Interaction of MIF-I or alpha-MSH with D-amphetamine or chlorpromazine on thermoregulation and motor activity of rats maintained at different ambient temperatures

Administration of several doses of MIF-I or alpha-MSH did not modify colonic temperature or the level of motor activity of rats in ambient temperatures of 4 degree or 20 degrees C. However, the thermoregulatory but not motor effects of the interaction between MIF-I or alpha-MSH with d-amphetamine were dependent upon ambient temperature. At 4 degree C, 1.0 mg/kg of both peptides enhanced the d-amphetamine-induced hypothermia, but at 20 degrees C both peptides blocked the hyperthermic effects of d-amphetamine. The hypothermic effect of chlorpromazine (CPZ) at 4 degree C and 20 degrees C was blocked by 1.0 mg/kg MIF-I but not by 1.0 mg/kg alpha-MSH. No linear dose response relationships between various doses of MIF-I or alpha-MSH and thermal responses were found. Administration of melanin or the use of hypophysectomized rats did not alter the significant interactions observed after peripheral injections.     

The effect of single and chronic administration of imipramine on clonidine-induced hypothermia in the rat

The effect of imipramine (IMI) on the hypothermic action of clonidine, 50 μg/kg iv., was examined after a single dose and after 7, 14 and 21 days of IMI administration in doses of 2 and 10 mg/kg i.p. in rats. Single administration of IMI both in a dose of 2 and 10 mg/kg does not effect clonidine-induced hypothermia. IMI in a dose of 10 mg/kg given for one week significantly blocks the response to clonidine administration, but it has practically no effect in a dose of 2 mg/kg. After a three-week treatment also a dose of 2 mg/kg blocks clonidine-induced hypothermia. It has been demonstrated that the chronic administration of IMI in contrast to the single one significantly blocks clonidine hypothermia.     

The effects of verapamil and ethanol on body temperature and motor coordination

Male, adult mice of the Binghamton heterogeneous stock received one of two doses of ethanol (1.0 g/kg or 2.0 g/kg in saline) alone or in combination with the calcium (Ca2+) slow channel blocker, verapamil (5.45 mg/kg in 25% v/v ethanol in saline). Hypothermic responses and motor incoordination were assessed in terms of rectal temperatures and rotorod activity both 20 and 60 min after drug administration. Verapamil alone did not affect body temperature, but it potentiated ethanol-induced hypothermia at both post-administration test times. Both verapamil and ethanol impaired muscular coordination and these effects were additive at the two observation periods. Verapamil did not affect ethanol blood levels from 10 to 80 min after administration of the drugs. Since motor impairment was observed when verapamil was administered with only its ethanol vehicle, this suggests a powerful interactive effect between the two drugs.     

Implication of prostaglandins and histamine H1 and H2 receptors in radiation-induced temperature responses of rats

Exposure of rats to 1-15 Gy gamma radiation (60Co) induced hyperthermia, whereas 20-200 Gy induced hypothermia. Exposure either to the head or to the whole body to 10 Gy induced hyperthermia, while body-only exposure produced hypothermia. This observation indicates that radiation-induced fever is a result of a direct effect on the brain. The hyperthermia due to 10 Gy was significantly attenuated by the pre- or post-treatment with a cyclooxygenase inhibitor, indomethacin. Hyperthermia was also altered by the central administration of a mu-receptor antagonist naloxone but only at low doses of radiation. These findings suggest that radiation-induced hyperthermia may be mediated through the synthesis and release of prostaglandins in the brain and to a lesser extent to the release of endogenous opioid peptides. The release of histamine acting on H1 and H2 receptors may be involved in radiation-induced hypothermia, since both the H1 receptor antagonist, mepyramine, and H2 receptor antagonist, cimetidine, antagonized the hypothermia. The results of these studies suggest that the release of neurohumoral substances induced by exposure to ionizing radiation is dose dependent and has different consequences on physiological processes such as the regulation of body temperature. Furthermore, the antagonism of radiation-induced hyperthermia by indomethacin may have potential therapeutic implications in the treatment of fever resulting from accidental irradiations.     

Effects of beta-endorphin on body temperature in mice at different ambient temperatures

The effect of intracerebroventricular injection of beta-endorphin (beta-END) on body temperature of mice was studied at ambient temperatures (Ta) of 10 degrees, 20 degrees and 31 degrees C. Doses between 0.1 and 10.0 microgram/mouse were studied. The lower (less than 1 microgram) doses of beta-END produced a hyperthermia at all Ta's studied. The higher doses of beta-END produced hyper- or hypothermia depending on the Ta. The subcutaneous injection of naloxone (1 mg/kg) antagonized the high dose hypothermic effects, but not the hyperthermic effect of beta-END. These data suggest that there may be different receptors and/or sites of action for high and low doses of beta-END.     

Thermic response of selective muscarinic agonists and antagonists in rat

Effect of some selective agonists and antagonists of cholinergic M receptor subtypes on rectal temperature was investigated in rats at an ambient temperature of 25 degrees +/- 2 degrees C. Centrally administered acetylcholine (ACh) induced transient hypothermia, whereas the muscarinic M1 receptor agonists, arecholine (ip) and McN-A-343 (McN) (icv), induced sustained and dose-related hypothermia. However, the nonspecific muscarinic receptor agonist, oxotremorine, and physostigmine, induced hypothermia at a lower dose and hyperthermia, accompanied by tremors, at higher doses. The muscarinic M2 receptor agonist, carbachol (icv) also produced a dose-related dual effect, hyperthermia and hypothermia being induced by the lower and higher doses, respectively. The M1 receptor antagonists, scopolamine (ip) and pirenzepine (icv), induced hyperthermia, whereas the M2 receptor antagonists, gallamine (icv) and AF-DX 116 (AFDX) (ip), produced hypothermia. The hypothermic effects of ACh. arecholine, McN, physostigmine, oxotremorine and carbachol were attenuated by scopolamine and pirenzepine. However, although scopolamine also inhibited the hyperthermic and tremorogenic effects of the higher dose of oxotremorine, it had a synergistic effect with the hyperthermia-inducing higher dose of physostigmine. AFDX attenuated the hyperthermic effect of the lower dose of carbachol, indicating that it was M2 receptor-mediated. Hemicholinium, an ACh synthesis inhibitor, had a transient hypothermic effect followed by slight hyperthermia. However, it markedly antagonized the hypothermic effects of gallamine and AFDX, indicating that their effects were dependent upon the availability of neuronal ACh. The results indicate that cholinergic hypothermia is a function of central muscarinic M1 receptors, with the M2 receptors serving as automodulators.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of adrenals in morphine-induced hyperthermia in restrained rats

Role of adrenals in morphine-induced hyperthermia was studied in normal, neurotransmitter antagonist-pretreated, chemical-sympathectomized, adrenalectomized or adrenal-demedullated rats. In restrained female rats, 5 mg/kg morphine produced hyperthermia whereas 20 mg/kg and 40 mg/kg produced hypothermia. Pretreatment with either phenoxybenzamine, propranolol, pentolinium or scopolamine inhibited the hyperthermia. After adrenalectomy, neither 5 mg/kg nor chronic administration of 20 mg/kg morphine produced previously demonstrated hyperthermia. After adrenal-demedullation, a dose of 5 mg/kg morphine also did not produce hyperthermia. In contrast to female rats, restrained male rats showed no significant effect on body temperature after 5 mg/kg morphine, requiring 20 mg/kg and 40 mg/kg morphine to produce hyperthermia. In adrenalectomized male rats, 20 mg/kg morphine did not produce the usual hyperthermia. The results suggest that male rats are more resistant to the hyperthermic effects of morphine than female rats and that in the rat, the adrenals, likely the medulla, play an important role in morphine-induced hyperthermia.     

Characterization of alpha-adrenoceptors involved in central thermoregulation in rabbits

Intracerebroventricular (icv) injection of methyldopa induced body temperature changes in the rabbits. The dose of 100 micrograms/kg did not produce any significant change on body temperature whereas 250 micrograms/kg of the drug induced hyperthermia. Higher dose of 500 micrograms/kg produced initial hypothermia which was followed by hyperthermia. On further increase of the dose to 1 mg/kg, consistent hypothermia was evident. Prazosin, a specific post-synaptic alpha 1 adrenoceptor blocker, induced hypothermia whereas piperoxan (presynaptic alpha 2 antagonist) produced hyperthermia. The pretreatment with prazosin, blocked the hyperthermic response of methyldopa. The initial hypothermia by 500 micrograms/kg of methyldopa was also potentiated. The pretreatment with piperoxan completely blocked the hypothermia but had no effect on hyperthermic response of methyldopa. Pretreatment of rabbits with both prazosin and piperoxan completely blocked the hypothermia as well as hyperthermic response of methyldopa. Thus it appeared that both presynaptic alpha 2 and postsynaptic alpha 1 adrenoceptors are involved in central thermoregulation in rabbits.     

Thermoregulation in rats: opposing effects of thyrotropin releasing hormone and its metabolite histidyl-proline diketopiperazine.

Intraventricular administration of histidyl-proline diketopiperazine to rats produces a dose-dependent hypothermia at 4° or 24°, but not at 31°. At 4°, administration of thyrotropin releasing hormone elicits a dose-dependent hypothermia up to 0.1 μmole/kg which is not evoked at higher doses. At 24°, thyrotropin releasing hormone administration results in no change in core temperature, whereas it induces hyperthermia at 31°. At 4°, thyrotropin releasing hormone antagonizes and thyrotropin releasing hormone antiserum potentiates the hypothermic effect of histidyl-proline diketopiperazine, suggesting opposing actions of thyrotropin releasing hormone and histidyl-proline diketopiperazine on thermoregulation.     

Hypothermic and antipyretic effects of centrally administered ACTH (1--24) and alpha-melanotropin

ACTH (1--24) and alpha-melanotropin (alpha-MSH), peptides previously shown to influence body temperature when administered centrally and to occur naturally in brain regions important to temperature control, were injected intracerebroventricularly (ICV) in rabbits. The peptides in doses of 1.25, 2.5 and 5.0 micrograms produced dose-related hypothermias in a 23 degrees C environment, and greater decreases in body temperature when the experiments were repeated in the cold (10 degrees C), but the largest dose had no effect on temperature in the heat (30 degrees C). These results indicate that the peptides do not reduce the central set-point of temperature control. Rather, they appear to selectively inhibit heat conservation and production responses. Five microgram of ACTH reversed vasoconstriction and inhibited rises in temperature caused by leukocytic pyrogen (LP) given IV and ICV. The same dose of alpha-MSH also reduced fever produced by IV and ICV LP, but the reduction was not as great as after ACTH. Both peptides (5 micrograms) also reduced temperature rises and vasoconstriction caused by ICV PGE2. ACTH reduced d-amphetamine-induced hyperthermia without altering vasoconstriction which suggests that this peptide can reduce temperature rises by inhibiting heat production alone. One of the most important findings was that the peptides are antipyretic in that they reduce fever at doses (0.25 microgram, ICV) that do not affect normal temperature. The powerful effects of these peptides on resting body temperature, hyperthermia and fever, together with their presence in brain tissue important to temperature control, suggest that the endogenous central peptides participate in thermoregulation, perhaps by limiting fever and influencing normal temperature.     

Actions of intracerebroventricular administration of kyotorphin and an analog on thermoregulation in the mouse

Intracerebroventricular (ICV) administration of kyotorphin (L-Tyr-L-Arg) and cyclo (N-methyl-L-Tyr-L-Arg), its analog, produced significant dose-dependent hypothermic responses in mice at an ambient temperature of 24°C. The hypothermic action of kyotorphin was much greater than that of Met-enkephalin (Met-ENK) but less than that of cyclo NMTA. This action was slightly but not significantly reversed by intraperitoneally administered naloxone (8 mg/kg), an opioid receptor antagonist. Met-ENK utilized as a control peptide in this study also produced a dose-dependent hypothermia which was slightly antagonized by naloxone (8 mg/kg, IP). Thyrotropin releasing hormone (TRH) injected ICV produced hyperthermia dose-dependently. The hypothermia induced by kyotorphin, its cyclic analog and Met-ENK was prevented by a small dose of TRH (0.18 μg=0.5 nmol/animal) which by itself had little effect on body temperature. A TRH neuronal system in the brain may explain the mechanism of kyotorphin-induced hypothermia. However, there was little evidence of involvement of opioid receptors. The present study demonstrates a potent action of kyotorphin and its analog on thermoregulation.     

Intravenous alpha-MSH reduces fever in the squirrel monkey

alpha-MSH reduces fever in rabbits when administered IV, ICV, or by gavage; however, the applicability of this finding to higher species, specifically to primates, has not been determined. In this study, we chose the squirrel monkey as an appropriate primate model since it responds reliably to peripheral administration of bacterial endotoxins that cause fever in man. From pilot studies, doses of S. typhosa endotoxin necessary to produce maximum fever and doses of alpha-MSH which did not cause hypothermia were determined for each animal. In the main experiments endotoxin was given via an indwelling catheter in the saphenous vein, followed by alpha-MSH injections when the rectal temperature increased 0.3 degrees C. alpha-MSH (100-400 micrograms) reduced the area under the fever curve an average of 50.0%, but had no effect on afebrile temperature. Molar equivalent amounts of the antipyretic drug acetaminophen had little effect on fever. These findings support the idea, based on research on rabbits, that alpha-MSH has a role in central modulation of fever.     

CGS8216 noncompetitively antagonizes the discriminative effects of diazepam in rats

The benzodiazepine antagonist properties of CGS8216 were evaluated in rats trained to discriminate between saline and 1.0 mg/kg of diazepam in a two-choice, stimulus-shock termination procedure. CGS8216 (0.3 to 100 mg/kg) administered alone, either s.c., p.o. or i.p., occasioned only saline-appropriate responding. When administered concomitantly with a constant 1.0 mg/kg dose of diazepam, CGS8216 produced dose-related decreases in drug-appropriate responding. CGS8216 was most potent by the i.p. route, and approximately tenfold less potent by the oral route. CGS8216 was dermatotoxic after s.c. administration. CGS8216 i.p. had a long duration of action. A dose of 30 mg/kg completely antagonized the discriminative effects of the 1.0 mg/kg training dose of diazepam when the antagonist was administered 8 hr before the start of the test session. In order to determine the type of antagonism by CGS8216, the dose-effect curve for diazepam was redetermined in the presence of varying doses of CGS8216 (0.3 to 3.0 mg/kg, i.p.). CGS8216 produced a dose-related rightward shift in the diazepam dose-effect curve, but also decreased the slope and appeared to decrease the maximal effect. These results are consistent with the interpretation that CGS8216 antagonizes diazepam in a noncompetitive manner. It may do so because either it interacts with a subpopulation of benzodiazepine receptors, it functions as a pseudo-irreversible antagonist due to its high affinity, or because it is an antagonist with agonist properties.     

Effects of ethanol on plasma corticosterone and rectal temperature modification by U50488H and WIN 44441-3

Endogenous opiates are believed to subserve various behaviors and physiological functions. We have examined the effect of U50488H (0-12 mg/kg), a kappa agonist, and WIN 44441-3 (0-4.0 mg/kg), a kappa antagonist, on ethanol (ET)-induced changes in rectal temperature and in plasma corticosterone (CS) levels in rats. The 12 mg/kg dose of U50488H produced marked hypothermia, the other doses either produced hyperthermia comparable to that seen in control animals, or had no effect. The 0.5 mg/kg of WIN44441-3 had a small hypothermic effect while the 4.0 mg/kg produced hyperthermia. U50488H potentiated and the low dose of WIN 44441-3 reversed the hypothermic effect of ethanol. By contrast, neither WIN 44441-3 nor U50488H pretreatments affected the ethanol-induced elevation in plasma CS. These results indicate that kappa agonists increase plasma CS concentration and affect thermoregulatory mechanisms. Furthermore, our data indicate a possible role of endogenous kappa opioids in the hypothermic effect of ethanol, but not in the elevation of plasma CS.     

Histamine and histamine receptors: behavioral thermoregulation in the salamander Necturus maculosus

Low doses (0.01, 0.1 mg/kg, i.p.) of histamine (HA) caused selection of significantly lower temperatures, and higher doses (0.5, 1.0 mg/kg) increased temperatures by mudpuppies in linear thermal gradients. Injection of the HA precursor, L-histidine (500 mg/kg) produced an increase in the temperatures selected. Results from injections of HA H1-receptor agonist (2-pyridylethylamine) and antagonist (pyrilamine), and H2-receptor agonist (dimaprit) and antagonist (cimetidine) had significant effects on thermoregulation; H1-receptors may mediate behavioral hyperthermia and H2-receptors behavioral hypothermia. Responses to these histaminic compounds are significantly influenced by the time of day at which the responses are measured and by season and acclimation temperature. The equivalent behavioral responses in both endotherms and ectotherms to agents which produce physiological hyperthermia and hypothermia are probably behavioral hypothermia ("cold seeking") and behavioral hyperthermia ("heat seeking"), respectively.     

Interoceptive "satiety" signals produced by leptin and CCK

The present studies assessed the extent to which the adiposity signal leptin and the brain-gut hormone cholecystokinin (CCK), administered alone or in combination, give rise to interoceptive sensory cues like those that are produced by a low (1h) level of food deprivation. Rats were trained with cues arising from 1 to 24-h food deprivation as discriminative stimuli. For one group, 24-h food deprivation predicted the delivery of sucrose pellets, whereas 1-h food deprivation did not. Another group received the reversed deprivation level-sucrose contingency. After asymptotic performance was achieved, the effects of leptin and CCK on food intake and on discrimination performance were tested under 24-h food deprivation. In Experiment 1a, leptin administered into the third cerebroventricle (i3vt) at 3.5 or 7.0 microg doses had little effect, compared to saline on food intake or discriminative responding. In Experiment 1b, leptin (7.0 microg, i3vt) combined with CCK-8 (2 microg/kg, i.p.) reduced food intake significantly, but the findings indicated that CCK-8 alone produces interoceptive discriminative cues more like those produced by 1- than 24-h food deprivation. Experiment 2a tested rats with i.p. leptin (0.3 and 0.5mg/kg). Although neither dose suppressed intake, the 0.3mg/kg dose produced interoceptive cues like 1-h food deprivation. Experiment 2b tested two doses of CCK-8 (2 and 4 mg/kg, i.p.) and found significant intake suppression and generalization of discrimination with both doses of CCK-8. These findings suggest a role for both leptin and CCK in the production of sensory consequences that correspond to "satiety".     

Acute effects of a parkinsonism-inducing neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on mouse body temperature

The parkinsonism-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) given in single systemic doses (i.p.) to mice produced marked hyperthermia, and subsequent long-lasting hypothermia. Administration of MPTP or its oxidized product, 1-methyl-4-phenylpyridinium ion, MPP+, via i.c.v. resulted in only hypothermia. In contrast, i.p. MPP+ administration resulted in only hyperthermia. The MPTP-induced hyperthermia (i.p.) was blocked by quaternary derivatives of anti-cholinergic agents, atropine and scopolamine, but not by the tertiary-derivative of atropine. Duration of this hyperthermic effect was potentiated by neostigmine. Pretreatment with 1-deprenyl did not prevent hypothermia, but nomifensine partially or clorgyline completely prevented the effect without preventing MPTP-induced hyperthermia. The thermic effects by MPTP, unlike its neurotoxicity for the nigrostriatal DA system, may not require metabolism to MPP+. These results indicate that peripheral cholinergic functions are responsible for the MPTP-induced hyperthermia, whereas its hypothermic effect may be centrally mediated via dysregulation of the various neuron systems.     

Effects of cocaine on conflict behavior in the rat

The present studies examined the effects of acute cocaine administration, chronic cocaine administration and cocaine withdrawal on behavior in the Conditioned Suppression of Drinking (CSD) conflict paradigm, an animal model for the study of anxiety. In daily 10-minute sessions, water deprived rats were trained to drink from a tube that was occasionally electrified (0.25 mA), electrification being signalled by a tone. Within 3-4 weeks, control (i.e., non-drug) CSD behavior stabilized (30-50 shocks and 10-12 ml/session) and drug studies were initiated. Acute administration of cocaine (30-min pretreatment) produced a selective pro-conflict effect only at a dose of 10 mg/kg cocaine, with lower doses (2.5, 5 mg/kg) exerting no effect on CSD behavior and a higher dose (20 mg/kg) depressing both punished and unpunished responding. In a second experiment, cocaine (10 mg/kg, IP, 2/day) or saline was administered to separate groups of subjects for 7 weeks. In this chronic treatment study, CSD testing was conducted 12 hours after each evening cocaine administration. Although it had no effect on CSD behavior during the first week of treatment, this chronic cocaine administration produced a significant and selective pro-conflict effect which was stable during the period from Weeks 2-7. In a final experiment, a high dose of cocaine (20 mg/kg, 3/day) or saline was given to separate groups of subjects for 2 weeks and the behavioral effects of these treatments and their subsequent termination were examined. In this study, CSD testing was conducted 8 hours after each evening cocaine treatment. During the first week of high dose cocaine treatment, a decrease in punished responding was observed; this parameter returned to baseline levels by Week 2. Discontinuation of this high dose chronic cocaine treatment resulted in a selective decrease in punished responding. This pro-conflict effect was greatest at 3 days, and lasted for 6 days after the last cocaine dose. These data are consistent with clinical findings demonstrating the anxiogenic effects of both acute and chronic cocaine treatment as well as cocaine withdrawal and suggest that conflict paradigms such as the CSD may be useful for the study of cocaine-induced anxiety states.     

Potency of L-364,718 as an antagonist of the behavioral effects of peripherally administered cholecystokinin

A new antagonist of the peripheral cholecystokinin receptor, L-364,718, was found to block the reductions in food intake and exploratory activity induced by intraperitoneal administration of cholecystokinin octapeptide sulfate. L-364,718 significantly reversed the cholecystokinin-induced reduction in feeding at doses of 10 micrograms/kg - 10 mg/kg i.p. L-364,718 significantly reversed the cholecystokinin-induced reduction in exploratory activity at doses of 500 ng/kg - 10 mg/kg i.p. The time course of antagonist activity of L-364,718 was immediate to 90 minutes after intraperitoneal administration. L-364,718 had no significant effect on food intake or exploratory activity when administered alone, over the dose range of 100 ng/kg-10 mg/kg i.p. This compound appears to be at least one hundred times more potent than proglumide or benzotript as an antagonist of the behavioral effects of peripherally administered cholecystokinin.     

Interaction of apolipoprotein AIV with cholecystokinin on the control of food intake

Apolipoprotein AIV (apo AIV) and cholecystokinin (CCK) are peptides that act both peripherally and centrally to reduce food intake by decreasing meal size. The present study examined the effects of intraperitoneally administered bolus doses of recombinant apo AIV, CCK-8, and a combination of subthreshold doses of apo AIV and CCK on 4-h food intake in rats that were fasted overnight. Apo AIV at 100 microg/kg reduced food intake significantly relative to the saline control for 1 h, as did doses of CCK-8 at or above 0.125 microg/kg. Doses of apo AIV (50 microg/kg) or CCK (0.06 microg/kg) alone had no effect on food intake. However, when these subthreshold doses of apo AIV and CCK were administered together, the combination produced a significant inhibition of food intake relative to saline controls (P < 0.001), and the duration of the effect was longer than that caused by the administration of either apo AIV or CCK alone. The satiation effect produced by CCK-8 + apo AIV was attenuated by lorglumide, a CCK1 receptor antagonist. We conclude that, whereas the intraperitoneal administration of doses of either recombinant apo AIV or CCK at or above threshold levels reduces food intake, the coadministration of subthreshold doses of the two peptides is highly satiating and works via CCK1 receptor.