A simple screening procedure for imipramine-like antidepressant agents

1 The minimal dose which significantly potentiates the hyperthermia induced by thyrotrophin releasing hormone (TRH, 40mg/kgi.p.) in mice has been established for tricyclic and other antidepressants (imipramine, amitriptyline, clomipramine, nortriptyline, maprotiline, nomifensine, viloxazine) including a specific inhibitor of noradrenaline (NA) uptake (nisoxetine). 2 The minimal effective dose in this test has been compared with the minimal dose of the same compounds antagonizing reserpine-induced hypothermia. The ratio of the two doses for each substance indicates that potentiation of TRH-induced hyperthermia is, in general, the more sensitive test.3 A correlation seems to exist between the a-adrenergic effect of antidepressants and the potentiation of TRH-induced hyperthermia. Those antidepressants which do not act on aadrenergic systems (butriptyline, amineptine, trazodone, danitracen, fluoxetine) are inactive in this test. 4 This property may be used to select antidepressants that activate a-adrenoceptor systems.

Section: Introductionmentioning

confidence: 99%

USE OF POTENTIATION OF THYROTROPHIN RELEASING HORMONE (TRH)‐INDUCED HYPERTHERMIA AS a TEST FOR SCREENING ANTIDEPRESSANTS WHICH ACTIVATE Α‐ADRENOCEPTOR SYSTEMS

Desiles

Rips

1981

“…One of the many pharmacological effects induced by reserpine in rodents is a profound hypothermia (Askew, 1963), which is thought to result from the depletion of central and peripheral neuronal stores of catecholamines (noradrenaline (NA) and dopamine) and 5-hydroxytryptamine (5-HT) (Shore, 1962). In this paper we present evidence suggesting that the thermogenic action of a series of selective a2-adrenoceptor agonists in reserpine-treated mice is mediated via activation of a central postsynaptic a2-adrenoceptor mechanism.…”

mentioning

confidence: 99%

The thermogenic actions of α₂‐adrenoceptor agonists in reserpinized mice are mediated via a central postsynaptic α₂‐adrenoceptor mechanism

Bill

Hughes²,

Stephens³

1989

1 The dose-related effects of the selective a2-adrenoceptor agonists clonidine, UK-14,304 and B-HT 933 on the body temperature of untreated and reserpine-treated mice were investigated. 2 In untreated mice all three agonists induced a dose-related hypothermia. The highest doses of UK-14,304 and B-HT 933, 3 and lOOmgkg-I respectively, elicited a marked (10C) hypothermia, whereas the maximal hypothermic effect of clonidine (5.50C) was less pronounced and reached a plateau at a dose of 0.5 mg kg-i.p. 3 Reserpine (2.5mg kg-1, s.c.) induced a marked hypothermia in the mouse; 18 h after injection body temperature had decreased to only slightly (0.5-1.50C) above ambient (19'C). 4 All three a2-agonists produced a partial dose-related reversal of reserpine-induced hypothermia; maximal thermogenic responses (9-100C increases in body temperature) were elicited by doses of 0.2, 0.5 and 16mgkg-I i.p. of clonidine, UK-14,304 and B-HT 933 respectively, and the log doseresponse curves for all 3 agonists were bell-shaped. 5 Following intracerebroventricular administration to reserpine-treated mice, the thermogenic response to clonidine was more rapid in onset, and the agonist was 20 fold more potent than when injected i.p.6 The selective a2-adrenoceptor antagonists, idazoxan (0.05-0.5 mgkg-'), Wy 26392 (0.3-5.0mg kg 1) and yohimbine (0.1-1.6mg kg 1) given orally attenuated the thermogenic responses to all 3 agonists in reserpinized mice in a dose-related manner. Pretreatment with a single dose of idazoxan (0.3 mg kg 1, orally) elicited a 6 fold parallel shift to the right in the dose-response curve to clonidine. 7 The selective al-adrenoceptor antagonists, prazosin (lOmgkg 1) and indoramin (3-lOmgkg-'), and the f,-adrenoceptor antagonist, propranolol (lOmgkg 1), only partially attenuated the thermogenic responses to the a2-agonists in reserpinized mice. These effects were variable and not clearly dose-related. 8 Pretreatment of reserpinized mice with the catecholamine synthesis inhibitor, a-methyl-p-tyrosine, markedly attenuated (60-95%) the thermogenic response to the noradrenaline uptake inhibitor, desipramine (0.13-12.5mgkg-1, i.p.), but only slightly reduced (10-35%) that to clonidine (0.032-0.5 mg kg-1, i.p.). 9 These results suggest that a2-adrenoceptor agonists reverse reserpine-induced hypothermia via a central mechanism involving activation of postsynaptic a2-adrenoceptors.

“…The effects of drLugs on the hypothermia induced by prior treatment with reserpine were investigated using the methods of Askew (1963). The oesophageal temperatures of the mice were measured at 60 min intervals after intraperitoneal injection of the test drug for a total period of 5 hr.…”

Section: Methodsmentioning

confidence: 99%

The interactions of noradnamine and imipramine‐like antidepressant drugs

Cowell

1969

1. The hypothesis of Roberts & Broadley (1965) that noradnamine formation in the brain is responsible for endogenous depression has been investigated in mice. 2. Injections of noradnamine given directly into the lateral ventricles caused convulsions and profound hypothermia, but were without effect if given subcutaneously. 3. The hypothermia, but not the convulsions, induced by noradnamine was reversed by imipramine-like antidepressant drugs given before or after the injection of noradnamine. The convulsions but not the hypothermia were abolished by phenobarbitone. 4. Increasing doses of nortriptyline produced a parallel shift of the hypothermic log dose-response curve for intraventricular injections of noradnamine to the right. 5 The minimal effective dose of nortriptyline required to reverse noradnamine hypothermia was the same whether the nortriptyline was injected directly into the lateral ventricle or suibcutaneously. 6. No evidence was found to substantiate the claim that reserpine hypothermia is mediated by noradnamine formation in the brain. 7. Intraventricular, but not intraperitoneal, injection of noradnamine caused a depletion of brain noradrenaline and an increase in brain 5jhydroxytrypt-amine. These changes did not result from the convulsive activity and were not modified by pretreatment with nortriptyline. No effect on heart noradrenaline levels was recorded. 8. Noradrenaline, given sulbcutaneously, also antagonized the hypothermic response to noradnamine. 9. The reversal of noradnamine hypothermia by both noradrenaline given subcutaneously and nortriptyline was 'blocked by a and fl-adrenoceptive receptor blocking agents. 10. It is considered that the mode of action of the antagonism of noradnamine hypothermia by imipramine-like antidepressant drugs is a peripheral and not a central mechanism and probalbly results from a potentiation of the effects of circulating noradrenaline released by noradnamine.Roberts & Broadley (1965) confirmed and extended the observation of Kawazu (1958) that adrenaline and noradrenaline formed 5-methylaminomethyl and 5-amino-