Antagonism Of Reserpine-induced Hypothermia Research Articles

Role of 5-hydroxytryptaminergic and adrenergic mechanism in antagonism of reserpine-induced hypothermia in mice.

Role of 5-hydroxytryptaminergic and adrenergic mechanism in antagonism of reserpine-induced hypothermia in mice.

The Selective α2-Adrenoceptor Antagonist Mirtazapine (Org 3770) Enhances Noradrenergic and 5-HT1A-Mediated Serotonergic Neurotransmission

Mirtazapine (Org 3770) is a selective antagonist at α2-adrenergic auto- and heteroreceptors, which are involved in regulation of neuronal noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) release. It was identified as a potential antidepressant in rat sleep studies, showing characteristic REM sleep suppression, as well as activity in the bulbectomised rat and an operant behaviour model. However, mirtazapine does not inhibit monoamine reuptake and is inactive in classical tests predictive of antidepressant activity (antagonism of reserpine-induced hypothermia, Porsolt test, and muricidal behaviour). As an α2-antagonist, mirtazapine inhibits clonidine-induced mydriasis and resembles idazoxan in evoking conditioned taste aversion. In addition, mirtazapine induces lower lip retraction, a response characteristic of 5-HT1A receptor stimulation, and resembles the 5-HT1A agonist 8-hydroxy-dipropylaminotetraline (8-OH-DPAT) in producing conditioned taste aversion. Thus, mirtazapine may have indirect serotonin-enhancing effects, since its affinity for 5-HT1A receptors is low.

2-Phenyl-2-(1-hydroxycycloalkyl)ethylamine derivatives: synthesis and antidepressant activity

A series of 2-phenyl-2-(1-hydroxycycloalkyl)ethylamine derivatives was examined for the ability to inhibit both rat brain imipramine receptor binding and the synaptosomal uptake of norepinephrine (NE) and serotonin (5-HT). Neurotransmitter uptake inhibition was highest for a subset of 2-phenyl-2-(1-hydroxycyclohexyl)dimethylethylamines in which the aryl ring has a halogen or methoxy substituent at the 3- and/or 4-positions. Potential antidepressant activity in this subset was assayed in three rodent models--the antagonism of reserpine-induced hypothermia, the antagonism of histamine-induced ACTH release, and the ability to reduce noradrenergic responsiveness in the rat pineal gland. An acute effect seen in the rat pineal gland with several analogues, including 1-[1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl]cyclohexanol (23) and 1-[2-(dimethylamino)-1)-(4-methoxyphenyl)ethyl]cyclohexanol (4), was taken as a possible correlate of a rapid onset of antidepressant activity. Compound 4 (venlafaxine) is presently undergoing clinical evaluation.

Antidepressant Profile of Bupropion and three Metabolites in Mice

Bupropion is a novel antidepressant, distinct from tricyclic antidepressants both neurochemically and behaviorally. Bupropion forms several metabolites in both rodents and humans. Three chemically different molecules - BW 306, BW 494, and BW 287 - were selected. Comparative assessment of antidepressant activity of bupropion and its metabolites in mice, and pharmacological analysis of possible mechanisms of action of the parent drug and its metabolites (using interaction studies with pimozide, D,L-propranolol, and prazosin) were carried out. The results obtained show that: bupropion has a pharmacological spectrum in various animal models which predicts both antidepressant and stimulatory activity in man. BW 306 is the most active of the metabolites studied and, compared to bupropion, seems more "antidepressant" and less stimulant. BW 494, compared to bupropion or BW 306, has a lower degree of activity in various tests used to evaluate antidepressants. BW 287 has no effect in any of the tests used in this study. The interaction studies with pimozide, D,L-propranolol, and prazosin in the various tests have shown that: the stimulatory effect of bupropion, BW 306, and BW 494 is antagonized by both pimozide and prazosin. in the behavioral despair test, the reduction in the duration of immobility by bupropion and BW 494 is antagonized by pimozide, but not by prazosin or D,L-propranolol. the antagonism of reserpine-induced hypothermia by bupropion and BW 306 is significantly decreased by prazosin and D,L-propranolol, but not by pimozide. These data suggest that the clinical antidepressant profile (without a major stimulatory effect) observed in man after administration of bupropion is related to metabolite BW 306 and possibly to BW 494, rather than to bupropion itself.

Is it possible to predict the activity of a new antidepressant in animals with simple psychopharmacological tests?

Behavioural tests for predicting antidepressant activity in the animal provide a closer approximation than other tests of states of depression in man but are often long and costly to perform (except the behavioural despair test). The tests proposed here presuppose a pharmacological interaction (except the Porsolt test) but are simple enough to allow screening: included are antagonism of reserpine hypothermia, ptosis and akinesia; antagonism of effects induced by oxotremorine; antagonism of high-dose apomorphine; and potentiation of yohimbine toxicity. In combination with the study of motor activity in the mouse, these tests allow assessment of the specificity of antidepressant activity by establishing a ratio between the "antidepressant" dose and the "stimulant" or "sedative" dose. It can be predicted that a substance will be antidepressant and sedative or stimulant at the same dose if the ratio is close to 1; if the ratio is less than 1, at antidepressant doses the substance will be very sedative or stimulant according to the case. The specificity of the tests discussed can be debatable. Antagonism of reserpine-induced hypothermia indicates substances with direct or indirect beta-mimetic activity, ptosis antagonism, substances with alpha-adrenergic (not antidepressants) or serotoninergic (possibly antidepressants) activity; and akinesia antagonism, a direct or indirect dopaminergic activity (sometimes found in antidepressants) with psychostimulant activity. The oxotremorine test is related to the anticholinergic activity of substances, except in the case of hypothermia antagonism. The high-dose apomorphine test seems to be specific for substances inhibiting norepinephrine reuptake. The yohimbine test is simple to carry out, relatively inexpensive and does not fail to screen any molecule known to be effective to-date. The behavioural despair test is a good complement for screening except for drugs having a beta-agonist activity, it appears that this test is dependent on functional relationships between alpha 2 and serotonergic systems.

Potential antidepressant activity of rolipram and other selective cyclic adenosine 3′,5′-monophosphate phosphodiesterase inhibitors

Following intraperitoneal administration, the selective cAMP phosphodiesterase (PDE) inhibitors rolipram, ICI 63 197 and Ro 20-1724 were investigated in mice in comparison with imipramine for their effectiveness in two classical test models for prediction of clinical antidepressant activity: antagonism of reserpine-induced hypothermia or hypokinesia and potentiation of yohimbine lethality. Rolipram was approximately 15 times more potent than imipramine or Ro 20-1724 and approximately as potent as ICI 63 197 in antagonizing reserpine-induced hypothermia. The antihypothermic effect of the phosphodiesterase inhibitors occurred at a smaller dose than that of imipramine. In contrast to imipramine, the phosphodiesterase inhibitors reversed reserpine-induced hypokinesia. Rolipram was approximately as potent as ICI 63 197 and about 15 times more potent than Ro 20-1724. Rolipram was approx. 5 times more potent than Ro 20-1724 and approx. as potent as imipramine or ICI 63 197 in potentiating the lethality of yohimbine. In both test models the (−)-isomer of rolipram was approx. 10–15 times more potent than the (+)-isomer, indicating a stereospecific mechanism of action. The present data suggest an antidepressant action of selective cAMP phosphodiesterase inhibitors due to enhancement of central noradrenergic transmission. The hypothesis is put forward that the increase of noradrenaline turnover induced by phosphodiesterase inhibitors with the inhibitory action of the compounds on cAMP metabolism enables more efficient adaptative changes to occur at central synapses resulting in a rapid onset of the antidepressant activity. Preliminary results with rolipram in patients with endogenous depression seem to support this assumption.

Antagonism of reserpine-induced hypothermia in mice by some beta-adrenoceptor agonists.

The reversal of reserpine-induced hypothermia in mice be three beta-adrenoceptor agonists, terbutaline, salbutamol and clenbuterol, was examined. Terbutaline, 5 and 20 mg/kg intraperitoneally, caused a slight reversal of the hypothermia. Salbutamol, 5 mg/kg intraperitoneally, produced a pronounced and 1 mg/kg a slight reversal. Clenbuterol was very potent in reversing the hypothermic effect of reserpine with significant effect at 0.02 mg/kg intraperitoneally. Propranolol, 2.5 mg/kg intraperitoneally, and the selective beta 2-receptor antagonist IPS 339, 5 mg/kg intraperitoneally, almost completely antagonized the effect of clenbuterol, 1 mg/kg intraperitoneally. The beta-receptor antagonist metoprolol at 5 and 25 mg/kg intraperitoneally only partially antagonized the effect of clenbuterol. Since clenbuterol is much more lipophilic than salbutamol and terbutaline, it is suggested that the reserpine reversal produced by clenbuterol is at least partially of central origin and possibly mediated by stimulation of noradrenergic beta 2-receptors.