Reserpine-induced Hypothermia Research Articles

Possible explanations for the antagonism by nicotine against reserpine-induced depletion of monoamines in mouse brain.

The inhibitory effect of nicotine pretreatment on reserpine-induced depletion of monoamines in mouse brain was investigated. The depletion of brain monoamines by 24 h after intraperitoneal injection of reserpine (2 mg/kg) was dose-dependently inhibited by nicotine (0.3-10 mg/kg, s.c.) pretreatment 20 min before reserpine injection. This effect of nicotine was more marked on dopamine depletion than on noradrenaline or 5-hydroxytryptamine depletion. The nicotine pretreatment also inhibited the reserpine-induced hypothermia and decrease in the locomotor activity. When reserpine (2 mg/kg) was injected intraperitoneally, the inhibitory effect of nicotine (3 mg/kg, s.c.) on the reserpine-induced depletion of brain monoamines and heart noradrenaline was not antagonized by hexamethonium (8 mg/kg, s.c.) but rather potentiated by mecamylamine (2 mg/kg, s.c.). However, when reserpine (0.5 mg/kg) was injected intravenously, pretreatment with nicotine (3 mg/kg, s.c.) inhibited the reserpine-induced dopamine depletion only, and this effect of nicotine was completely blocked by mecamylamine but not by hexamethonium. These results suggest that inhibitory effect of nicotine on the intraperitoneal reserpine-induced depletion of brain monoamines is due to an inhibition of absorption of reserpine, and that central nicotinic action is also involved in the antagonism by nicotine of reserpine-induced dopamine depletion.

Potential Antidepressive Properties of Amantadine, Memantine and Bifemelane

The effects of amantadine, its dimethyl derivative, memantine and the chemically unrelated compound bifemelane were tested for antidepressant activity. Reserpine-induced hypothermia and the forced swim test (Porsolt test) were selected for this purpose. In the former test amantadine and bifemelane but not memantine were effective. In the forced swim test all three agents produced antidepressive-like activity (decreased immobility time), but in case of bifemelane it was less pronounced. The effect in the forced swim test was specific i.e. it was apparently not the result of an increase in general activity as evidenced by control experiments in the open field. The mechanism of amantadine and memantine action may involve indirect dopaminomimetic activity resulting from the blockade of NMDA receptors. However in reserpine-induced hypothermia this explanation is not valid considering the lack of effect of memantine and positive action of amantadine. Hence, amantadine may have an additional central sympathomimetic action that memantine is lacking. Bifemelane antidepressant-like activity might be attributed to an enhancement of noradrenergic transmission. We suggested that amantadine and bifemelane could be particularly useful therapeutically when depressive symptoms are present in patients suffering from Parkinson's disease and dementia.

<b>EFFECTS OF NS-3, AN ANALOGUE OF THYROTROPIN-RELEASING HORMONE, ON THE CENTRAL NERVOUS </b><b>SYSTEM </b>

The central nervous system (CNS) effects of thyrotropin-releasing hormone (TRH) and of its analogue, (3R,6R)-6-methyl-5-oxo-3-thiomorpholinylcarbonyl-L-histidyl-L-prolinamide tetrahydrate (NS-3, CG-3703) on the CNS were compared in mice and rats. NS-3 and TRH increased the spontaneous locomotor activity, reversed reserpine-induced hypothermia, antagonized narcosis caused by pentobarbital Na and protected mice from loss of consciousness caused by head concussion

Effects of bupropion on core body temperature of mice.

The effects of bupropion on core body temperature of intact or reserpinized mice were studied. Intraperitoneal (IP) administration of bupropion to mice induced a dose-dependent hypothermia. The response of bupropion was decreased by the D-2 antagonist sulpiride or pimozide, but not by the D-1 antagonist SCH 23390, antimuscarinic drug atropine, alpha-adrenergic blocker phenoxybenzimine, beta-adrenergic antagonist propranolol or antiserotonergic methergoline. Reserpine induced hypothermia, which was reversed by bupropion administration. The reversal response of bupropion was reduced by propranolol, but not sulpiride, SCH 23390, phenoxybenzamine, atropine or methergoline. It is concluded that bupropion-induced hypothermia may be mediated through D-2 receptor activation, while the reversal of reserpine-induced hypothermia by bupropion may be exerted through beta-adrenergic stimulation.

New Hybrids of Quipazine and Trazodone as Selective Inhibitors of Uptake of 5-Hydroxytryptamine

Two new congeners, 4-(chloropropyl)-1-(2-quinolyl)piperazine- and 2-[3-[4-[2-(quinolyl)]-1-piperazinyl]propyl]-1,2,4-triazolo]4,3-a]pyridin-3(2H)-one, of trazodone were synthesized and found to be potent and selective inhibitors of synpatosomal uptake of 5-hydroxy-tryptamine [5-HT, serotonin; IC50 = norepinephrine > 5 μM, 5-HT = 210-890 nM], with minimal effects in antagonizing (−)-apomorphine-induced climbing behavior and suppression of spontaneous locomotor activity in mice (ED50 > 50 mg/kg). The two compounds behaved like atypical antidepressants, since they weakly antagonized reserpine-induced hypothermia. The acute toxicity studies have shown that these compounds were less lethal when compared with imipramine or quipazine. Furthermore, chronic treatments (20 mg/kg, daily for 10 and 21 days) significantly decreased the isoprenaline-induced increase in cyclic AMP in the rat brain cortex, suggesting desensitization of 0-adrenocep-tors. These findings point to the effects of these compounds as potential antidepressants dealing with specific serotonergic mechanisms.

Nicotinamide ethers: novel inhibitors of calcium-independent phosphodiesterase and [3H]rolipram binding

The synthesis and biological properties of a series of nicotinamide ethers are described. These compounds, structurally novel calcium-independent phosphodiesterase inhibitors, also inhibit the binding of [3H]rolipram to rat brain membranes and reverse reserpine-induced hypothermia in the mouse. Several compounds exhibited potent in vivo activity comparable to the standard agent, rolipram.

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.

Close correlation between behavioural response and binding in vivo for inhibitors of the rolipram-sensitive phosphodiesterase

The antidepressant rolipram interacts in vitro with a binding site in brain tissue labeled by 3H-rolipram. A 3H-rolipram binding assay was employed in vivo to compare the affinity of rolipram-related compounds and reference phosphodiesterase (PDE) inhibitors with their potency in behavioural measures for potential antidepressant property. In two species, mice and rats, the potency of a number of compounds to antagonise reserpine-induced hypothermia (mice) and to induce head twitches (rats) was determined, as well as their potency to displace 3H-rolipram from forebrain binding sites in vivo. The treatment schedules for the two series of experiments were identical. Significant correlations between pharmacological effects and displacement of 3H-rolipram binding in vivo were observed in both species. Since the reference PDE inhibitors closely fit into the binding-pharmacological activity relationship, the PDE inhibitory properties of the substances involved are discussed.

Synthesis and central nervous system actions of thyrotropin-releasing hormone analog containing a dihydroorotic acid moiety

A series of thyrotropin-releasing hormone (TRH) analogues in which the pyroglutamic acid residue was replaced by (S)-4,5-dihydroorotic acid (Dio-OH) and the related derivatives were prepared. Their central nervous system actions based on spontaneous locomotor activity, antagonistic effect on reserpine-induced hypothermia, and antagonistic effect on pentobarbital anesthesia were evaluated and the structure-activity relationships are discussed. Of these, (1-methyl-(S)-4,5-dihydroorotyl)-L-histidyl-L-prolinamide (14b) showed the most potent activities, which were 30-90 times greater than those of TRH. Moreover, the thyrotropin-releasing activity of 14b was about 50 times weaker than that of TRH, and compound 14b (TA-0910) was selected as a potent candidate.

Comparison of the effects of three indirect dopamine agonists, GK 13, GBR 12783 and dexamphetamine on behavioural tests involving central catecholaminergic transmissions

GK 13 (N-[1-(2-benzo (b) thiophenyl)-cyclohexyl] piperidine), GBR 12783 (1-[2-(diphenylmethoxy)-ethyl] 4-(3-phenyl propenyl)-piperazine and dexamphetamine are three indirect catecholaminergic agonists, acting via different neurochemical mechanisms. We have compared their effects in rodents, in several behavioral tests. All three drugs increased locomotion. The stimulant locomotor effect of dexamphetamine was more easily antagonized by haloperidol than that of GBR 12783 and GK 13. Only dexamphetamine reversed reserpine-induced akinesia. This reversal was prevented by pretreatment with either GK 13 or GBR 12783. The three drugs reduced pentobarbital sleeping time in mice. They induced rotation ipsilateral to a unilateral 6-OHDA lesion of the nigrostriatal dopaminergic pathway. The stereotypies induced by GK 13 and GBR 12783 were essentially limited to sniffing. Haloperidol-induced catalepsy was apparently more easily antagonized by dexamphetamine than by GK 13 or GBR 12783. GK 13 and GBR 12783 had no significant effects on body temperature. The three drugs displayed an anti-immobility effect in the "despair test". Dexamphetamine and GK 13 reversed the hypothermia induced by apomorphine (16 mg/kg), as well as reserpine-induced hypothermia and reserpine-induced ptosis. Dexamphetamine induced a dose-dependent anorectic effect, whereas GK 13 and GBR 12783 induced only a brief and partial anorexia. Similar observations were made on water intake. Pretreatment with either GBR 12783 or GK 13 did not affect the dexamphetamine-induced anorexia. Effects of the three drugs are discussed by reference to their known neurochemical properties on catecholaminergic transmission.

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.

Behavioural and neurochemical effects of Ro 40-7592, a new COMT inhibitor with a potential therapeutic activity in Parkinson's disease

Behavioural and some neurochemical effects of Ro 40-7592 (3,4-dihydroxy-4'-methyl-5-nitrobenzophenone), a new COMT inhibitor, were studied in rats and mice. Ro 40-7592 increased the effect of L-DOPA (plus benserazide) on locomotor activity, reserpine-induced hypothermia, and catalepsy induced by pimozide, haloperidol and fluphenazine. Locomotor hyperactivity induced by amphetamine or nomifensine, as well as stereotypy induced by amphetamine (but not apomorphine), were also increased by Ro 40-7592. The drug stimulated exploratory activity in the open field test. It decreased the levels of HVA and 3-MT, increased the level of DOPAC but did not change the levels of dopamine in the striatum, nucleus accumbens and frontal cortex. These results indicate that Ro 40-7592 may improve the therapy with L-DOPA (plus decarboxylase inhibitor) of Parkinson's disease.

The rise of body temperature induced by the stimulation of dopamine D 1 receptors is increased in acutely reserpinized mice

In naive mice, the selective D 1 agonist, SK & F 38393 (7.5–30 mg/kg s.c.), induced a significant rise of body temperature (0.51°C) which was antagonized by SCH 23390 (100 μg/kg s.c.) and by flupenthixol (0.4 mg/kg i.p.). In mice treated with reserpine (5 mg/kg s.c.) 18 h before testing, which on its own caused intense hypothermia (10–12°C), SK & F 38393 (1.87–30 mg/kg s.c.) induced a dose-dependent and more marked rise of body temperature (5–7°C). Similarly, SK&F 38393 (30 mg/kg s.c.) partially prevented reserpine-induced hypothermia. The central origin of the SK&F 38393 effects in reserpine-treated mice is indicated by the rise of body temperature induced by the i.c.v. administration of the drug (12.5–50 μg per mice). The SK&F 38393-induced rise of body temperature in acutely reserpinized mice was antagonized by SCH 23390 (50–200 μg/kg s.c.), clozapine (1.87–30 mg/kg i.p.) or chlorpromazine (2–32 mg/kg i.p.) but not by metoclopramide (25 or 100 mg/kg i.p.) or amisulpride (12.5 or 50 mg/kg). In naive mice, apomorphine (1 mg/kg s.c.) or LY 171555 (0.4 mg/kg s.c.) induced hypothermia which was antagonized by amisulpride (12.5 mg/kg i.p.); a transiently increased body temperature was even measured 30 min after apomorphine injection in amisulpride-treated mice. Apomorphine (1 mg/kg s.c.) induced a rise of body temperature in acutely reserpinized mice which was significantly reduced by SCH 23390 (50 and 200 μg/kg s.c.) and significantly increased by amisulpride (12.5 and 50 mg/kg i.p.). These data suggest that pharmacologically different dopamine receptor subtypes mediate different effects on body temperature in mice: D 1 dopamine receptors mediate a rise of body temperature which is increased in hypothermic reserpinized animals and dopamine receptors of the D 4 subtype mediate the decrease of body temperature in naive mice.

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.

Dopamine D 1 and D 2 receptors mediate opposite effects of apomorphine on the body temperature of reserpinized mice

In mice, rendered poikilothermic by a prior (18 hr) subcutaneous administration of reserpine (3 mg/kg), the subcutaneous administration of apomorphine increased dose-dependently the body temperature. This effect was potentiated by the specific D 1 dopamine antagonist sulpiride. On the contrary, it was reduced by the specific d 1 dopamine antagonist SCH 23390. A desensitization of D 2 receptors was produced by the repeated administration of the specific D 2 agonist RU 24926. This pretreatment led to an increased efficacy of apomorphine in antagonizing reserpine-induced hypothermia. Similarly, a desensitization of D 1 receptors was created by the repeated administration of the specific D 1 agonist CY 208–243. This pretreatment significantly diminished the efficacy of apomorphine in antagonizing reserpine-induced hypothermia. The repeated administration of the D1 agonist CY 208–243, in non-reserpinized mice, significantly increased the hypothermie effect of apomorphine (1 mg/kg). Thus, it appears that, in normal mice, but especially in reserpinized mice, the stimulation of D 1 receptors by apomorphine induces an increase in body temperature that is masked, especially in normal mice, by the hypothermic effect, resulting from the simultaneous stimulation of D 2 receptors.

Pharmacological Study of TA-0910, a New Thyrotropin-Releasing Hormone (TRH) Analog, (I): Effects on the Central Nervous System by Oral Administration

Effects of orally administered TA-0910, a new thyrotropin-releasing hormone (TRH) analog, on the central nervous system (CNS) were investigated and compared with those of TRH. TA-0910 shortened the duration of pentobarbital-induced sleep and antagonized reserpine-induced hypothermia at 0.3 mg/kg or more in mice. TA-0910 enhanced the spontaneous motor activity at the higher dose of 30 mg/kg in mice. The drug also activated acute spontaneous EEGs in rabbits at 1 mg/kg. TRH produced these effects at about 100 times higher doses than TA-0910. In antagonizing pentobarbital-induced sleep, the dose ratios of i.v. versus p.o. of TA-0910 and TRH were about 1/10 and 1/100, respectively. The duration of the antagonistic action of TA-0910 on pentobarbital-induced sleep in mice was about 8 times longer than that of TRH when administered orally as well as intraveneously. These potent and long-acting TA-0910 effects on the CNS are discussed in connection with its biotransformation.

Pharmacological effects of indeloxazine, a new cerebral activator, on brain functions distinct from other cerebral metabolic enhancers

The effects of indeloxazine hydrochloride [(±)-2-[(inden-7-yloxy)methyl]morpholine hydrochloride, YM-08054], a new cerebral metabolic enhancer, on learned behavior and central monoaminergic function were compared to those of other cerebral metabolic enhancers in animals. Indeloxazine enhanced passive learned behaviour in rats and ameliorated cerebral ischemia-induced learned disturbances in gerbils. Reserpine-induced hypothermia in mice, ponto-genicullo-occipital (PGO) waves in reserpinized cats and caudate spindle activity in cats were reduced by the administration of indeloxazine, suggesting that the drug possesses facilitatory effects on central monoaminergic systems. In contrast, piracetam, calcium-hopantenate. idebenone and bifemelane had no significant effect on learned behavior or central monoaminergic function, with the exception of bifemelane which antagonized reserpine-induced hypothermia. These results are in contrast to the findings that all tested cerebral metabolic enhancers, including indeloxazine, prolonged the survival time of mice subjected to anoxia. The greater effect of indeloxazine to other cerebral metabolic enhancers, in facilitating learned behavior, may be attributable to its broader effects on central monoaminergic systems.

Stimulation of central D1 dopamine receptors reverses reserpine-induced hypothermia in mice

In mice rendered poikilothermic by a prior (18 h) subcutaneous administration of reserpine (3 mg/kg) the injection of the D1 dopamine agonist SKF 38393 in doses of 1 mg/kg or more increased dose-dependently, the body temperature. The D1 dopamine antagonist SCH 23390, administered subcutaneously, antagonized, with an ID50 of 16 micrograms/kg, the reversal by SKF 38393 of reserpine-induced hypothermia. The intracerebroventricular administration of 1 microgram per mouse of SKF 38393 was sufficient to elevate by about 7 degrees C the temperature of reserpinized mice. It is concluded that stimulation of central D1 dopamine receptors leads to a marked reversal of reserpine-induced hypothermia; this may constitute a new test to investigate interaction of drugs with these receptors. In reserpine-pretreated mice, the dopamine (DA) agonist apomorphine, which stimulates both the D1 and D2 subtypes of DA receptors, increases body temperature according to a mechanism insensitive to the specific D2 DA antagonist sulpiride (Horowski 1978) or the preferential D2 DA antagonist haloperidol (Danielson, Coutts, Keashly and Tang 1985). This observation led us to believe that D1 DA receptors could be involved in the reversal of the hypothermia induced by reserpine. To check more directly the involvement of D1 DA receptors in the reversal of the reserpine-induced hypothermia we have tested the specific D1 agonist SKF 38393 (Setler, Sarau, Zirckle and Saunders, 1978), administered peripherally or intracerebroventricularly and we have studied its interaction with the specific D1 antagonist SCH 23390 (Iorio, Barnett, Leitz, Houser and Korduba, 1983).

Effect of reserpine on N-methylthiobenzamide-induced pulmonary edema: Role of lung norepinephrine and hypothermia

N-Methylthiobenzamide (NMTB) is a pneumotoxin which causes pulmonary edema and hydrothorax in rodents. Reserpine has been shown to attenuate the pneumotoxicity induced by NMTB [1]. Some of that evidence suggests that the protection afforded by reserpine occurs independently of its capacity to reduce peripheral 5-hydroxytryptamine (5-HT). We therefore investigated 2 other pharmacologic properties of reserpine, namely: (1) its capacity to reduce lung norepinephrine (NE); and (2) its capacity to induce hypothermia, in order to more fully understand its mechanism of protection. Pretreatment of mice or rats with 6-hydroxydopamine at a dose which reduced lung NE by approximately 80% did not affect the pneumotoxic response to NMTB. Thus a decrease in lung NE probably does not account for reserpine's protective effect. An investigation of reserpine's effects on core temperature revealed that mice dosed with a combination of reserpine + NMTB presented with core temperatures lower than mice treated with either compound alone. Mice placed in a cold environment (2°C) and dosed with NMTB presented with hypothermia and an attenuated toxic response to NMTB. Thus a reserpine-induced hypothermia could be allowing for a reduction of NMTB metabolism and consequent diminution of toxicity. These observations suggest that reserpine's capacity to protect animals against NMTB-induced pulmonary edema may in part be due to its capacity to induce hypothermia.

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

1. The dose-related effects of the selective alpha 2-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 100 mg kg-1 respectively, elicited a marked (10 degrees C) hypothermia, whereas the maximal hypothermic effect of clonidine (5.5 degrees C) was less pronounced and reached a plateau at a dose of 0.5 mg kg-1 i.p. 3. Reserpine (2.5 mg kg-1, s.c.) induced a marked hypothermia in the mouse; 18 h after injection body temperature had decreased to only slightly (0.5-1.5 degrees C) above ambient (19 degrees C). 4. All three alpha 2-agonists produced a partial dose-related reversal of reserpine-induced hypothermia; maximal thermogenic responses (9-10 degrees C increases in body temperature) were elicited by doses of 0.2, 0.5 and 16 mg kg-1 i.p. of clonidine, UK-14,304 and B-HT 933 respectively, and the log dose-response 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 alpha 2-adrenoceptor antagonists, idazoxan (0.05-0.5 mg kg-1), Wy 26392 (0.3-5.0 mg kg-1) and yohimbine (0.1-1.6 mg 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 alpha 1-adrenoceptor antagonists, prazosin (10 mg kg-1) and indoramin (3-10 mg kg-1), and the beta-adrenoceptor antagonist, propranolol (10 mg kg-1), only partially attenuated the thermogenic responses to the alpha 2-agonists in reserpinized mice. These effects were variable and not clearly dose-related. 8. Pretreatment of reserpinized mice with the catecholamine synthesis inhibitor, alpha-methyl-p-tyrosine, markedly attenuated (60-95%) the thermogenic response to the noradrenaline uptake inhibitor, desipramine (0.13-12.5 mg kg-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 alpha2-adrenoceptor agonists reverse reserpine-induced hypothermia via a central mechanism involving activation of postsynaptic alpha 2-adrenoceptors.