Clonidine-induced Hypothermia Research Articles

Involvement of monoaminergic system in the antidepressant effect of 3-substituted thietane-1,1-dioxide derivative

Introduction: The aim of the study was to assess the involvement of the monoaminergic system in the antidepressant effect of a new 3-substituted thietane-1,1-dioxide derivative (N-199/1) using tests with several pharmacological antag­onists and agonists. Materials and methods: We conducted 3 sets of experiments in white outbred male mice. In Experiment 1, we as­sessed the antidepressant effect of N-199/1 in the forced swimming test (FST) and tail suspension test (TST) when administered repeatedly for 2 weeks intraperitoneally (i.p.). In Experiment 2, we evaluated the antidepressant effect of N-199/1 in FST and TST when co-administered with 5HT1A- (WAY100635, 0.1 mg/kg), 5HT2A/2C- (ketanserin, 5 mg/kg), 5HT3- (ondansetron, 1 mg/kg) serotonergic and α2-adrenergic (yohimbine, 1 mg/kg) receptors antagonists. In Experiment 3, we assessed the effect of N-199/1 on the hypothermia induced by i.p. injection of α2-adrenergic recep­tors agonist clonidine (0.3 mg/kg). Results and discussion: N-199/1 reduced immobility time (IT) and index of depression (ID) in FST, and did not affect IT in TST, either when administered repeatedly in Experiment 1, or acutely in Experiment 2. In Experiment 2, ketanse­rin enhanced the effect of N-199/1, decreasing ID by 36%, while WAY100635 and yohimbine antagonized it, increasing ID by 27% and IT by 115%, respectively, in comparison with N-199/1. N-199/1 attenuated the effect of ondansetron, increasing IT by 36%. In Experiment, 3 N-199/1 reduced clonidine-induced hypothermia 1 h after the injection of clonidine. N-199/1 exhibited pronounced antidepressant properties in FST, an agonism to 5HT1A-receptors and an antagonism to 5HT2A/2C- and α2-receptors in tests of neuropharmacological interaction, which indicates an atypical mechanism of its antidepressant action. Conclusion: The antidepressant effect of N-199/1 is due to the stimulation of 5HT1A-receptors and blockade of 5HT2A/2C- and α2-receptors. Graphical abstract:

REVERSAL OF CLONIDINE-INDUCED HYPOTHERMIA BY DECAFFEINATED TEA/COFFEE EXTRACT, AND THEIR FRACTIONS IN MICE

Objective: To study the effect of decaffeinated tea extract (DTE) and decaffeinated coffee extract (DCE) and their respective fractions viz: chloroform fractions (DTCf and DCCf), ethyl acetate fractions (DTEa and DCEa), diethyl ether fractions (DTDe and DCDe) and acetone-water fractions (DTAw and DCAw) against clonidine-induced hypothermia in mice. Methods: Clonidine (0.1 mg/kg, i. p.) administered to a group of mice pretreated 30 min before with the dose of DTE or DCE or their respective fractions. Rectal temperature was measured at the time of clonidine administration and thereafter at every 30 min up to 2 h test period. Results: DTE 200 DTE 300 has significantly inhibited clonidine-induced hypothermia. Among the fractions tested, DTE fraction-DTEa 100 and 200 and DCE fractions DCDe 200 and DCAw 200 significantly (p<0.0001) reversed clonidine-induced hypothermia; the effect of DTEa was found to be more sustained. Conclusion: Both, the decaffeinated tea and coffee contain ingredients that reverse clonidine-induced hypothermia, but they are required to do so in very large doses which are not achievable with normally administered doses of decaffeinated tea or coffee.

The effect of new derivatives of tietan-1,1-dioxide on some mediator systems of the brain

Aim. To study the effect of new derivatives of 3 substituted tietan-1,1-dioxide on some mediator systems of the brain in order to determine the possible mechanism of antidepressant effect of these compounds. Methods. In an experiment with male mice studied was the effect of three most active derivatives of tietan-1,1-dioxide, which exhibit antidepressant properties [3 methooxytietan-1,1-dioxide (H14), 3-(2-isopropoxy-5-methylphenoxy)-tietan-1,1-dioxide (H40) and 3-phenylsulphonyltietan-1,1-dioxide (N69)] on the neurotransmitter systems of the brain. In the experiments used were the tests of pharmacological interaction with a sympatholytic reserpine, with a nonselective agonist of dopamine receptors apomorphine, with a dopamine receptor antagonist haloperidol, with a precursor of serotonin 5-oxytryptophan, with a precursor of dopamine levodopa, with an α2-adrenoceptor agonist clonidine, and with an agonist of M-cholinoceptors arecoline. Results. It has been shown that the spectrum of neuropharmacological effects of new derivatives of tietan-1,1-dioxide (H14, H40, N69) is diverse and is associated with the effects on the adrenergic, dopaminergic and serotonergic brain structures. Thus, H14 reduces the severity of hypothermia induced by reserpine, apomorphine, clonidine, and levodopa, as well as the severity of reserpine ptosis, haloperidol catalepsy and 5- oxytryptophan hyperkinesis. H40, in contrast to H14, has no effect on haloperidol catalepsy and hypothermia induced by levodopa, while H69 has no effect on clonidine-induced hypothermia. All the compounds do not alter the latent period and duration of the arecoline tremor. Conclusion. New derivatives of tietan-1,1-dioxide possess properties, which are inherent to antidepressants, and may be recommended for further in-depth study of their antidepressant activity.

Effect of ethanolic extract of Rubia peregrina L. (Rubiaceae) on monoamine-mediated behaviour

In the traditional system of medicine in Sardinia, Rubia peregrina (RP) is reported as an aphrodisiac herb. Since aphrodisiacs may also have dopaminergic activity, and there can be a reciprocal relationship between dopaminergic and serotonergic functions in the central nervous system, the aim here was to study the effect of the ethanolic extract of the aerial parts of R. peregrina on monoamine-mediated behaviour. The RP (100 and 200 mg kg−1 intraperitoneally) significantly inhibited haloperidol (1 mg kg−1 i.p.) induced catalepsy in mice (p < 0.01, dopamine-mediated response) lithium sulphate induced head twitches in rats (serotonin-mediated response) and was without effect on clonidine-induced hypothermia in rats (noradrenaline-mediated response). The study concludes that R. peregrina improves the dopaminergic function, diminishes the serotonin-mediated function and is devoid of any effect on the noradrenergic function. The study suggests that we should carry out further experiments to investigate the psychopharmacological profile of R. peregrina.

Study of Adrenergic, Imidazoline, and Endothelin Receptors in Clonidine-, Morphine-, and Oxycodone-Induced Changes in Rat Body Temperature

Objectives: The potentiation of morphine or oxycodone analgesia by endothelin-A (ET_A) receptor antagonists and imidazoline/α₂-adrenergic agonists is well documented. However, the effect of morphine or oxycodone in combination with an ET_A receptor antagonist or an imidazoline/α₂ adrenergic agonist on body temperature is not known. The present study was carried out to study the role of ET_A and imidazoline/α₂ adrenergic receptors in body temperature effects of morphine, oxycodone, and clonidine in rats. Methods: Body temperature was determined in male Sprague-Dawley rats treated with morphine, oxycodone, or clonidine. Yohimbine, idazoxan, and BMS182874 were used to determine the involvement of α₂-adrenergic, imidazoline, and ET_A receptors, respectively. Key Findings: Morphine and oxycodone produced hyperthermia which was not affected by α₂-adrenergic antagonist yohimbine, imidazoline/α₂-adrenergic antagonist idazoxan, or ET_A receptor antagonist BMS182874. Clonidine alone produced hypothermia that was comparable to the hypothermia observed with clonidine plus morphine or oxycodone. The hypothermic effect of clonidine was blocked by idazoxan and yohimbine. The blockade by idazoxan was more pronounced compared to yohimbine. Clonidine hypothermia was not affected by BMS182874. Conclusions: This is the first report demonstrating that ET_A receptors do not influence morphine- and oxycodone- induced hyperthermia or clonidine-induced hypothermia. Imidazoline receptors and α₂-adrenergic receptors are involved in clonidine-induced hypothermia, but not in morphine- and oxycodone-induced hyperthermia.

Evaluations of antidepressant activity of Anacyclus pyrethrum root extract

The present study was designed to screen antidepressant activity of Anacyclus pyrethrum (AP) root extract. An experiment was designed by different method such as Locomotor activity, Haloperidol-induced catalepsy, Forced swim test (FST), Tail suspension test (TST), Clonidine-induced hypothermia and Reserpine-induced hypothermia on Swiss male albino mice. Standard root extract of Anacyclus pyrethrum (AP root extract) showed an increase in ambulatory behaviour indicating a stimulant effect of the photoactometer. AP root extract produces a significant antidepressant effect in both FST and TST as they reduced the immobility. AP root extract was found to be effective in reversing hypothermia produced by clonidine and reserpine. In our study, we found that AP root extract inhibited haloperidol-induced catalepsy. These study suggest that AP root extract might produce antidepressant effect by interaction with adrenergic and dopamine receptor thereby increasing the level of noradrenaline and dopamine in brains of mice. Key words: Anacyclus pyrethrum, antidepressant activity, forced swim test and tail suspension test

Chronic oral nicotine increases brain [3H]epibatidine binding and responsiveness to antidepressant drugs, but not nicotine, in the mouse forced swim test

Smoking rates among depressed individuals is higher than among healthy subjects, and nicotine alleviates depressive symptoms. Nicotine increases serotonergic and noradrenergic neuronal activity and facilitates serotonin and noradrenaline release. In mice, acute nicotine administration enhances the activity of antidepressants in the mouse forced swim (mFST) and tail suspension tests. Here, we investigated if this action of nicotine is also reflected in a chronic treatment regimen. After chronic treatment with nicotine in the drinking water, mice were challenged with nicotine, duloxetine, citalopram, and reboxetine in the mFST. Additionally, 8-OH-DPAT- and clonidine-induced hypothermia was tested in vehicle- and nicotine-pretreated mice, as a measure of 5-HT(1A) and alpha(2)-adrenoceptor function, respectively. Finally, the effects on the brain expression levels of high- and low-affinity nicotinic acetylcholine receptors (nAChRs) and the transporters for serotonin (SERT) and noradrenaline (NET) were assessed using [(3)H]epibatidine, [(3)H]alpha-bungarotoxin, [(3)H]citalopram, and [(3)H]nisoxetine binding, respectively. In the mFST, nicotine-pretreated mice did not show altered response to the nicotine challenge, but increased responses to all three antidepressants tested were observed when compared to mice that had been administered drinking water without nicotine. There was no change in hypothermic responses to 8-OH-DPAT or clonidine. [(3)H]epibatidine binding was significantly increased in all brain regions investigated; whereas, [(3)H]alpha-bungarotoxin, [(3)H]citalopram, and [(3)H]nisoxetine binding were not altered, indicating that chronic oral nicotine increases the expression and/or affinity of high-affinity nAChRs, but not low-affinity nAChRs, SERT, or NET. It is suggested that the increased sensitivity to antidepressants after chronic nicotine exposure involves increased high-affinity nAChR-mediated neurotransmission.

Nootropic and Behavioural Actions of Saponins Isolated from Bark of Albizia lebbeck

Objectives: In the previous study saponins isolated from leaves of Albizzia lebbeck exhibited nootropic activity in mice. The objectives of the present study were therefore to assess the nootropic activity of saponin containing fraction isolated from the bark of Albizzia lebbeck using different paradigms and to study its effect on the behaviour mediated by various neurotransmitters like acetylcholine, noradrenaline, serotonin, dopamine and gamma-aminobutyric acid. Materials and methods: The nootropic effect of saponin containing n-butanolic fraction (ALBF) obtained from dried bark of A. lebbeck was studied in male albino mice using passive shock avoidance, elevated plus maze, and object recognition. The effect of ALBF was studied on sodium nitrite-induced respiratory arrest (acetylcholine mediated behaviour), clonidine-induced hypothermia and passivity (noradrenaline mediated behaviour), baclofen-induced hypothermia and passivity (gamma-aminobutyric acid mediated behaviour), haloperidol-induced catalepsy (dopamine mediated behaviour), and lithium-induced head twitches (serotonin mediated behaviour). The effects were compared with those of piracetam. Results: ALBF reduced latency to reach shock free zone and number of mistakes in the passive shock avoidance paradigm. ALBF antagonized amnesic effect of scopolamine in this test. ALBF per se reduced transfer latency on the elevated plus maze. The inflexion ratio reduced by scopolamine was not increased significantly by ALBF. In the object recognition test, ALBF explored the familiar object significantly earlier compared to that by piracetam. Both piracetam and ALBF antagonized the amnesic effect of scopolamine in this experiment. ALBF potentiated hypothermic effect of clonidine but could not antagonize the baclofen-induced hypothermia significantly. ALBF increased clonidine-induced passivity and inhibited baclofen-induced passivity. ALBF was without any effect on sodium nitrite-induced respiratory arrest and haloperidol-induced catalepsy but reduced lithium-induced head twitches. Conclusion: The ALBF, saponins containing fraction of A. lebbeck per se exhibited nootropic activity and reversed amnesic effect of scopolamine. The ALBF exhibited decreased noradrenergic and serotonergic transmission and was without any effect on cholinergic and dopaminergic transmission. The study indicates that the saponins isolated from A. lebbeck possess potential nootropic activity. The absence of cholinergic and dopaminergic involvement in nootropic activity of ALBF may be utilized to study the involvement of other neurotransmitters in the cognitive function.

Effect of Butea monosperma on Memory and Behaviour Mediated via Monoamine Neurotransmitters in Laboratory Animals

Objective: To identify the fraction responsible for the nootropic activity of Butea monosperma and to correlate nootropic activity with monoamine and acetyl choline mediated behaviour. Materials and methods: The acetone soluble part of petroleum ether and ethanolic extracts of dried flowers of Butea monosperma exhibited nootropic activity in the elevated plus maze paradigm and active avoidance learning. The effect of active fraction was observed on clonidine-induced hypothermia (noradrenaline mediated behaviour), haloperidol-induced catalepsy (dopamine mediated behaviour), lithium-induced head twitches (serotonin mediated behaviour) and sodium nitrate induce respiratory arrest (acetylcholine mediated behaviour). Results: The elevated plus maze paradigm indicated that the nootropic activity resides in the ethyl acetate (PEF) fraction of petroleum ether extract and ethyl acetate fraction (AEF) and methanolic fraction (AMF) of alcoholic extract. These fractions reversed scopolamine-induced amnesia in mice. The fractions influenced the monoamine-mediated behavior differentially. The approximate LD 50 of PEF, AEF and AMF were estimated as 0.3g/kg, >5.0g/kg and 3g/kg i.p. respectively. Conclusion: The PEF, AEF and AMF exhibited significant nootropic activity had differential effect on the monoamine mediated behaviour indicating different modes of their nootropic activity. These fractions need to be investigated further to understand mechanism of their action.

Reboxetine: a pharmacologically potent, selective, and specific norepinephrine reuptake inhibitor

Background: Reboxetine is a potent antidepressant, with efficacy comparable to that of imipramine, desipramine, and fluoxetine, and has improved side-effect profile. The basis of its efficacy and improved tolerability is sought through studies of reboxetine in a number of pharmacological models of depression. Methods: Pharmacological selectivity for uptake systems was defined by uptake and binding assays for the three monoamine uptake sites. Specificity was determined in 39 different receptor and 6 enzyme assays. In vivo selectivity was defined by measurement of neuronal firing rates in the locus coeruleus, dorsal raphe, and substantia nigra. Reserpine-induced blepharospasm and hypothermia, clonidine-induced hypothermia, defined reboxetine’s in vivo pharmacology. Reboxetine’s antidepressant potential was evaluated behaviorally by the tail-suspension test, forced swimming, and the DRL 72 operant responding test. Results: Reboxetine is a potent, selective, and specific norepinephrine reuptake inhibitor (selective NRI) as determined by both in vitro and in vivo measurements. Unlike desipramine or imipramine, reboxetine has weak affinity (Ki > 1000 nmol/L) for muscarinic, histaminergic H1, adrenergic α 1, and dopaminergic D 2 receptors. In vivo action of reboxetine is entirely consistent with the pharmacological action of an antidepressant with preferential action at the norepinephrine reuptake site. Reboxetine showed an antidepressant profile in all tests of antidepressant activity used. Significant decreases in immobility were observed in the tail suspension test and behavioral despair test. Increased efficiency in responding was observed in the DRL 72 test. Conclusions: Reboxetine is a potent, selective, and specific noradrenergic reuptake inhibitor. It has a superior pharmacological selectivity to existing tricyclic antidepressants and selective serotonin reuptake inhibitors when tested in a large number of in vitro and in vivo systems. Given the pharmacological profile, reboxetine is expected to be a selective and potent tool for psychopharmacological research. The use of reboxetine in the clinic will also help clarify the role norepinephrine plays in depression.

Psychopharmacological profile of the selective serotonin reuptake inhibitor, paroxetine: implication of noradrenergic and serotonergic mechanisms.

The present study was designed to evaluate the psychopharmacological profile of the selective serotonin reuptake inhibitor paroxetine, and thus assess potential noradrenergic and/or serotonergic activity. Paroxetine dose-dependently increased mobility time in the mouse forced swimming test (8, 16, 32 and 64 mg/kg, i.p.) and reduced spontaneous locomotor activity when administered at a high dose (64 mg/kg, i.p.). Prior administration of 8-hydroxy-2-(di-n-propylamino)tetralin (1 mg/kg, i.p.), (+/-) pindolol (32 mg/kg, i.p.) or 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (RU 24969) (1 mg/kg, i.p.) potentiated the antidepressant-like effects of subactive doses of paroxetine (1, 2 and 4 mg/kg, i.p.) in the mouse forced swimming test. These effects were antagonized by prior administration of 1-(2-methoxyphenyl)-4-[-(2-phthalimido)butyl]piperazine) (0.5 mg/kg, i.p.). Complementary studies suggested that RU24969-induced anti-immobility effects were a result of an increase in locomotor activity; other interactions were without increase/decrease in locomotor activity. Acute administration of paroxetine (8, 16, and 32 mg/kg, i.p.) antagonized the hypothermia induced by the D2/D1 receptor agonist, apomorphine (16 mg/kg, s.c.), while repeated treatment with paroxetine (32 mg/kg) attenuated clonidine-induced (0.5 mg/kg, i.p.) hypothermia. Pre-treatment with the serotonergic neurotoxin, para-chlorophenylalanine attenuated the anti-immobility effects of low doses of paroxetine (8 and 16 mg/kg, i.p.) in the forced swimming test, whereas a higher dose of paroxetine remained active (32 mg/kg, i.p.). The results of the present study indicated that paroxetine displayed both noradrenergic-like and serotonergic-like activity in the pre-clinical psychopharmacological tests employed.

The pharmacology of fluparoxan: a selective α2‐adrenoceptor antagonist

1. This paper describes the pharmacology of the novel alpha 2-adrenoceptor antagonist fluparoxan (GR 50360) which is currently being studied clinically as a potential anti-depressant. Idazoxan and yohimbine were included in many studies for comparison. 2. In the rat isolated, field-stimulated vas deferens and the guinea-pig isolated, field-stimulated ileum preparations, fluparoxan was a reversible competitive antagonist of the inhibitory responses to the alpha 2-adrenoceptor agonist UK-14304 with pKB values of 7.87 and 7.89 respectively. In the rat isolated anococcygeus muscle, fluparoxan was a much weaker competitive antagonist of the contractile response to the alpha 1-adrenoceptor agonist phenylephrine with a pKB of 4.45 giving an alpha 2: alpha 1-adrenoceptor selectivity ratio of greater than 2500. 3. In the conscious mouse, fluparoxan (0.2-3.0 mg kg-1) was effective by the oral route and of similar potency to idazoxan in preventing clonidine-induced hypothermia and antinociception. In the rat, UK-14304-induced hypothermia (ED50 = 1.4 mg kg-1, p.o. or 0.5 mg kg-1, i.v.) and rotarod impairment (ED50 = 1.1 mg kg-1 p.o. or 1.3 mg kg-1, i.v.) were antagonized by fluparoxan. Fluparoxan, 0.67-6 mg kg-1, p.o., also prevented UK-14304-induced sedation and bradycardia in the dog. 4. In specificity studies fluparoxan had low or no affinity for a wide range of neurotransmitter receptor sites at concentrations up to at least 1 x 10(-5) M. It displayed weak affinity for 5-HT1A (pIC50 = 5.9) and 5-HT1B (pKi = 5.5) binding sites in rat brain. 5. We conclude that fluparoxan is a highly selective and potent alpha 2-adrenoceptor antagonist. The density of rat brain [3H]-dihydroalprenolol binding sites was reduced by 26% when fluparoxan was administered chronically for 6 days at a dose of 12 mg kg- 1 orally twice daily. The down-regulation of beta-adrenoceptors by fluparoxan is consistent with its antidepressant potential.

Antagonism of the hypothermic effect of clozapine in mice by centrally-active α2-adrenergic antagonists and α1-adrenergic agonists

Hypothermia induced by either clozapine or clonidine in mice was blocked by the alpha 2-adrenergic antagonists yohimbine, idazoxan, CH-38083, SKF 86466, and L-657,743. These effects were dose related, and the ID50 values for inhibition of clozapine- or clonidine-induced hypothermia were fairly comparable. The order of potency for blocking clonidine-induced hypothermia was: L-657,743 greater than CH-38083 greater than yohimbine greater than idazoxan greater than SKF 86466. A very similar blockade hierarchy for clozapine-induced hypothermia was observed, with the order of the two most effective compounds being reversed. Hypothermia induced by either compound was not blocked by the peripherally-acting, selective alpha 2-adrenergic antagonist, L-659,066, indicating that blockade by the other compounds occurred centrally. The centrally-acting, alpha 1-adrenergic agonists St 587, cirazoline, and SKF 89748 were very effective in blocking the response to clozapine, but ineffective in antagonizing clonidine-induced hypothermia. The ED50 values for the blockade of this response to clozapine, however, did not correlate with their reported potencies in stimulating either peripheral or central alpha 1-adrenergic receptors. This indicates that clozapine-induced hypothermia in mice is not a suitable model for evaluating the properties of central alpha 1-adrenergic compounds. Moreover, since the clonidine-induced hypothermia is not influenced by alpha 1-adrenergic agonists, this paradigm is preferable to clozapine-induced hypothermia in the assessment of alpha 2-adrenergic antagonism The ability of alpha 2-adrenergic antagonists to block clozapine-induced hypothermia may result from the central overflow of norepinephrine, which is known to be brought about by this group of compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Mafoprazine, a Phenylpiperazine Derivative, on the Central Dopaminergic System

The effects of mafoprazine, a new phenylpiperazine derivative, on the central dopaminergic system were studied. Mafoprazine, like chlorpromazine and haloperidol, reduced the apomorphine-induced cage-climbing behavior in mice, emesis in dogs and stereotyped behavior in monkeys; methamphetamine-induced hyperlocomotion and group toxicity in mice; and agitation in rats. Mafoprazine inhibited the unilateral circling behavior induced by methamphetamine and apomor-phine in rats with 6-hydroxydopamine-induced lesions in the unilateral nigrostriatal neuronal tract. The potency of mafoprazine in these experiments was almost equal to that of chlorpromazine and about one-tenth that of haloperidol. The cata-leptogenic activity of mafoprazine was lower than those of chlorpromazine and haloperidol. Mafoprazine potentiated clonidine-induced hypothermia. These results suggest that mafoprazine has a relatively selective postsynaptic dopamine D2-receptor blocking action in the nucleus accumbens compared with chlorpromazine and haloperidol and suggest that mafoprazine also has α2-adrenoceptor-stimulating actions.

Effects of mafoprazine, a phenylpiperazine derivative, on the central dopaminergic system.

The effects of mafoprazine, a new phenylpiperazine derivative, on the central dopaminergic system were studied. Mafoprazine, like chlorpromazine and haloperidol, reduced the apomorphine-induced cage-climbing behavior in mice, emesis in dogs and stereotyped behavior in monkeys; methamphetamine-induced hyperlocomotion and group toxicity in mice; and agitation in rats. Mafoprazine inhibited the unilateral circling behavior induced by methamphetamine and apomorphine in rats with 6-hydroxydopamine-induced lesions in the unilateral nigrostriatal neuronal tract. The potency of mafoprazine in these experiments was almost equal to that of chlorpromazine and about one-tenth that of haloperidol. The cataleptogenic activity of mafoprazine was lower than those of chlorpromazine and haloperidol. Mafoprazine potentiated clonidine-induced hypothermia. These results suggest that mafoprazine has a relatively selective postsynaptic dopamine D2-receptor blocking action in the nucleus accumbens compared with chlorpromazine and haloperidol and suggest that mafoprazine also has alpha 2-adrenoceptor-stimulating actions.

Antagonism of clonidine-induced hypothermia by alpha adrenoceptor antagonists in electrically stimulated mice

The involvement of receptor subtypes in clonidine-induced hypothermia in electrically stimulated mice was studied using various alpha-adrenoceptor antagonists. Yohimbine, the selective alpha 2-adrenoceptor antagonist significantly blocked the action of low dose (50 micrograms/kg i.p.) of clonidine pretreated with Minimal Threshold Shock (12 mA, 0.2 Sec), while prazosin, selective alpha 1-adrenoceptor antagonist partially blocked the action, suggesting predominant involvement of alpha 2 and partial involvement of alpha 1-adrenoceptors. Under similar conditions when clonidine was used in higher dose (500 micrograms/kg i.p.), its action was blocked by prazosin, phenoxybenzamine and yohimbine suggesting involvement of both alpha 1 and alpha 2-adrenoceptors. In case of animals pretreated with Maximal Threshold Shock (36 mA, 0.2 Sec) the hypothermic action of clonidine in lower dose was blocked by all the three antagonists viz. prazosin, phenoxybenzamine and yohimbine, suggesting involvement of both alpha 1 and alpha 2-adrenoceptors, however, when clonidine was used in the higher dose, the action was significantly antagonised by prazosin and partially by yohimbine, suggesting predominant involvement of alpha 1 and partial involvement of alpha 2-adrenoceptors.

α 2-antagonistic effect of N-carbamoyl-2-(2,6-dichlorophenyl) acetamidine hydrochloride (LON-954)

The effect of N-carbamoyl-2-(2,6-dichlorophenyl) acetamidine hydrochloride (LON-954) on α 2-adrenoceptors was studied in in vivo and in vitro preparations. Like yohimbine, LON-954 antagonised the clonidine-induced inhibition of twitch responses in the Auerbach's plexus of guinea pig ileum and rat vas deferens preparations. It also reversed the anti-convulsant effect of clonidine on pentylenetetrazol (PTZ)-induced convulsions in the rat, a property shared by yohimbine. However LON-954 failed to prevent the hypothermic response to clonidine in mice. The dissimilarity in action of LON-954 and yohimbine on clonidine-induced hypothermia could be due to the fact that the anticlonidine effect of yohimbine on hypothermia is mediated through its antiserotonin action. The results indicate that LON-954 acts as an α 2-antagonist both centrally and peripherally.

Effect of long-term rolipram administration on the sensitivity of [formula omitted] in rat brain

The effects of single and chronic doses of rolipram on the sensitivity of α 2- adrenoceptors have been compared with the phosphodiesterase inhibitors, isobutylmethylxanthine (IBMX) and ICI 63,197, and the antidepressant, desipramine. While pretreatment with a single dose of rolipram, ICI 63,197 or IBMX administered either 1 or 24 h prior to clonidine (0.1 mg/kg) enhanced clonidine-induced hypothermia and hypoactivity, chronic dosing (twice daily for 14 days) with desipramine (10 mg/kg) or rolipram (5 mg/kg) antagonized these behavioural effects. In contrast, chronic dosing with IBMX or ICI 63,197 failed to antagonize clonidine-induced hypothermia and hypoactivity. In binding studies neither ICI 63,197, IBMX, rolipram nor desipramine induced changes in the binding of 3H-labelled clonidine to rat cerebral cortical membranes following chronic administration. The failure of ICI 63,107 and IBMX to antagonize clonidine-induced hypothermia and hypoactivity suggests that the antidepressant effect of rolipram is independent of its phosphodiesterase inhibitor property.

Chronic treatment with antidepressant drugs and ECT differentially modifies the hypothermic action of clonidine and guanfacine.

The hypothermia inducing action of clonidine and guanfacine was abolished by yohimbine and idazoxan pretreatment which suggests an alpha 2-adrenoceptor involvement in this effect. The effects of acute and chronic treatment with the antidepressant drugs desipramine (DMI), amitriptyline (AMI), maprotiline (MAP), mianserin (MIAN), iprindol (IPR), alaproclate (ALA) and electroconvulsive treatment (ECT) on the hypothermic action of the alpha 2-adrenoceptor agonists clonidine and guanfacine were studied. Acute administration of MIAN potentiated clonidine induced hypothermia whereas acute MIAN, IPR and ALA potentiated guanfacine induced hypothermia. Repetitive DMI, AMI and MAP treatment attenuated clonidine-induced hypothermia whereas guanfacine-induced hypothermia was potentiated by chronic treatment with DMI, AMI, MAP and MIAN, ECT applied without anaesthesia attenuated both clonidine and guanfacine hypothermia, however, under ethyl ether anaesthesia ECT was effective only towards guanfacine hypothermia. This discrepancy is discussed in terms of the relative selectivity of the agonists used, the reliability of agonist studies for indexing receptor function, and possible pharmacokinetic interaction.

Central action of ipsapirone, a new anxiolytic drug, on serotoninergic, noradrenergic and dopaminergic functions.

Ipsapirone (TVX Q 7821, 2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-1,2-benzisothiazol-3- (2H)one-1, 1-dioxidehydrochloride), a new anxiolytic drug in respect of the evaluation of its effect on central 5-hydroxytryptamine (5-HT), noradrenaline and dopamine functions was studied. It was found that ipsapirone inhibits induced by 8-OH-DPAT and 5-methoxydimethyltryptamine (agonists of 5-HT1A receptors) behavioural effects (flat body posture and forepaw treading) in normal and reserpinized rats. Ipsapirone partly inhibited in rats but not in mice the 8-OH-DPAT-induced hypothermia. Ipsapirone, administered at high doses, decreased the body temperature in rats and mice, inhibited the 5-hydroxytryptophan-induced head twitches in mice and the tryptamine-induced convulsions and tremor in rats. In the hind limb flexor reflex preparation of the spinal rat only high doses of the drug inhibited stimulation induced by quipazine, m-chlorphenylpiperazine, 8-OH-DPAT and St 587 (an agonist of alpha 1-adrenoceptors). Ipsapirone did not block the fenfluramine- and m-chlorphenylpiperazine-induced hyperthermia in rats at an ambient temperature of 28 degrees C. The drug did not affect clonidine-induced sedation and inconsiderably attenuated clonidine-induced hypothermia in mice. It attenuated the d-amphetamine-induced locomotor hyperactivity in mice and rats but, given alone, decreased the locomotor activity. The obtained results indicate that ipsapirone exhibits 5-HT1A antagonistic effect, and only at high doses it can also produce an inhibitory effect on 5-HT2 and the alpha 1-adrenergic function.