine, propranolol, thymoxamine, mepyramine, and diphenhydramine at concentrations of 0.5-1 mM also significantly reduced the uptake of (3)H-GABA. However, atropine, hexamethonium and (+)-tubocurarine had little effect on the uptake of (3)H-GABA by cortical slices.4. Centrally acting drugs, which did not significantly inhibit (3)H-GABA uptake, included barbiturates, local anaesthetics, hallucinogens, monoamine oxidase inhibitors, anticonvulsants, and convulsants (except picrotoxin).5. Chlorpromazine, prochlorperazine, L-2,4,diaminobutyric acid, desmethylimipramine, and iprindole inhibited the uptake of (3)H-GABA by 50% (IC50) at concentrations of 30-100 muM. The most potent inhibitor of (3)H-GABA uptake was p-chloromercuriphenylsulphonate (IC50 = 18 muM).6. With the exception of L-2,4,diaminobutyric acid, an outstanding characteristic of these drugs was their complete lack of specificity. Thus at the IC50 for GABA, p-chloromercuriphenylsulphonate, chlorpromazine, prochlorperazine, iprindole, desmethylimipramine, apomorphine and diphenylhydramine also inhibited the uptake of radioactive glycine, alanine, noradrenaline, and 5-hydroxytryptamine. The uptake of the latter two compounds was often inhibited to a greater extent than GABA, glycine and alanine.7. Kinetic analysis indicated that the inhibition of (3)H-GABA by p-chloromercuriphenylsulphonate, chlorpromazine, and desmethylimipramine was noncompetitive. L-2,4,Diaminobutyric acid reduced the uptake of (3)H-GABA by a ;mixed' type of inhibition.8. The present results do not support the suggestion that some centrally acting drugs may produce their effects by reducing the uptake of GABA in the brain after its release from inhibitory nerve terminals. Conceivably, the design of compounds which interfere effectively with the mechanisms of GABA operated synapses may lead to the introduction of whole new groups of centrally acting drugs.

Alanine↗
PubMed1991

Effect of antidepressants and neuroleptics on phosphoinositide metabolism in human platelets.

The effect of tricyclic antidepressants (imipramine, desipramine, amitriptyline) and several other antidepressants like iprindole, a monoamine oxidase inhibitor phenelzine, trazodone and mianserin as well as cocaine (a potent inhibitor of norepinephrine uptake), and neuroleptics (haloperidol, thioridazine, chlorpromazine) on [3H]inositol phosphate formation was investigated in human platelets. Basal and thrombin-induced [3H]inositol monophosphate ([3H]IP1), [3H]inositol bisphosphate ([3H]IP2) and [3H]inositol trisphosphate ([3H]IP3) production were measured in [3H]myoinositol-labeled platelets in the presence of lithium chloride and in the presence or absence of test drugs. Desipramine, imipramine, amitriptyline and iprindole inhibited thrombin-stimulated formation of [3H]IP2 and [3H]IP3 in human platelets but had no significant effect on [3H]IP1 formation. In contrast, trazodone, mianserin, cocaine and phenelzine had no effect on inositol phosphate formation in thrombin-stimulated human platelets. The neuroleptics thioridazine and chlorpromazine also decreased thrombin-stimulated [3H]IP2 and [3H]IP3 production but not [3H]IP1 in human platelets, whereas haloperidol had no significant effect. The effect of antidepressants and neuroleptics on the level of [3H]phosphatidylinositol ([3H]PI), [3H]phosphatidylinositol 4-phosphate ([3H]PIP) and [3H]phosphatidylinositol 4,5-bisphosphate ([3H]PIP2) was also determined. All of the drugs tested except phenelzine and thioridazine increased the accumulation of [3H]PI, [3H]PIP and [3H]PIP2. Thioridazine increased levels of [3H]PI but decreased the level of [3H]PIP and [3H]PIP2, whereas phenelzine had no effect on [3H]PI, [3H]PIP and [3H]PIP2 interconversion in human platelets.(ABSTRACT TRUNCATED AT 250 WORDS)

Antidepressive Agents, Tricyclic↗
PubMed1986

Effects of antidepressant drugs injected into the amygdala on behavioral responses of rats in the forced swim test.

Experiments were conducted to determine if the actions of antidepressant drugs in a pharmacological screen would be localized to specific brain regions. Rats were infused in discrete brain regions with drugs of different pharmacological properties and processed in the forced swim test. Infusion of imipramine and pargyline into the amygdala produced behavioral responses similar to i.p. injections of the drugs. The regions of the amygdala from which positive responses could be elicited were highly selective. From cannula placements and diffusion studies with autoradiography it appears that a locus of action of imipramine and pargyline is confined to the central, basolateral and/or lateral nuclear regions of the amygdala. Behavioral responses of rats in which imipramine was infused into the anterior amygdala or caudate-putamen did not differ from saline controls. When infused into regions of the amygdala in which imipramine was active, iprindole, an "atypical" antidepressant, did not produce a behavioral response in the forced swim test. Two "false positives" in the forced swim test, atropine and amphetamine, were also not active when infused into the amygdala. These results indicate that the amygdala is a critical site of action for certain antidepressant drugs in the forced swim test, and that behavioral activation in the test induced by iprindole, amphetamine and atropine involve brain regions other than the amygdala.

Amygdala↗
PubMed1986

Rapid changes in central beta-adrenergic receptors after chronic intravenous infusion of antidepressants.

The effects of intravenous infusion of desipramine (1, 3, 10, and 60 mg/kg/24 hr), amitriptyline, zimelidine, iprindole (3, 10, 30, 60, and 100 mg/kg/24 hr each), imipramine (10, 30, and 100 mg/kg/24 hr), or U-48,753E (1, 3, 10, and 30 mg/kg/24 hr) on the density of central beta-adrenergic receptors were investigated in Sprague-Dawley rats. A comparative study with oral desipramine (3 mg/kg/24 hr) for 74 hrs was also carried out. Desipramine, amitriptyline, zimelidine, iprindole, imipramine, and U-48,753E reduced the density of beta-adrenergic receptors in the cerebral cortex, and the effect seems to be dose-dependent. In the oral study, desipramine failed to down-regulate beta-adrenergic receptors. These results indicate that down-regulation of beta-adrenergic receptors can be rapidly achieved by intravenous infusion of drugs.

Administration, Oral↗
PubMed1985

Effects of amfonelic acid, alpha-methyltyrosine, Ro 4-1284 and haloperidol pretreatment on the depletion of striatal dopamine by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) given in 4 daily s.c. injections to mice resulted in marked depletion of striatal dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) 1 week after the last dose. Pretreatment of mice with alpha-methyltyrosine or Ro 4-1284 to deplete dopamine prior to MPTP injection did not prevent these effects of MPTP, nor did pretreatment with haloperidol, a dopamine receptor antagonist. The depletion of striatal dopamine by MPTP in mice therefore differs from the persistent depletion of striatal dopamine by amphetamine in iprindole-treated rats, which is prevented by pretreatment with either alpha-methyltyrosine or haloperidol. The depletion of dopamine, DOPAC and HVA in mouse striatum by MPTP was totally prevented by pretreatment with amfonelic acid, an inhibitor of dopamine uptake. This finding suggests that these effects of MPTP, like those of amphetamine in iprindole-treated rats, are dependent upon a functional transport system into the dopamine neuron.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1977

Biological disposition of rigid analogs of amphetamine.

Tissue levels of amphetamine and of amphetamine analogs with a rigid conformation (2-aminoindan, 2-aminotetralin, and 2-aminobenzocycloheptene) were measured in rats by a spectrofluorometric method involving the reaction of the primary amine group with fluorescamine. All drugs were concentrated in tissues, the order of distribution being lungs greater than kidneys greater than liver=spleen=brain greater than muscle greater than fat=heart greater than blood. In brain, amphetamine and 2-aminoindan were present mostly in the supernatant fraction after high speed centrifugation onbrain homogenates; the two higher molecular weight drugs were present at slightly greater concentrations in the particulate fraction. All four drugs disappeared from rat brain with half-lives of 1-2 hr. Iprindole pretreatment increased drug levels in brain and prolonged the half-lives by two- to threefold. The data suggest that the biological disposition of the rigid analogs resembles generally that of amphetamine and that all of the drugs are probably metabolized by ring hydroxilation in the rat.

Amphetamines↗
PubMed1975

Involvement of biogenic amines in drug-induced aggressive pecking in chicks.

Pairs of neonate chicks were administered psychoactive agents and pecks against each other were recorded during 4-hr test sessions. The first experiment assessed where drug-induced aggressive pecking could serve as a useful anti-depressant screening model. Although pecking was induced by tricyclics, d-amphetamine, and L-Dopa, ineffective agents included a MAO inhibitor (pargline) and a tricyclic indole antidepressant (iprindole). These data cast doubt on the validity of the chick pecking model as a specific antidepressant tests. A second experiment attempted to determine where different amines were involved in pecking induced by an antidepressant and a CNS stimulant. Pairs of chicks were pretreated with various doses of amine antagonists, and a standard dose of imipramine (IMI) or d-amphetamine (AMP) was administered. Haloperidol completely antagonized AMP but not IMI pecking, while phentolamine and propranolol did not modify AMP pecking, suggesting involvement of dopamine. Pecking induced by IMI was partially antagonized by a dose of methysergide ineffective in modifying AMP pecking. Neither phentolamine nor propranolol blocked IMI pecking. Serotonin was further implicated in IMI pecking in a third experiment, whether chronic PCPA pretreatment significantly decreased IMI, but not AMP pecking. These data suggest that aggressive pecking induced by AMP and IMI may be mediated by different amine systems.

Aggression↗
PubMed1976

Retinal lipidosis in albino rats treated with chlorphentermine and with tricyclic antidepressants.

Retinal pigment epithelium is known to be engaged in continuous phagocytosis and digestion of old discs of visual cell outer segments, which have a high phospholipid content. The present ultrastructural study was focused mainly on the effects, upon pigment epithelium, of several drugs that are thought to interfere with the enzymatic degradation of phospholipids. Albino rats received high oral doses of chlorphentermine, iprindole, 1-chloroamitriptyline, imipramine, or clomipramine. After treatment for several weeks the pigment epithelial cells were doubled in height due to deposition of excessive amounts of abnormal cytoplasmic inclusions which had a crystalloid substructure. Such inclusions which are known from previous studies to be associated with drug-induced phospholipid storage are suggested to contain nondigestible phospholipids, which in pigment epithelium originate mainly from phagocytosed outer segment discs. The alterations were reversible by withdrawal of the drugs. The functional implications of the epithelial alterations remain to be elucidated. Additional examination of the neuroretina revealed numerous abnormal inclusions, mainly of multilamellated structure. Ganglion cells were affected most. The neuroretinal alterations were reminiscent of those described in human cases of inherited lipidoses.

Amitriptyline↗
PubMed1979

Differential effects of chloroquine and of several other amphiphilic cationic drugs upon rat choroid plexus.

Several cationic amphiphilic drugs, each of which is known to induce generalized lipidosis in rats, were compared with respect to their cytological effects on rat choroid plexus epithelium. Chloroquine induced large cytoplasmic vacuoles, whereas the other drugs (quinacrine, 4,4'-diethylaminoethoxyhexestrol, chlorphentermine, iprindole, 1-chloro-amitriptyline, clomipramine) caused formation of lamellated or crystalloid inclusions as usually seen in drug-induced lipidosis. The ultrastructure of the chloroquine-induced vacuoles suggested storage of water-soluble materials (polar lipids and/or non-lipid materials) in addition to non-water-soluble polar lipids.

Amitriptyline↗
PubMed1982

Sensitivity in vivo of central alpha 2- and opiate receptors after chronic treatment with various antidepressants.

Recent studies suggest that the antidepressant activity could be explained by gradually developing modifications in the sensitivity of some central monoaminergic receptors. As concerns alpha 2-receptors, some largely indirect informations suggest that a subsensitivity develops following chronic treatment with desipramine or imipramine. However it is not clear whether this effect is shared by other antidepressants. In view of the important role of these receptors in the regulation of noradrenergic neuro-transmission, single cell recording and microiontophoretic techniques were used in this work to systematically assess locus coeruleus (L.C.) alpha 2-receptor sensitivity following acute and chronic administration of various antidepressants. The responsiveness of L.C. alpha 2-receptors to iontophoretically applied clonidine was studied simultaneously with the responsiveness of L.C. opiate receptors to iontophoretically applied morphine in order to test the specificity in the putative modifications induced by the antidepressants. The compounds studied were desipramine (DMI), imipramine (IMI), clomipramine (CIMI), zimelidine (ZIM), mianserin (MIAN), iprindole (IPR) and chlorpromazine (CPZ). Long-term treatment with DMI, IMI and ZIM but not with the other clinically effective antidepressant drugs induced a decrease in the responsiveness of L.C. neurons to iontophoretically applied clonidine. None of the drugs tested altered the responsiveness of these neurons to iontophoretically applied morphine. Consequently the therapeutic effectiveness of antidepressant drugs can not be generally related to modulation of the sensitivity of central alpha 2- or opiate receptors.

Animals↗
PubMed1975

Lipidosislike renal changes in rats treated with chlorphentermine or with tricyclic antidepressants.

Histological, histochemical and ultrastructural examinations were performed on renal tissues of rats after prolonged oral administration of the anorectic drug chlorphentermine or of the tricyclic antidepressants iprindole, imipramine and clomipramine. All drugs caused the formation of multilamellated cytoplasmic inclusions throughout the nephron and the collecting duct system, and in interstitial cells. The cytological alterations were most prominent in the glomerular podocytes, in the proximal convoluted tubules, and in the collecting duct system. In view of the histochemical properties (staining with Baker's acid hematein) and the ultrastructural appearance of the cytoplasmic inclusions the cellular alterations are interpreted as a renal manifestation of a generalized lipidosis induced by drugs of amphiphilic character.

Animals↗
PubMed1992

A gas chromatographic procedure for separation and quantitation of the enantiomers of the antidepressant tranylcypromine.

A novel assay procedure has been developed that allows for the separation and quantification of the enantiomers of the monoamine oxidase inhibitor tranylcypromine (TCP) in brain and liver of rats. The analytical method involves extraction of the drug from rat tissue with an organic solvent. TCP is then derivatized with S-(-)-N-(trifluoroacetyl)-prolyl chloride to allow gas chromatographic analysis of the resulting diastereoisomers. Conditions for analysis by a gas chromatograph equipped with a nitrogen-phosphorus detector and a capillary column are described. The method has been applied to the separation and quantification of the enantiomers of TCP in samples of brain and liver of rats that had been injected with this drug alone and after pretreatment with iprindole, a drug known to block aromatic ring hydroxylation.

Animals↗
PubMed1976

Tricyclic antidepressant drugs as antagonists of muscarinic receptors in sympathetic ganglia.

Close arterial injection of McN-A-343 into the superior cervical ganglion of the cat resulted in contractions of the nictitating membrane. The ganglionic effects of McN-A-343 but not those of DMPP were antagonized in a dose-related manner by 2-10 mug of desipramine, imipramine, chlorimpramine, iprindole and viloxazine. No correlation was found between the dose of each drug which blocked the effects of McN-A-343 and that required to potentiate the responses of the nictitating membrane to intra-arterial administration of noradrenaline. It is concluded that clinically effective antidepressant agents can block muscarinic receptors in neural tissue, even if they do not do so in smooth muscle and gland cells.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1986

Hypoalgesia induced by antidepressants in mice: a case for opioids and serotonin.

The tail flick assay was used to evaluate pain perception in mice treated acutely with either of the two classical antidepressant drugs (AD) imipramine or amitriptyline, or the atypical antidepressant iprindole. A sustained hypoalgesic effect, sensitive to the opiate antagonist naloxone, was detected for the AD used in this study. Administration of the aminopeptidase inhibitor bestatin or the enkephalinase blocker thiorphan made subeffective doses of AD hypoalgesic. This synergistic effect was reversed by naloxone. The antinociceptive action of the AD wore off in mice rendered tolerant to morphine by subcutaneous implantation of a pellet of the opiate. Subchronic treatment with p-chlorophenylalanine did not alter the effect of AD on pain perception, but in animals whose serotonin (5-HT) receptors were blocked by methysergide AD did not produce any change in pain threshold. It was concluded on the basis of these findings that short-chain opioids and 5-HT appear to have a role in the hypoalgesic effect of either classical or atypical AD.

Amitriptyline↗