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PubMed1986

Chronic antidepressant treatment reduces central beta-adrenoceptor sensitivity in a behavioural test.

The ability of beta-adrenoceptor agonists to potentiate the head-twitch response to 5-hydroxytryptophan (5-HTP) in mice was used to assess the in vivo sensitivity of beta-adrenoceptors 48 h after cessation of acute or chronic administration of desmethylimipramine (DMI) or iprindole (IPD). Neither acute nor chronic antidepressant administration significantly altered the head-twitch response to 5-HTP alone. Forty-eight hours after withdrawal from chronic but not acute pretreatment with DMI or IPD the potentiating effects of dobutamine, prenalterol and salbutamol were significantly decreased. This is consistent with a reduction in beta-adrenoceptor density and suggests that the 'spare' beta-adrenoceptor pool is small enough for this to result in functional subsensitivity. Implications of these findings are discussed.

5-Hydroxytryptophan↗
PubMed1986

Antidepressants and protein kinases: desipramine treatment affects pineal gland cAMP-dependent protein kinase activity.

To further describe the molecular mechanisms involved in reductions in noradrenergic responsiveness induced by antidepressants, the effects of antidepressant treatment on the rat pineal gland cAMP-dependent protein kinase system were examined. The concentration of cyclic AMP-dependent protein kinase activity was reduced 24 h after acute treatment with desipramine, as well as in animals treated repeatedly with desipramine. Assays performed in the presence of cAMP protein kinase inhibitor showed no significant effects of either acute or repeated desipramine treatment on the concentration of cAMP-independent protein kinase activity. Neither acute nor repeated treatment with other antidepressants (zimelidine, iprindole or fluoxetine) significantly altered the concentration of cAMP-dependent or cAMP-independent protein kinase activity. Using activity ratios to judge the extent of activation of cAMP-dependent protein kinase in vivo, it was found that isoproterenol-induced increases in cAMP protein kinase activity were similar in control and acutely-treated animals, but were reduced with repeated desipramine treatment. The extent of protein kinase activation was also elevated by both acute and repeated treatment in the absence of isoproterenol. In further studies, desipramine (10 microM) did not directly affect activation of the kinase by cAMP or maximum kinase catalytic activity. These results show that the concentration and extent of activation of cAMP protein kinase is altered following desipramine treatment in the rat pineal gland and that modulation of cAMP protein kinase may be a locus of regulation for desipramine-mediated reduction in noradrenergic responsiveness.

Animals↗
PubMed1987

Effect of cysteine on the persistent depletion of brain monoamines by amphetamine, p-chloroamphetamine and MPTP.

The administration of L-cysteine (500 mg/kg i.p.) 30 min before and 5 h after the administration of (+)-amphetamine sulfate markedly attenuated the persistent decreases in striatal dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in rats one week after the administration of a single dose of amphetamine (9.2 mg/kg i.p.) to iprindole-treated animals and in mice one week after the last of four daily injections of amphetamine (30 mg/kg i.p.). Cysteine prevented the persistent decreases in striatal serotonin (5HT) and 5-hydroxyindoleacetic acid (5HIAA) one week after the administration of p-chloroamphetamine to rats, but failed to alter the persistent decreases in striatal DA, DOPAC and HVA in mice one week after the last of four daily doses of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 30 mg/kg s.c.). The results suggest that the mechanisms by which amphetamine and p-chloroamphetamine, but not MPTP, produce persistent depletions of striatal monoamines involve the generation of neurotoxic electrophilic intermediates which can be inactivated by the administration of cysteine.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

Acute or chronic antidepressants do not modify [125I]cyanopindolol binding to 5-HT1B receptors in rat brain.

Acute or chronic treatment of young or adult rats with chlorimipramine, tianeptine or iprindole, antidepressants with different effects on 5-HT uptake mechanisms, did not modify the density or the affinity of 5-HT1B receptors of the frontal cortex. No significant receptor change was found after prenatal exposure to these antidepressants. The lack of effect of the antidepressants was not related to the density of 5-HT1B receptors, which was significantly lower in younger animals.

Animals↗
PubMed1983

Functional supersensitivity of CNS alpha 1-adrenoceptors following chronic antidepressant treatment.

Chronic but not acute administration (21 days) of desipramine (10 mg/kg), amitriptyline (10 mg/kg) or iprindole (5 mg/kg) enhanced the stimulatory effect of the alpha 1-adrenergic agonist phenylephrine on the acoustic startle reflex when phenylephrine was infused into the subarachnoid space of the spinal cord. Comparable supersensitivity to phenylephrine also occurred 1 week after selective depletion of norepinephrine in the spinal cord via intrathecal administration of 6-hydroxydopamine. Behavioral supersensitivity to phenylephrine was associated with an increase in the number of 3H-prazosin binding sites following denervation but not following chronic antidepressant treatments. The results indicate that chronic antidepressant treatments may enhance functional alpha 1-adrenergic transmission through mechanisms different than those following denervation.

Amitriptyline↗
PubMed1985

Central and peripheral catecholamine depletion by 1-methyl-4-phenyl-tetrahydropyridine (MPTP) in rodents.

1-Methyl-4-phenyl-tetrahydropyridine (MPTP) given in single doses to rats depleted norepinephrine concentration in heart and mesenteric artery but had little effect on catecholamine concentration in brain. MPTP did not share with amphetamine the ability to cause persistent depletion of striatal dopamine in iprindole-treated rats. Administration of MPTP via osmotic minipumps implanted s.c. for 24 hrs after a loading dose of MPTP in rats resulted in depletion of striatal dopamine and its metabolites one week later. MPTP in vitro was a reasonably potent, competitive and reversible inhibitor of MAO-A (monoamine oxidase type A). MPTP appeared to inhibit MAO-A in rat brain in vivo as determined by its antagonism of the inactivation of MAO-A by pargyline and by its antagonism of the increase in dopamine metabolites resulting from the administration of Ro 4-1284, a dopamine releaser. The inhibition of MAO-B by MPTP in vitro was noncompetitive, time-dependent, and not fully reversed by dialysis, consistent with the findings of others that MPTP is acted upon by MAO-B. In mice, four successive daily doses of MPTP is acted upon by MAO-B. In mice, four successive daily doses of MPTP given s.c. resulted in marked depletion of dopamine and its metabolites one week later, and the depletion of dopamine was completely prevented by pretreatment with deprenyl, which inhibited MAO-B but not MAO-A. These and other studies in rodents may help in elucidating the mechanisms involved in the destructive effects of MPTP on striatal dopamine neurons that lead to symptoms of Parkinson's disease in humans and in monkeys.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1992

Ventricular defibrillating properties of catecholamine uptake inhibitors.

Ventricular fibrillation (VF) is a fatal event in humans unless electrical defibrillation is applied within minutes. Recent publications describe spontaneous termination of VF in various animals and even in humans. Certain drugs can transfer a fatal, sustained VF (SVF) into a self-terminating, transient VF (TVF). Based on results obtained in animals of various species and ages, we have suggested that the occurrence of TVF requires a high cardiac catecholamine level at the time of VF. According to our hypothesis, drugs which decrease catecholamine reuptake by the sympathetic nerve terminals will increase the ability of the heart ventricles to defibrillate spontaneously. In the present study, we examined the effects of desipramine, maprotiline, mianserin, iprindole, cocaine and amphetamine on the type of VF in cats exhibiting SVF prior to the treatment. The results show that the ability of these compounds to transfer SVF to TVF is closely related to their potency to inhibit catecholamine reuptake. The establishment of the catecholamine related mechanisms of TVF may lead to the development of a new class of antiarrhythmic-defibrillatory drugs.

Amphetamine↗
PubMed1985

Prenatal exposure of rats to antidepressant drugs down-regulates beta-adrenoceptors and 5-HT2 receptors in cerebral cortex. Lack of correlation between 5-HT2 receptors and serotonin-mediated behaviour.

Changes in the binding of beta-adrenoceptors and 5-HT2 receptors and in behaviour mediated by serotonin were studied after either acute treatment or prenatal exposure of rats to antidepressant drugs. Chlorimipramine, iprindole and mianserin reduced the density of [3H]dihydroalprenolol-labelled beta-adrenoceptors and of [3H]spiperone-labelled 5-HT2 receptors in 25-day-old rats after prenatal exposure to these drugs from gestational day 6 to delivery. Prenatal exposure to nomifensine reduced also the number of beta-adrenoceptors but, in contrast, the density of 5-HT2 receptors and the KD for binding of [3H]spiperone were markedly increased. Acute treatment of 25-day-old rats with the same antidepressants did not modify in any case the characteristics of binding to beta-adrenergic or 5-HT2 receptors. The behavioural syndrome induced by 5-hydroxytryptophan and clorgyline was only antagonized on acute treatment by mianserin. Chronic treatment in utero with the antidepressants produced varied effects on the serotonin syndrome and there was no correlation between the number of 5-HT2 receptors and the intensity of the behaviour mediated by serotonin. The observed changes in beta-adrenergic and 5-HT2 receptors after prenatal exposure to antidepressant drugs appear to be more marked and longer-lasting than those induced by chronic treatment of adult rats.

Animals↗
PubMed1981

Postsynaptic action by four antidepressive drugs in an animal model of depression.

To further test the new hypersensitive postsynaptic serotonin (5-HT) receptor theory of depression bases on or animal model, it was necessary to demonstrate that some of the currently used antidepressive drugs can block D,L-5-hydroxytryptophan (5-HTP) induced depression acting through postsynaptic rather than presynaptic mechanisms. Rats working for milk reinforcement and exhibiting behavioral depression following administration of 5-HTP (IP) were pretreated (1 hour before the 5-HTP injection) with fluoxetine (5 mg/kg IP) or methysergide (5 mg/kg IP) to establish a behavioral basis for distinguishing between pre- and postsynaptic events, respectively. Fluoxetine, a known specific uptake blocker of 5-HT, potentiated the depressive effect of 12.5 mg/kg 5-HTP by 200%. Methysergide, a postsynaptic blocker of 5-HT, almost completely (93%) abolished the depressive effect of 50 mg/kg 5-HTP. Since acute pretreatment with comparable clinical doses of the antidepressive drugs, mianserin, amitriptyline, imipramine, or iprindole, resulted in blockade of the 5-HTP induced depression by 70, 50, 40, and 20% respectively, these drugs can act as antagonists of 5-HT at the postsynaptic serotonin receptor. When these results are viewed in terms of recent data reported from CNS binding studies, the therapeutic effects of some antidepressants may be explained by their postsynaptic rather than presynaptic effects at central serotonergic receptors.

5-Hydroxytryptophan↗
PubMed1982

Animal model of depression: tests of three structurally and pharmacologically novel antidepressant compounds.

Previous studies have identified behavioral and neuroendocrine abnormalities in chronically stressed rats which resemble some of the more prominent features of clinical depression. These abnormalities have proved responsive to pharmacotherapy by standard antidepressant drugs and related somatic treatments. Several structurally and pharmacologically atypical compounds, resembling neither standard agents, nor each other, have recently been identified as clinically effective antidepressants. There drugs do not show typical preclinical response profiles in other drug screening tests and, therefore, represent critical instances for evaluating the selectivity of the chronic stress model. Three drugs were tested, these being iprindole, bupropion, and mianserine; a tricyclic indole, propriophenone, and tetracyclic compound respectively. Four circulating measures, which previously proved most useful in discriminating antidepressant potential, and a measure of circulating corticosterone were obtained for subjects examined factorially in a 2x2x2 experimental design (chronic stress vs none, acute stress vs none, and drugs vs control). All compounds proved capable of reversing chronic stress induced behavioral deficits, and all but one compound reversed the attendant basal hypersecretion of corticosterone. These findings argue that the chronic stress model provides an accurate and selective assessment of the therapeutic potential of both standard and structurally novel compounds.

Animals↗
PubMed1984

Effects of norepinephrine and serotonin uptake inhibitors on the schedule-controlled behavior of the pigeon.

The effects of nortriptyline, amitriptyline, desipramine, chlorimipramine, protriptyline, doxepin, nisoxetine, fluoxetine and iprindole were determined on responding by pigeons under a multiple fixed-ratio 30-response, fixed-interval 10-minute schedule of grain presentation. Those drugs which have been shown to block uptake of norepinephrine decreased fixed-interval quarter-life values. Those which are considered most selective as norepinephrine uptake inhibitors also increased overall fixed-interval responding. These increases in fixed-interval responding, both on local and overall rates, in pigeons appear to be due to the actions of these drugs to inhibit uptake of norepinephrine rather than to other actions.

Amitriptyline↗
PubMed1991

Long-lasting dopamine receptor up-regulation in amphetamine-treated rats following amphetamine neurotoxicity.

Amphetamine (A) (9.2 mg/kg, IP), in combination with iprindole (I) (10.0 mg/kg, IP), caused long-lasting dopamine (DA) depletions in striatum (-49%, 4 weeks) but not in nucleus accumbens following one A/I injection. Striatal DA had recovered by 4 months. DA receptors (DAr) were up-regulated: 1) behavioral responses to a DA receptor agonist (apomorphine) were significantly elevated. These included apomorphine-induced locomotor activity (+103% and +160%, on weeks 3 and 10) and apomorphine-induced stereotypy (day 10). 2) Bmax for [3H]spiroperidol binding to striatal D2 DAr (12 weeks) increased (+53%, week 12). Injection of the DAr neuromodulator cyclo(leucyl-glycyl) (8 mg/kg/day x 4 days, SC) reversed the Bmax increase. Thus toxicity (DA depletion) following high-dose amphetamine appears to induce compensatory changes in DAr. This DAr upregulation may explain the lack of abnormal movements despite enduring DA depletion. Additionally, the A/I paradigm as an animal model of long-lasting DAr up-regulation, could be used to screen neuromodulatory agents, like CLG, that might treat disorders (e.g., tardive dyskinesia and schizophrenia) thought to involve up-regulated DAr.

Animals↗
PubMed1986

Differential effects of antidepressant drugs on [3H]dihydroalprenolol and [3H]imipramine ligand recognition sites in olfactory bulbectomized and sham-lesioned rats.

In the olfactory bulbectomy rat model of major depression, the binding of [3H]imipramine is increased by 60% in the midbrain, reduced by 30% in the pons and by 20% in the hippocampus, and unchanged in the hypothalamus 6 weeks after the bulbectomy. Binding of [3H]dihydroalprenolol is unchanged in the midbrain but is increased by 30% in the pons and 15% in the hippocampus. The i.p. administration of the antidepressants amitriptyline, mianserin, tranylcypromine (all at a dose of 10 mg/kg) or iprindole (25 mg/kg) for 28 days followed by a 5-day drug washout period, alters brain part [3H]imipramine and [3H]dihydroalprenolol binding in a manner that is a function of the particular drug, brain part and lesion effect. Only in the hippocampus did the lesion increase beta-binding that was reduced by all four antidepressant drugs.

Amitriptyline↗
PubMed1982

3H-mepyramine binding in various regions of rat brain following chronic treatment with different classes of antidepressant drugs.

1. The possible role of the histamine system in the mechanism of action of the antidepressant drugs was proposed. 2. We studied the 3H-mepyramine binding to histamine H1-receptor following chronic treatment with different classes of antidepressant products which possess diverse pharmacological action at the synaptic level. 3. Administration of chlorimipramine in clinical dosage caused a complete disappearance of the 3H-mepyramine affinity for its receptor in the occipital cortex. The number of H1-receptors was decreased in the hypothalamus, the posterior hippocampus and the occipital cortex following chronic desipramine treatment. Nomifensine administration increased the Bmax in the anterior hippocampus while iprindole treatment have not affected the H1-receptor in the rat brain. 4. We conclude that the modification of H1-receptors is not a general property of antidepressants indicating that is not causally related to their main therapeutic action.

Aminopyridines↗
PubMed1982

Role of neuronal signal input in the down-regulation of central noradrenergic receptor function by antidepressant drugs.

Rats with unilateral lesions of the locus coeruleus were used to study the role of norepinephrine (NE) signal input in the down-regulation by antidepressants of the noradrenergic cyclic AMP-generating system in the cortex. Chronic administration of both desipramine (blockade of NE reuptake) and iprindole (no blockade of NE reuptake) reduced the cyclic AMP response to NE on the nonlesioned side, but had little or no effect on the lesioned side. The results indicate that NE signal input and thus the formation of the NE-receptor complex are prerequisites for inducing noradrenergic subsensitivity.

Animals↗
PubMed1991

Chronic electroconvulsive treatment augments coupling of the GTP-binding protein Gs to the catalytic moiety of adenylyl cyclase in a manner similar to that seen with chronic antidepressant drugs.

A significant increase of guanylylimidodiphosphate (GppNHp)-, fluoride-, and forskolin-stimulated adenylyl cyclase was observed in synaptic membrane preparations from rat cerebral cortex subsequent to chronic electroconvulsive shock (ECS) treatment. This effect required at least five treatments over a course of 10 days. The inhibition of adenylyl cyclase induced by GppNHp was not affected by these treatments. The dissociation constant (KD) and maximal binding for the photoaffinity GTP analog, [32P]P3-(4-azidoanilido)-P1-5'-GTP [( 32P]AAGTP), to each of the synaptic membrane G proteins also were unchanged after ECS treatment. Nonetheless, the transfer of [32P]AAGTP from Gi to Gs, which we suggest is indicative of the coupling between Gs and the adenylyl cyclase catalytic moiety, was accelerated by chronic ECS treatment but not by acute or sham treatment. Furthermore, chemical uncoupling of Gs from adenylyl cyclase rendered membranes from treated animals indistinguishable from controls. Finally, in all cases tested, membranes prepared from animals subjected to chronic treatment with amitriptyline or iprindole showed similar changes in the Gs-mediated activation of adenylyl cyclase. Acute treatments produced effects similar to controls, and liver and kidney membranes from animals receiving chronic treatment showed no changes in adenylyl cyclase despite the marked changes seen in brain. These results suggest that chronic administration of ECS enhances coupling between Gs and adenylyl cyclase enzyme and modifies interactions between Gs and Gi.

Adenylyl Cyclase Inhibitors↗
PubMed1975

The role of p-hydroxylation of amphetamine in its peripheral mode of action.

Desipramine completely abolished the blood pressure response to (+) amphetamine in the rat, whereas the tricyclic antidepressant iprindole did not reduce this response. Since both tricyclic drugs inhibit the aromatic hydroxylation of amphetamine, these studies do not support the hypothesis that hydroxylated metabolites of amphetamine, p-hydroxyamphetamine and p-hydroxynorephedrine are essential for the peripheral sympathomimetic effects of amphetamine.

Amphetamine↗