Naturally occurring hypothermia is more advantageous than fever in severe forms of lipopolysaccharide- and Escherichia coli-induced systemic inflammation.

The natural switch from fever to hypothermia observed in the most severe cases of systemic inflammation is a phenomenon that continues to puzzle clinicians and scientists. The present study was the first to evaluate in direct experiments how the development of hypothermia vs. fever during severe forms of systemic inflammation impacts the pathophysiology of this malady and mortality rates in rats. Following administration of bacterial lipopolysaccharide (LPS; 5 or 18 mg/kg) or of a clinical Escherichia coli isolate (5 × 10(9) or 1 × 10(10) CFU/kg), hypothermia developed in rats exposed to a mildly cool environment, but not in rats exposed to a warm environment; only fever was revealed in the warm environment. Development of hypothermia instead of fever suppressed endotoxemia in E. coli-infected rats, but not in LPS-injected rats. The infiltration of the lungs by neutrophils was similarly suppressed in E. coli-infected rats of the hypothermic group. These potentially beneficial effects came with costs, as hypothermia increased bacterial burden in the liver. Furthermore, the hypotensive responses to LPS or E. coli were exaggerated in rats of the hypothermic group. This exaggeration, however, occurred independently of changes in inflammatory cytokines and prostaglandins. Despite possible costs, development of hypothermia lessened abdominal organ dysfunction and reduced overall mortality rates in both the E. coli and LPS models. By demonstrating that naturally occurring hypothermia is more advantageous than fever in severe forms of aseptic (LPS-induced) or septic (E. coli-induced) systemic inflammation, this study provides new grounds for the management of this deadly condition.

Food deprivation alters thermoregulatory responses to lipopolysaccharide by enhancing cryogenic inflammatory signaling via prostaglandin D2.

We tested the hypothesis that food deprivation alters body temperature (T(b)) responses to bacterial LPS by enhancing inflammatory signaling that decreases T(b) (cryogenic signaling) rather than by suppressing inflammatory signaling that increases T(b) (febrigenic signaling). Free-feeding or food-deprived (24 h) rats received LPS at doses (500 and 2,500 microg/kg iv) that are high enough to activate both febrigenic and cryogenic signaling. At these doses, LPS caused fever in rats at an ambient temperature of 30 degrees C, but produced hypothermia at an ambient temperature of 22 degrees C. Whereas food deprivation had little effect on LPS fever, it enhanced LPS hypothermia, an effect that was particularly pronounced in rats injected with the higher LPS dose. Enhancement of hypothermia was not due to thermogenic incapacity, since food-deprived rats were fully capable of raising T(b) in response to the thermogenic drug CL316,243 (1 mg/kg iv). Neither was enhancement of hypothermia associated with altered plasma levels of cytokines (TNF-alpha, IL-1beta, and IL-6) or with reduced levels of an anti-inflammatory hormone (corticosterone). The levels of PGD(2) and PGE(2) during LPS hypothermia were augmented by food deprivation, although the ratio between them remained unchanged. Food deprivation, however, selectively enhanced the responsiveness of rats to the cryogenic action of PGD(2) (100 ng icv) without altering the responsiveness to febrigenic PGE(2) (100 ng icv). These findings support our hypothesis and indicate that cryogenic signaling via PGD(2) underlies enhancement of LPS hypothermia by food deprivation.

A reappraisal on the ability of leptin to induce fever.

Leptin is often regarded as a mediator of fever, even though an in-depth analysis of the dose-dependent effects of leptin on body temperature (T(b)), pro-inflammatory cytokines, and circulating leptin has never been performed. In the present study, such an analysis was performed in rats that were food deprived (lower baseline levels of leptin) or free feeding (higher baseline levels of leptin). In a relatively cool environment (22 degrees C), rats deprived of food for 24 h exhibited mild (approximately 0.5 degrees C) hypothermia. Leptin infusion (250 microg/kg iv) elevated the T(b) of the food-deprived rats to a normothermic level, an effect that peaked (120 min post-infusion) when plasma leptin was at a level (approximately 8 ng/mL) often found in leptin-responsive subjects. Increasing the leptin dose to 1000 microg/kg did not produce any further (febrile) elevation in the T(b) of food-deprived rats. The anti-hypothermic effect of leptin in food-deprived rats was not associated with any rise in the plasma levels of the pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. In free-feeding rats kept in a cooler (22 degrees C) or warmer (28 degrees C) environment, leptin infusion failed to alter T(b) or to produce any surge in plasma TNF-alpha or IL-6, even when the dose infused (3500 microg/kg iv) resulted in excessive, non-physiological rises in plasma leptin (approximately 542 ng/mL at 30 min; approximately 75 ng/mL at 120 min post-infusion). In contrast, free-feeding rats in the same experimental set-up were able to respond to a low dose (2 microg/kg iv) of IL-1beta with a typical biphasic fever, which was associated with surges in plasma TNF-alpha and IL-6. Collectively, our data show that an acute rise in plasma leptin to a level within or fairly above the physiological range does not induce fever. These results challenge the idea that leptin may be a mediator of fever.

Effects of early methylphenidate exposure on morphine- and sucrose-reinforced behaviors in adult rats: relationship to dopamine D2 receptors.

Methylphenidate is commonly used to treat Attention Deficit Hyperactivity Disorder (ADHD) in school-aged children, and there is an increasing trend to prescribe methylphenidate to younger preschool-aged children. While the efficacy of methylphenidate is not in question, there is evidence that early methylphenidate treatment may have long-term effects on later drug responsiveness. The goal of this study was to determine whether early exposure to methylphenidate would alter morphine-induced conditioned place preference (CPP) and sucrose-reinforced lever-pressing in young adult rats. We also assessed whether early methylphenidate exposure would impact dopamine D(2) binding sites. Sprague-Dawley rats were treated with methylphenidate (0, 2, or 5 mg/kg) once a day from PD 11-PD 20. On PD 60, morphine-induced CPP or sucrose-reinforced lever-pressing was assessed. A 10-day CPP procedure was used, which included 1 preconditioning day, 8 conditioning days, and 1 test day. After CPP testing, D(2) receptor binding was determined in striatal and accumbal tissue samples. In the sucrose experiment, rats were trained to lever-press on a progressive ratio schedule for one sucrose pellet. Results showed that early exposure to methylphenidate (5 mg/kg) increased the magnitude of morphine-induced CPP. Exposure to methylphenidate did not alter the number of D(2) binding sites, however, there were positive correlations between the number of D(2) binding sites and the strength of the CPP. In the sucrose-reinforced lever-press experiment, rats exposed to methylphenidate (2 and 5 mg/kg) had higher break points than saline controls. These results suggest that early exposure to methylphenidate alters reward system functioning, thereby making these systems more sensitive to appetitive stimuli.

Ultrasonic vocalization production of preweanling rats: effects of central and peripheral administration of alpha2-adrenoceptor agonists.

Stimulation of alpha2-adrenoceptors increases the ultrasonic vocalization production of preweanling rats, however it is not known whether these critical alpha2-adrenoceptors are located peripherally or centrally. In a series of three experiments, ultrasonic vocalizations were measured after 11-day-old rats had been administered clonidine or 2-[2,6-diethylphenylamino]-2-imidazole (ST-91) either systemically (i.p.) or into the third ventricle (i.c.v.). These particular alpha2-adrenoceptor agonists were chosen because clonidine is lipophilic and enters the central nervous system, while ST-91 is hydrophilic and does not readily cross the blood-brain barrier. In the third experiment, clonidine- (1 microg, i.c.v.) and ST-91-induced (15 microg, i.c.v.) ultrasonic vocalizations were measured after systemic injection of the alpha2-adrenoceptor antagonist yohimbine (0.5 or 1 mg/kg, i.p.). Results showed that central administration of both clonidine and ST-91 increased the ultrasonic vocalization production of 11-day-old rats, whereas peripheral administration of only clonidine, and not ST-91, increased ultrasonic vocalizations. These results indicate that the alpha2-adrenoceptors mediating ultrasonic vocalization production are located in the central nervous system. Yohimbine fully attenuated clonidine-induced ultrasonic vocalizations but only partially attenuated ST-91-induced vocalizations. This pattern of results may have been due to the differential selectivity of clonidine and ST-91 for alpha2-adrenoceptor subtypes (alpha2A, alpha2B, and alpha2C) or imidazoline receptors. When combined with past research, the present results are consistent with the hypothesis that centrally located alpha2-adrenoceptors are a component of a neural system that mediates ultrasonic vocalization production.

Effects of a partial dopamine D2-like agonist on the cocaine-induced behavioral sensitization of preweanling rats.

Partial D(2)-like receptor agonists act as functional antagonists when given during periods of high dopaminergic tone (e.g., when self-administering cocaine or amphetamine). For this reason, we determined whether pretreatment with the partial D(2)-like agonist terguride would block the induction and/or expression of cocaine-induced behavioral sensitization in preweanling rats. More specifically, we examined (a). whether repeated administration of terguride alone (0.4-1.6 mg/kg) would support behavioral sensitization (Experiment 1); (b). whether injecting preweanling rats with terguride (0.1-1.6 mg/kg) during the pretreatment phase would block the induction and ultimate expression of cocaine-induced behavioral sensitization (Experiment 2); and (c). whether injecting rats with terguride (0.2-0.8 mg/kg) on the test day would block the expression of cocaine sensitization (Experiment 3). Results showed that repeated terguride administration did not induce behavioral sensitization by itself, nor did it block the induction of cocaine sensitization in preweanling rats. Interestingly, terguride reduced, but did not fully attenuate, the locomotor activity of cocaine-treated rats during the pretreatment phase. When given on the test day, terguride also depressed cocaine-induced locomotor activity, but rather than blocking the expression of behavioral sensitization, terguride seemed to cause a general reduction in locomotion. Because partial D(2)-like agonists attenuate cocaine- and amphetamine-induced reward, it has been proposed that this class of drug might serve as an effective pharmacotherapy for psychostimulant abuse. Although partial D(2)-like agonists may prove useful in this regard, results from the present study suggest that terguride would not block sensitization components of the addiction process.

Role of D1-like receptors in amphetamine-induced behavioral sensitization: a study using D1A receptor knockout mice.

RATIONALE: The role played by D(1)-like receptors in amphetamine-induced behavioral sensitization has been examined using both the D(1)-like receptor antagonist, SCH 23390, and the D(1A) receptor knockout mouse (i.e. D(1A)-deficient mice). Studies using these two approaches have provided conflicting evidence about the importance of D(1)-like receptors for amphetamine-induced behavioral sensitization. OBJECTIVE: The purpose of the present study was to determine: (a) whether D(1A)-deficient mice exhibit amphetamine-induced locomotor sensitization after 3 and 17 drug abstinence days, and (b) whether SCH 23390, which binds to both D(1A) and D(1B) receptor subtypes, blocks development of amphetamine sensitization in wild-type and D(1A)-deficient mice. METHODS: In the first experiment, adult wild-type and D(1A)-deficient mice were injected with amphetamine (0, 1, 2, 4, or 8 mg/kg, IP) for 7 consecutive days. In the second experiment, wild-type and D(1A)-deficient mice were pretreated with SCH 23390 (0, 0.15, or 0.5 mg/kg, IP) 30 min prior to being injected with amphetamine (0 or 8 mg/kg, IP). After each daily amphetamine injection, mice were placed in activity chambers where distance traveled (i.e. horizontal locomotor activity) was measured for 60 min. On the test days, which occurred after 3 or 17 drug abstinence days, mice were injected with 1 mg/kg amphetamine and locomotion was measured for 120 min. RESULTS: Both wild-type and D(1A)-deficient mice exhibited amphetamine-induced locomotor sensitization. Pretreatment with 0.5 mg/kg SCH 23390 blocked the development of locomotor sensitization in wild-type mice, but did not alter the sensitized responding of D(1A)-deficient mice. CONCLUSIONS: It appears that D(1)-like receptors are necessary for the development of amphetamine sensitization in wild-type mice, while neither the D(1A) nor D(1B) receptor subtypes are necessary for the amphetamine-induced locomotor sensitization of D(1A)-deficient mice. A possible explanation for these conflicting results is that D(1A)-deficient mice may have a compensatory mechanism (not involving D(1B) receptors) that allows them to exhibit amphetamine-induced behavioral sensitization in the absence of the D(1A) receptor.