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Exposure to organophosphates (OP) has been associated with sleep disorders such as insomnia and "excessive dreaming." The central mechanisms of these effects are not well understood. OPs inhibit acetylcholinesterase (AChE) activity, leading to a hyperactivity of the brain cholinergic systems that are involved in sleep regulation. We studied alterations in the EEG, behavioral states, motor activity and core temperature in rats orally administered with 10 or 40 mg/kg of the OP insecticide chlorpyrifos (CHP). Occipital EEG, motor activity and core temperature were recorded with telemetric transmitters. Behavioral sleep-wake states were visually scored. Both doses of CHP produced alterations of the EEG (decrease in power of sigma/beta and increase in slow theta and fast gamma bands) characteristic of arousal. EEG alterations were consistent with behavioral changes such as an increase in wakefulness and a decrease in sleep. Waking immobility was a prevalent behavior. We did not detect any overt signs of CHP toxicity, such as an abnormal posture or gait, suggesting that reduced locomotion can be a result of central effects of CHP (such as activation of cholinergic motor inhibitory system) rather than peripheral (such as an impairment of neuromuscular function). Changes in the EEG and behavior occurred independently of the decrease in core temperature. Increased wakefulness together with reduced motor activity after exposure to CHP seems to be a result of hyperactivity in brain cholinergic neuronal networks.

A reduced body temperature is a common symptom of hypothyroidism and may result from a deficiency in metabolic heat production. However, a reduced metabolism does not necessarily imply a failure in thermoregulatory control if other thermoeffectors, in particular behavioral thermoregulation, are operative. To address this issue, selected ambient temperature (T a ) in a temperature gradient, core temperature (T c ), heart rate (HR), and motor activity (MA) were monitored via radiotelemetry in euthyroid rats and rats made hypothyroid by the administration of 0.05 mg/ml propylthiouracil (PTU) in drinking water for approximately 15 days. Core temperature of PTU-treated rats was reduced by 0.3°, whereas selected T a was increased by 2.3°. PTU treatment led to significant reductions in HR, whereas MA was unaffected. Thermoregulatory behavior did not reverse the PTU-induced hypothermia, suggesting that PTU-induced hypothyroidism leads to a regulated reduction in body temperature (i.e., decrease in the set point). A reduced set point seems to be an adaptive response that lowers the metabolic requirements for thermoregulation in the hypothyroid rat.

Humans acutely exposed to anticholinesterase (anti-ChE) pesticides often become febrile, whereas rats and other rodents become markedly hypothermic. The rat may nonetheless be a useful model for anti-ChE toxicity because recent work using radiotelemetry demonstrated an elevation in core temperature of unrestrained rats for several days following acute exposure to the anti-ChE, diisopropyl fluorophosphate (DFP). To discern the mechanisms of DFP-induced hypothermia and hyperthermia, various pharmacological agents were administered acutely or chronically to rats injected with 1.5 mg/kg DFP (SC). Core temperature, heart rate, and motor activity were monitored continuously via radiotelemetry. Methylscopolamine, a peripheral muscarinic antagonist, attenuated the DFP-induced hypothermia by 1.0 °C and reversed the DFP-induced bradycardia. Chronic scopolamine, a central and peripheral muscarinic antagonist, delivered via a subcutaneously implanted minipump (9.5 mg/kg/day) blocked DFP-induced hypothermia and hyperthermia. Propranolol (10 mg/kg; SC), a general beta blocker, augmented the bradycardic effects of DFP but had no effect on body temperature. Sodium salicylate (200 and 300 mg/kg; IP), an antipyretic that inhibits prostaglandin synthesis, administered during the period of DFP-induced hyperthermia produced a transient recovery in body temperature. Overall, DFP-induced hypothermia and hyperthermia in the rat appear to be mediated via cholinergic activation in the CNS because both are blocked by scopolamine. The decrease in core temperature following sodium salicylate suggests that prostaglandin release is involved in the manifestation of DFP-induced hyperthermia. The elevation in core temperature after DFP appears to involve neurochemical pathways similar to that of fever.

Diisopropyl fluorophosphate (DFP) and other anticholinesterase (antiChE) agents have been found to induce marked hypothermic responses in laboratory rodents. To characterize the effects of DFP on autonomic and behavioral thermoregulation, rats of the Long-Evans strain were injected with DFP while housed in a temperature gradient. The gradient allowed for the measurement of selected ambient temperature ( T a ) and motor activity (MA) over a 6- to 7-day period. Core temperature ( T c ) and heart rate (HR) were also monitored simultaneously using radiotelemetry. Injection of the peanut oil vehicle led to transient elevations in T c , HR, and MA, but no change in selected T a . The next day animals were injected with 0.25, 1.0, or 1.5 mg/kg DFP. DFP (1.0 AND 1.5 mg/kg) led to a marked reduction in T c . The decrease in T c was accompanied by reductions in HR, MA, and selected T a . During the first night after DFP, selected T a remained elevated as T c recovered to its preinjection level. The second 24-h period after 1.0 and 1.5 mg/kg DFP was associated with a significant elevation in the daytime T c . In conclusion, with the option of using behavioral thermoregulatory responses, the hypothermic effects of acute DFP treatment are mediated by a selection for cooler T a s . An elevation in T c during recovery from acute DFP corroborates the many incidents of fever in humans exposed to anti-ChE agents.

Alcohol preference and manifestation of alcoholism are thought by many to be associated with serotonin (5-HT) dysfunction in the brain. Thus, experiments were performed to determine the effect of acute and subchronic administration of (±) 3,4-methylenedioxymethamphetamine (MDMA), an amphetamine analog that stimulates 5-HT release, on alcohol preference in two strains of alcohol-preferring rats, the Fawn-Hooded (FH) and alcohol-preferring (P) rats. Rats were individually housed and provided free access to a solution of 10% ethanol, food, and water. Ethanol, food, and water intakes were measured daily. After establishing a stable baseline for ethanol and water intake, each rat was injected SC with a dose of 5.0 mg/kg MDMA or an equal volume of saline for 1 or 3 consecutive days. Body temperature was recorded immediately before and 120, 240, and 360 min after MDMA treatment. Ethanol, food, and water intake were measured for the preceding 24 h. Further, to determine the effect of MDMA on alcohol metabolism rats were injected with 5.0 mg/kg MDMA or saline and 15 min later with 2.5 g/kg alcohol. Then, blood alcohol levels were determined at 1,3, and 5 h after alcohol administration. Our results show that a single administration of 5.0 mg/kg MDMA significantly decreased ethanol intake in both FH and P rats and increased water intake. Subchronic administration of 5.0 mg/kg MDMA for 3 consecutive days significantly attenuated alcohol intake in both strains but only increased water intake in P rats. Administration of MDMA induced hyper- and hypothermia in FH and P rats, respectively. This drug failed to exert any significant effect on the pharmacokinetics of alcohol, indicating a central effect. These findings suggest that MDMA exerts an inhibitory action on alcohol preference, possibly by enhancing serotonergic and/or dopaminergic systems in the CNS.

3,4-Methylenedioxymethamphetamine (MDMA), a substituted amphetamine analogue which stimulates serotonin release in the CNS, has been shown to induce near lethal elevations in core temperature in the rat. To characterize the effects of MDMA on temperature regulation, we measured metabolic rate (MR), evaporative water loss (EWL), motor activity (MA), and colonic temperature (Tc) in male, Long-Evans rats at 60 min following 30 mg/kg (SC) MDMA or saline at ambient temperatures (Ta) of 10, 20, and 30°C. MDMA caused an elevation in MR at Ta's of 20 and 30°C but had no effect at 10°C. At a Ta of 30°C, MR of the MDMA group was double that of the saline group. EWL was elevated by MDMA, an effect which was potentiated with increasing Ta. MDMA also elicited an increase in MA at all three Ta's. MDMA led to a 3.2°C increase in Tc at 30°C, no change in Tc at 20°C, and a 2.0°C decrease in Tc at 10°C. A second study found that treatment with 20 mg/kg MDMA failed to elicit an increase in blood flow to the tail in spite of a hyperthermic core temperature of 41.4°C. Preliminary studies using radiotelemetry methodology suggested that MDMA lethality is preceded by precipitous elevations in heart rate and core temperature. The data suggest that, at relatively warm Ta's, MDMA-induced stimulation of serotonergic pathway causes an elevation in MR and peripheral vasoconstriction, thus producing life-threatening elevations in Tc. The increase in EWL following MDMA partially attenuates the hyperthermia at warm Ta's, but leads to hypothermia in the rat maintained at a cold Ta of 10°C.

d-Amphetamine has well-known behavioral and sympathomimetic effects in rodents, but its effects on thermoregulation are not well characterized. d-Amphetamine was administered IP to mice at doses of 0.1 to 10.0 mg/kg. Locomotor activity and preferred ambient temperature (Ta) were measured for 60 min after injection in a linear temperature gradient, and metabolic rate (MR) and evaporative water loss (EWL) were measured in a metabolic chamber at ambient temperatures of either 20 degrees C or 30 degrees C. Colonic temperatures (Tc) were obtained 60 min after injection in all cases. Doses of d-amphetamine at 0.3 mg/kg and above reduced preferred Ta from the control value of 30 degrees C to about 25 degrees C. Locomotor activity was reduced briefly by 0.3 mg/kg, and increased after 3.0 mg/kg d-amphetamine. Metabolic rate was suppressed by 0.3 mg/kg of the drug at both 20 and 30 degrees C. At 20 degrees C Ta, 10.0 mg/kg d-amphetamine increased MR but not EWL. At 30 degrees C, MR and EWL were both increased by doses of 3.0 and 10.0 mg/kg. Body temperatures varied both as a function of d-amphetamine dose and of apparatus, with pronounced hyperthermia (Tc greater than 38.5 degrees C) evident only after 10 mg/kg in the metabolic chamber. Thus, the behavioral and autonomic heat loss responses induced in mice by d-amphetamine suggest that its thermogenic action is detected by the animal at doses below those producing measurable thermogenesis and that appropriate effectors, from selection of a cool Ta to increasing EWL, are engaged in an orderly progression to maintain normothermia under all but the most challenging conditions.

In this study on behavioral thermoregulation, male Sprague-Dawley rats were given intraperitoneal (IP) injections of sodium pentobarbital in doses of 0, 1, 5, 10 or 15 mg/kg and male CBA/J mice were given doses of 0, 5, 10, 15 or 30 mg/kg. The animals were immediately placed in a temperature gradient which allowed them to select their preferred ambient temperature (Ta). The preferred Ta of rats increased following an injection of 10 mg/kg sodium pentobarbital, whereas, the barbiturate had no effect on the preferred Ta of mice. In another study, male rats and mice were given sodium pentobarbital in doses of 0, 5, 10 and 15 mg/kg and then placed into a temperature-controlled environmental chamber set at 30 degrees C for mice and 25 degrees C for rats (i.e., their approximate preferred Ta when dosed with sodium pentobarbital). Colonic temperatures were taken one hour after injection. Sodium pentobarbital induced dose dependent hypothermia in rats at 25 degrees C and hyperthermia in mice at 30 degrees C. These data suggest a direct or indirect block of heat gain/conserving effectors in rats treated with sodium pentobarbital which results in hypothermia and an appropriate compensatory selection of a warmer Ta.