Hypothermic Effects Of Oxotremorine Research Articles

Effects of calcium channel inhibitors on the hypothermic response to oxotremorine in normo and hypercholinergic rats

The Flinders Sensitive Line of rats (FSL) has been selectively bred to have increased sensitivity to cholinergic drugs. Typically, these rats react with twice as great a hypothermic effect to muscarinic agonists such as oxotremorine, as do similarly bred Flinders Resistant Line rats (FRL). We compared the effects of three chemically different calcium channel inhibitors (diltiazem, nicardipine and verapamil) on the hypothermia induced in FRL and FSL rats by oxotremorine (0.2 mg kg-1 s.c.). Each drug was injected i.p. in a dose of 20 mumol kg-1 30 min before oxotremorine. Methylatropine (2 mg kg-1 s.c.) was administered 15 min before oxotremorine to block the peripheral effects of the agonist. The hypothermic effect of oxotremorine in FSL rats was antagonized by nicardipine and diltiazem. In contrast, verapamil failed to influence the hypothermic response in FSL rats. Verapamil significantly (P less than 0.05) augmented oxotremorine hypothermia in FRL rats. Diltiazem and nicardipine were without effect on oxotremorine-induced hypothermia in FRL rats. There were no significant changes in temperature in separate groups of FRL and FSL rats treated with calcium channel inhibitors alone.

Oxotremorine-induced hypothermia as a method for evaluating long-term neuronal changes following poisoning by cholinesterase inhibitors in rats

Severe poisoning by inhibitors of cholinesterase (ChE) enzymes is often associated with prolonged central or peripheral neuronal damage. Oxotremorine is a cholinergic agonist known to induce acute hypothermia. Central and peripheral cholinergic signaling is involved in the induction of hypothermia as well as in its recovery. These processes were used in the present study to reveal prolonged neuronal abnormalities in poisoned rats, using oxotremorine with and without concomitant administration of the peripheral muscarinic antagonist methyl scopolamine. In non-poisoned naïve rats, the hypothermic effect of oxotremorine appeared faster while its recovery was delayed following co-administration of methyl scopolamine, suggesting predominantly peripheral processes in counteracting the hypothermia. One month after exposure to approximately 1LD 50 of the carbamates aldicarb and oxamyl, the hypothermic effect of oxotremorine was similar to that found in saline-treated control group. However, the effect of methyl scopolamine on the recovery process was significantly diminished, indicating that the impaired cholinergic mechanisms were predominantly peripheral. In contrast, 1 month following organophosphate (OP) poisoning by the nerve agents sarin and VX, oxotremorine-induced hypothermia was reduced, indicating mainly impaired central cholinergic mechanisms. The development of severe convulsions during nerve agent poisoning may explain the central neuronal damage in OP-poisoned rats, displayed as reduced hypothermia. As convulsions were not part of the poisoning symptoms with the carbamates tested, their long-term damage was displayed at the recovery stage. This method might be used as a relatively simple means for detecting differential long-term central and peripheral cholinergic injuries, long after toxicity signs have receded.

Thermoregulatory effects of chlorpyrifos in the rat: Long-term changes in cholinergic and noradrenergic sensitivity

Subcutaneous injection of a sublethal dose of chlorpyrifos (CHLP), an organophosphate (OP) pesticide, causes long-term inhibition in cholinesterase activity (ChE) of brain, blood, and other tissues. Such prolonged inhibition in ChE should lead to marked behavioral and autonomic thermoregulatory patterns, especially in terms of altered noradrenergic and cholinergic sensitivity. To evaluate the behavioral and autonomic effects of long-term ChE inhibition, Long-Evans rats were implanted with radiotelemetry transmitters that continuously monitored core temperature (Tc), heart rate (HR), and motor activity (MA). These parameters were monitored for 7 days following a single injection of peanut oil (vehicle control) or 280 mg/kg CHLP. CHLP led to a significant reduction in Tc during the first night after treatment but had no other effects on Tc. CHLP also resulted in a significant elevation in HR which lasted for ∼72 h. Motor activity was unaffected by CHLP. Cholinergic and noradrenergic drug sensitivity was assessed between 7 and 25 days after CHLP. CHLP-treated rats were more sensitive to norepinephrine as based on a greater hyperthermic response. MA of CHLP-treated rats was more sensitive to scopolamine. On the other hand, the hypothermic effects of oxotremorine (0.4 mg/kg) were nearly abolished by CHLP treatment, indicating tolerance to cholinergic stimulation. The tachycardic effects of methylscopolamine were also greater in the CHLP group. Overall, the acute effects of CHLP are unusual compared to other OP's in that there is no hypothermic response, an attenuated nocturnal elevation in Tc and a prolonged elevation in HR. The CHLP treated rat exhibits a prolonged elevation in HR, hypersensitivity to noradrenergic stimulation and cholinergic antagonism but hyposensitivity to central cholinergic stimulation.

Bright light blocks the capacity of inescapable swim stress to supersensitize a central muscarinic mechanism

Clinical and basic researchers have proposed that muscarinic cholinergic mechanisms mediate some effects of chronic stress. Chronic inescapable (forced) swim stress depletes brain biogenic amines and is used to produce learned helplessness in rats. Behavioral and biochemical characteristics of animals in the state of learned helplessness lead some investigators to believe this condition provides a useful animal model of depression. Inescapable swim stress also produces supersensitivity to the hypothermic effect of the muscarinic agonist oxotremorine in the rat. The authors previously demonstrated that bright light potently induces subsensitivity of a central muscarinic mechanism involved in the regulation of core temperature under a variety of circumstances. They now report using a repeated measures design that inescapable swim stress of five days duration produces supersensitivity to oxotremorine (increase in thermic response of 405%). This supersensitivity is reversed within five days by treatment with bright light, despite continuation of daily swim stress. Daily inescapable swim stress was continued beyond cessation of treatment with bright light. Five days later, supersensitivity to the hypothermic effect of oxotremorine was once again evident.

Chronic stress and memory: Implication of the central cholinergic system

Restraint stress for ten days (two times two hours daily) induces a hypersensitivity of the central cholinergic system, reflected by antagonism to amnesia induced by scopolamine at 0.1 mg/kg in a passive avoidance test and by hypersensitivity to the hypothermic effect of oxotremorine at 1 mg/kg. A restraint stress for 30 days, on the other hand, diminishes animal retention in the passive avoidance test and causes a hyposensitivity to oxotremorine-induced hypothermia, reflecting a hypoactivity of the central cholinergic system. An acute 24-hour stress causes no change. The relationship between chronic stress and associated memory deficits is discussed.

Genetic influences on cholinergic drug response

Three mouse strains were tested for oxotremorine effects on open-field activity and body temperature. Open-field activitiy was depressed less severely in C3H mice than in C57BL, which were less affected than DBA. While no differences in the hypothermic effects of oxotremorine were observed 15 min after injection, the time courses of the drug effect on body temperature indicated that C3H were less affected than C57BL or DBA. No differences in the activities of acetylcholinesterase or choline acetyltransferase were found among the three strains in cortex, cerebellum, hindbrain (pons-medulla), or total midbrain. While no differences in muscarinic receptor levels were found in the four large brain areas, finer dissection of the midbrain revealed small differences in total receptor number in striatum, hippocampus, and remaining midbrain areas. C3H mice exhibited greater QNB binding than C57BL and DBA mice in striatum; DBA mice exhibited greater QNB binding in hippocampus than C57BL (C3H mice were not different from either strain); and C57BL had less QNB binding than the other two strains in midbrain. All of these differences were small (20% or less). No differences in K D were observed. The inhibition of receptor binding by either oxotremorine or nicotine was the same in all strains, but the IC 50 for oxotremorine varied from region to region. While behavioral differences in the effects of oxotremorine are clear, ther is no obvious biochemical explanation for these differences.

Effects of various antihistamines on oxotremorine-induced hypothermia in mice

The hypothermic effect of oxotremorine, 0.5 mg/kg, i.p., in mice, at an environmental temperature of 22°C, has been found to be antagonized by atropine and a variety of antihistamines in a dose-related manner. The relative molar potency, at the ED 5 0 was atropine cyproheptadine chlorpheniramine diphenhydramine tripelennamine pyrilamine (mepyramine) chlorcyclizine; promethazine was inactive. Protection by these antihistamines could not be correlated with the relative antihistaminic or anticholinergic potencies of the compounds tested. Cyproheptadine caused a 2–3°C drop in temperature at a dosage range of 5–20 mg/kg.