Selective inhibition of MAO-A,not MAO-B,results in antidepressant-like effects on DRL 72-s behavior

The effects of monoamine oxidase inhibitors (MAOIs) that selectively inhibit the MAO-A or MAO-B forms of MAO were studied in rats performing under a differential-reinforcement-of-low-rate 72-s (DRL 72-s) schedule of reinforcement. Clorgyline and CGP11305A, irreversible and reversible MAO-A inhibitors, respectively, increased the reinforcement rate, decreased the response rate, and enhanced temporal discrimination. The irreversible MAO-B inhibitor (–)-deprenyl did not produce similar effects. Pargyline did not increase the reinforcement rate at low doses that selectively inhibit MAO-B, but did increase the reinforcement rate at doses that inhibit MAO-A by more than 90%. The present results are in accord with clinical data demonstrating that MAO-A inhibitors are effective therapeutic agents in treating depression while MAO-B inhibitors are of questionable antidepressant efficacy. The present findings provide further evidence that the DRL 72-s schedule may be useful both as a screen for identifying new antidepressants and for investigating the neurochemical effects of antidepressant drugs that are responsible for their therapeutic effects.     

Ro 11-2465 (cyan-imipramine), citalopram and their N-desmethyl metabolites: Effects on the uptake of 5-hydroxytryptamine and noradrenaline in vivo and related pharmacological activities

Ro 11-2465 (cianopramine, cyan-imipramine) and citalopram (CIT), putative antidepressant drugs, are very potent and selective 5-hydroxytryptamine (5-HT) uptake inhibitors in vitro. This study investigated the effects of these drugs and their desmethyl metabolites, Ro 12-5419 (desmethylcianopramine, cyan-desipramine) and desmethylcitalopram (DCIT), respectively, on the uptake of 5-HT and noradrenaline (NA) in vivo [protection against H 77/77 (4, alpha-dimethyl-metatyramine)-induced displacement of 5-HT and NA] and on related pharmacological activities. All the investigated drugs antagonized H 77/77-induced displacement of 5-HT in the rat brain, though the effects of the metabolites were considerably weaker than those of the parent compounds. The H 77/77-induced displacement of brain NA in rats and mice was antagonized only by Ro 12-5419 and Ro 11-2465. All the drugs potentiated the pressor response to 5-HT in pithed rats; however, Ro 12-5419 and particularly Ro 11-2465 could also block the response when used in higher doses (0.1 mg/kg). Only Ro 12-5419 and Ro 11-2465 were able to potentiate the pressor response to NA. Ro 12-5419 also potentiated thyrotropin releasing hormone (TRH) hyperthermia and antagonized reserpine hypothermia in mice; Ro 11-2465 potentiated the TRH hyperthermia only. CIT and DCIT were inactive in both these tests. Of all the four drugs only CIT and Ro 12-5419 considerably stimulated the hind limb flexor reflex in spinal rats. However, whereas the stimulatory effect of CIT was inhibited by the 5-HT antagonists metergoline and cyproheptadine, that of Ro 12-5419 was counteracted by the NA antagonist phenoxybenzamine only. Ro 11-2465, when used in low doses (ca. 1 mg/kg), slightly potentiated the flexor reflex, whereas in higher doses (4–16 mg/kg) it had no effect itself but antagonized the stimulatory action of the 5-HT agonists fenfluramine, quipazine and LSD. The results obtained indicate that Ro 11-2465 and CIT, as well as their desmethyl metabolites, are also potent 5-HT uptake inhibitors in vivo. However, only CIT and DCIT are concurrently devoid of effect on uptake of NA. In contrast, Ro 11-2465 and particularly Ro 12-5419 appear to also inhibit the uptake of NA. Moreover, Ro 11-2465 appears to block central and peripheral 5-HT receptors.The results were presented at the 14th CINP Congress, Florence, June 19–23, 1984     

Changes in rat dopamine- and serotonin function in vivo after prolonged administration of the specific 5-HT uptake inhibitor,citalopram

The effect of prolonged administration of the potent and specific 5-HT uptake inhibitor citalopram on behavioural measures of dopaminergic and serotonergic activity has been studied in rats. Administration of citalopram in the diet at a daily dose of 99 mol/kg led to supersensitivity to d-amphetamine-induced hypermotility and stereotypy and to subsensitivity to apomorphine-induced hypomotility 2 h after withdrawal. Forepaw clonus induced by 5-methoxy-N,N-dimethyltryptamine was decreased 2 h and 24 h after withdrawal and the number of head shakes induced by 1-5-HTP and citalopram were decreased 24 h after withdrawal. The d-amphetamine potentiation was still seen after 24 h, whereas the response had returned to normal 3 and 7 days after withdrawal. The content of amphetamine in three different brain regions was about 50% higher compared with controls 24 h after withdrawal of prolonged citalopram administration. At this time citalopram had been eliminated, and citalopram itself could not affect amphetamine metabolism. Other experiments indicated a linear relation between d-amphetamine brain concentration and motility level. Thus, a 50% increase in citalopram-treated rats cannot alone account for 3-fold increase in d-amphetamine-induced motility. Potentiation of d-amphetamine-induced hypermotility was also found after citalopram in a daily dietary dose of 25 mol/kg for 13 days and after oral bolus injection (49 mol/kg twice daily for 14 days). Acute citalopram injection had no effect in any of these models. The results suggest increased responsiveness of dopaminergic mechanisms mediating hypermotility, and decreased sensitivity of dopamine receptors mediating sedation (proposed autoreceptors). Sensitivity of 5-HT receptors was also decreased. The mechanisms by which citalopram induces d-amphetamine supersensitivity as well as subsensitivity to apomorphine and 5-HT agonists are presently unknown, since no changes in dopaminergic and serotonergic receptor binding have been found after an identical dose regimen.     

Inhibition of uptake1 by (+)-oxaprotiline reveals a differential central regulation of noradrenaline and adrenaline release

Summary Inhibition of uptake, in the central nervous system leads to a decrease of sympathetic outflow to many tissues; central a2-adrenoceptors are involved in this decrease. The aim of the present study was to compare the effects of the selective uptake, inhibitor (+)-oxaprotiline on the plasma kinetics of noradrenaline and adrenaline in anaesthetized and in conscious rabbits. [³H]Noradrenaline and [^3H]adrenaline were infused iv. The arterial plasma concentrations of endogenous and radiolabelled noradrenaline and adrenaline were measured, and the clearance from and spillover into the plasma of noradrenaline and adrenaline were calculated.Results obtained in conscious and anaesthetized rabbits were similar. (+)-Oxaprotiline 0.2, 0.6 and 1.8 mg kg^–1 iv. dose-dependently reduced the clearance of [³H]noradrenaline from the plasma. The clearance of [³H]adrenaline was reduced less. The spillover of endogenous noradrenaline was decreased by up to 35%. In contrast, the spillover of adrenaline tended to be enhanced. Prazosin 0.1 and 1 mg kg^–1 was injected iv. in a second part of each experiment. It lowered the blood pressure and caused a marked increase in noradrenaline spillover but no increase or even a decrease in adrenaline spillover.The results are compatible with the following hypothesis. The sympathetic outflow from the central nervous system is subject to a twofold a-adrenoceptor-mediated modulation: -adrenoceptor-mediated inhibition and ₁-adrenoceptor-mediated excitation. In the control of the sympathetic outflow to many extra-adrenal tissues, the ₂-adrenergic inhibition prevails. Uptake₁ inhibitors depress sympathetic outflow to such tissues by enhancing the ₂-adrenergic inhibition. In the regulation of the sympathetic outflow to the adrenal medulla, in contrast, ₂-adrenergic inhibition and ₁-adrenergic excitation have a similar impact. Uptake, inhibitors, hence, cause little change in adrenaline release: the two opposing influences cancel out. Prazosin produces an increase in noradrenaline but not adrenaline release because the loss of the central ₁ sympathoexcitation attenuates at best slightly the baroreflex to most extra-adrenal tissues but dampens markedly the baroreflex to the adrenal medulla. Correspondence to B. Szabo at the above address     

Increased catecholamine levels in specific brain regions of a rat model of depression: normalization by chronic antidepressant treatment

Alterations in catecholamine levels and neurotransmission have been shown in depressive disorders. However, the exact sites of alterations and the relation between these alterations to the etiology of the disease and the effectiveness of antidepressant therapy are poorly understood. In this study, catecholamine levels and metabolism were measured in specific brain regions of a genetic rat model of depression [Flinders Sensitive Line (FSL) rats], and compared to normal Sprague-Dawley rats. Norepinephrine levels were found to be two to threefold higher in the nucleus accumbens, prefrontal cortex, hippocampus and median raphe nucleus of FSL rats as compared with control Sprague-Dawley rats. Dopamine levels were sixfold higher in the nucleus accumbens and twofold higher in the striatum, hippocampus and hypothalamus of FSL rats as compared with control Sprague-Dawley rats. After chronic treatment with the antidepressant desipramine, the immobility score in a swim test, as a measure of a behavioral deficit, as well as catecholamine levels of the FSL rats became normalized, but these parameters in the control rats did not change. The results indicate that the behavioral deficits expressed in the FSL model for depression correlate with increased catecholamine levels in specific brain sites, and further suggest the FSL rats as a model for elucidation of the molecular mechanism of clinically used antidepressant drugs.     

Phenprocoumon requirement,whole blood coagulation time,bleeding time and plasmaγ-GT in patients receiving mianserin

Summary A possible interaction between the tetracyclic antidepressant mianserin and a coumarin derivative has been investigated. Sixty-three subjects, 61 of whom required anticoagulant therapy for a variety of medical conditions, were treated for 5 consecutive weeks with phenprocoumon, in a dose adjusted to reduce the prothrombin time to 15%–25%. After an initial control period of one week, subjects were randomly treated under double-blind conditions with mianserin 3×10 mg daily or 3×20 mg daily, or with a matching placebo. The dose of mianserin was gradually increased to reach the maximum by the 6th day. Three subjects dropped out and 60 completed the trial.The dose of phenprocoumon and the prothrombin, bleeding, and coagulation times were not significantly affected by administration of mianserin. It can be concluded that there is no clinically important interaction between phenprocoumon and doses of mianserin effective in depression. Sedation was more frequent in patients taking mianserin than in those given placebo.     

Anticonvulsant and proconvulsant properties of viloxazine hydrochloride: Pharmacological and pharmacokinetic studies in rodents and the epileptic baboon

Viloxazine HCl is evaluated as an anticonvulsant in a wide range of rodent seizure models and in the epileptic baboon (Papio papio). In the maximal electroshock test, the oral ED₅₀ for abolition of tonic extension was 9 mg/kg^-1 after 30-min pretreatment (mouse) rising to 30 mg/kg^-1 after 60 min (mouse and rat). Comparable ED₅₀ values were also found for protection against tonic extension in the mouse induced by the administration of the chemical convulsants metrazole or 3-mercaptopropionic acid. In DBA/2 mice the ED₅₀ for abolition of tonic extension during sound-induced seizures was 6.8 mg/kg^-1 IP (30-min pretreatment). Pharmacokinetic studies in the mouse showed peak plasma levels to occur 30 min following oral doses, with a mean half-life of 58 min. The anticonvulsant plasma concentration was within 0.5–1 g/ml^-1. In the baboon, significant protection against photomyoclonic responses is observed 1–2 h after viloxazine (2.6 mg/kg^-1 IV), during which period the plasma concentration was again 0.5–1 g/ml^-1. After administration of approximately ten-times this latter dose level, i.e. 24 mg/kg^-1 IV, a syndrome characterised by an abnormal EEG and, in some instances, seizure activity was observed.     

Effect of acute and chronic treatment of tandamine,a new heterocyclic antidepressant,on biogenic amine metabolism and related activities

Summary The effects of tandamine, a clinically effective heterocyclic antidepressant, administered either acutely (10 mg/kg i.p) or chronically (10 mg/kg i.p. daily for 21 days) on biogenic amine uptake and metabolism in the rat were determined and a comparison with desipramine was made. Tandamine, similarly to desipramine, blocked norepinephrine (NE) uptake in rat brain and heart following both acute and chronic administration. No effect of tandamine on dopamine (DA) or serotonin (5-HT) uptake was observed. Both drugs lowered endogenous brain NE when given chronically but not acutely. In contrast, no such effect on brain DA and 5-HT or heart NE was observed. Tandamine, like desipramine, administered chronically prior to an intraventricular injection of ³H-NE, produced increases in the decline of ³H-NE as indicated by decreased ³H-NE with increased levels of ³H-normetanephrine in brain stem of rats, suggesting an increased turnover of NE. No such effect was observed following acute treatment. Both drugs increased the behavioural effects of L-Dopa following an acute oral administration, with tandamine appearing superior to desipramine at the lower dose examined (10 mg/kg). Tandamine was 57–833 times less effective in binding to rat brain muscarinic receptors than desipramine, imipramine, butriptyline and amitriptyline, respectively. Thus, tandamine affects biogenic amine mechanism following either acute or chronic administration in a fashion similar to desipramine, but unlike desipramine, it exhibits relatively little anticholinergic properties, a further indication of the potential use of tandamine in the treatment of human depression, particularly where an increase in drive is desired.