Lipopolysaccharide reduces sodium intake and sodium excretion in dehydrated rats

The objective of this study was to find out if lipopolysaccharide (LPS) administered intraperitoneally affects sodium and water intake and renal excretion in dehydrated rats. LPS (0.3-5 mg/kg b.w.) inhibited 0.3 M NaCl intake induced by subcutaneous injection of the diuretic furosemide (FURO, 10 mg/kg b.w.) combined with the angiotensin converting enzyme inhibitor, captopril (CAP, 5 mg/kg b.w.). Only the highest doses of LPS (2.5 and 5 mg/kg) inhibited water intake induced by FURO/CAP. LPS (0.6 mg/kg) reduced urinary volume and sodium excretion, but had no effect on mean arterial pressure or heart rate of rats treated with FURO/CAP. LPS (0.3-5.0 mg/kg) abolished intracellular thirst and reduced by 50% the urine sodium concentration of rats that received 2 ml of 2 M NaCl by gavage. LPS (0.3-5.0 mg/kg) also reduced thirst in rats treated with FURO alone (10 mg/rat sc). The results suggest that LPS has a preferential, but not exclusive, inhibitory effect on sodium intake and on intracellular thirst. The inhibition of hydro-mineral intake and the antinatriuresis caused by LPS in dehydrated rats may contribute to the multiple effects of the endotoxin on fluid and electrolyte balance and be part of the strategy to cope with infections.     

FURO/CAP: A protocol for sodium intake sensitization

We investigated if a history of FURO/CAP, a protocol that increases brain angiotensin II (ANG II), sensitizes or enhances sodium intake. A subcutaneous injection of the diuretic furosemide (FURO, 10 mg/kg) was combined with a converting enzyme inhibitor captopril (CAP, 5 mg/kg) to induce a short latency stimulated sodium (0.3 M NaCl) and water intake in a 2 h FURO/CAP test. Repeated injections of only FURO/CAP, separated by one-week interval, enhanced stimulated and spontaneous (daily) sodium intake. Stimulated fluid intake was completely suppressed when FURO/CAP was combined with two intraperitoneal injections of the ANG II type-1 receptor antagonist losartan (10, 20, or 40 mg/kg each) given within 1 h prior to the FURO/CAP test. Losartan reduced by only 35% the FURO/CAP-induced natriuresis. A history of FURO/CAP, FURO/CAP + losartan (all doses), or vehicle produced similar stimulated fluid intake when all animals received only FURO/CAP in the third final FURO/CAP test. However, a history of vehicle or FURO/CAP + losartan 10 mg/kg precluded the enhancement in spontaneous sodium intake after the third final FURO/CAP. The FURO/CAP combined with losartan (all doses) also precluded the spontaneous sodium intake enhancement in the weeks that preceded the third final FURO/CAP test. A history of only FURO/CAP, but not vehicle, also enhanced water deprivation-induced sodium appetite. The results suggest that a history of FURO/CAP enhances stimulated and spontaneous sodium intake, as well as water deprivation-induced sodium appetite, and reinforce the role of ANG II as a peptide that mediates long-term effects on behavior.     

Co-supplementation of single and multi doses of vitamins C and E ameliorates cisplatin-induced acute renal failure in mice

Higher doses of antioxidant vitamins C and E have been proved to be effective against cisplatin-induced nephrotoxicity in animals. However, the possible effective equivalent dose in human was found to be higher than that of the upper tolerable intake level (UL) for these vitamins. Hence, the current study was aimed to evaluate the protective effect of co-supplementation of single and multi doses of vitamins C and E against cisplatin-induced acute renal failure in mice. Single dose of vitamin C (500 mg/kg), vitamin E (500 mg/kg), and vitamin C plus vitamin E (250 mg/kg each) were administered orally 1 h prior to cisplatin (12 mg/kg, i.p) injection, whereas in a multidose study they were administered 1 h prior, and 24 and 48 h after the cisplatin injection. Serum urea and creatinine levels were estimated 72 h after the injection of cisplatin. Renal concentrations of glutathione (GSH) and malondialdehyde (MDA) were also determined. Co-supplementation of vitamins significantly protected the cisplatin-induced increased levels of serum urea, creatinine, renal MDA, and the declined renal GSH level. Administration of single and multi doses of vitamin C plus E (250 mg/kg each) rendered significant nephroprotection. Therefore, accounting for the rare side effect from high intake of vitamins C and E observation of this study indicates that a multidose combination therapy of these vitamins at their lower doses can be effective in protecting the cisplatin-induced renal damage. The protection is partially mediated through the antioxidant effect of the vitamins.     

Striatal dopamine in the response of brain and liver unsaturated and saturated free fatty acids following administration of C75 in CD-1 mice

In order to clarify the mechanism of action of cerulenin analog, C75, known to suppress feeding behavior, food intake was measured in adult CD-1 male mice n = 5 per group, treated i.p. with 10 and 20 mg/kg of C75. Animals in both treatment groups had significantly lower 24 h food consumption rate relative to the control group injected with vehicle. Striatal monoamine neurotransmitters and striatal as well as liver long chain free fatty acids concentrations were subsequently evaluated in another group treated i.p. with 20 mg/kg C75. Acute exposure to C75 at 20 mg/kg led to approximately 50% increase in the striatal dopamine levels and a decrease in dopamine turnover for up to 24 h following the injection. The concentration of serotonin remained unchanged. Concentration of saturated fatty acids in the liver and striatum did not change, while striatal unsaturated myristoleic acid (cis-9-tetradecenoic acid) levels were significantly higher as early as 2 h post-injection and remained elevated at 24 h post-injection. These preliminary data suggest a central regulatory role of unsaturated fatty acids under dopaminergic control in the C75-induced anorexia. Pharmacological alterations in fatty acid metabolism may prove beneficial in the treatment of obesity.     

Electroacupuncture combined with clomipramine enhances antidepressant effect in rodents

The present study was designed to evaluate the antidepressant effect of electroacupuncture (EA) and the potential additive or synergistic effects of EA and clomipramine (CLO, a tricyclic antidepressant) in the mouse forced swimming test (FST) and chronic mild stress (CMS) induced depression-model rats. The FST is an antidepressant screening procedure performed initially to observe the immediate effects of EA and/or CLO on the immobility time. CLO (2.5, 5, 10, 20 and 60 mg/kg intraperitoneally) were administered at 23, 6 and 1h respectively prior to each test. EA was given at the ‘Bai-Hui’ (Du 20) and unilateral ‘An-Mian’ (EX 17) acupoints 1 h before each test. Immobility time was significantly reduced by EA and CLO at 2.5, 5, 10, 20 or 60 mg/kg, respectively. EA combined with 2.5 mg/kg CLO exhibited additive effects on the immobility time. In addition, rats were exposed chronically (1st–11th week) to a variety of mild unpredictable stressors. Depressed mood and anhedonia were recognized as a decrease in sucrose intake in the CMS rats. CLO at 2.5, 5 mg/kg and EA at the same acupoints and parameters were administrated on the CMS rats once every other day for 6 weeks (5th–11th week). The intake of 1% sucrose solution was reduced by CMS, which was restored to normal level after 6 weeks treatment with 5 mg/kg CLO or EA combined with 2.5 mg/kg CLO. However, neither the sucrose intake nor the sucrose preference in the depressive rats was significantly changed by the treatment with EA or 2.5 mg/kg CLO alone. These results demonstrated that EA combined with CLO at low doses has an additive or synergistic antidepressant action, and this combination may provide an effective strategy for depression management.     

Pica as an adaptive response: Kaolin consumption helps rats recover from chemotherapy-induced illness

Clay consumption can occur during illness but there has been little work to understand why. To investigate whether consuming clay confers an advantage to the sick animal, we compared the recovery from illness of adult male rats with or without access to kaolin. Illness was induced by injection of 6 mg/kg, ip, cisplatin, a toxic chemotherapy agent, and recovery was assessed by changes in daily food intake, water intake, and body weight. Relative to saline-injected controls, cisplatin-injected rats reduced food and water intake and lost weight. However, those with access to kaolin ate more food and lost less body weight than did those without access to kaolin. Thus, clay consumption appeared beneficial in that it either protected the rats from illness or enhanced recovery and might prove useful as an adjunct therapy for other animals, including humans, experiencing visceral malaise.     

Atorvastatin prevents early apoptosis after thoracic spinal cord contusion injury and promotes locomotion recovery

The systemic administration of atorvastatin has been shown to be neuroprotective after spinal cord injury (SCI), by decreasing the inflammatory response at the lesion site and by reducing neuronal and oligodendrocyte apoptosis. The latter effect spares white matter at the injury site and improves locomotion. The aim of this study was to confirm the neuroprotective efficacy of atorvastatin as well as its early action in limiting apoptosis with its administration post-SCI. Female Sprague-Dawley rats received an intra peritoneal injection of: (1) statin/saline (5 mg/kg) at 2 h after the contusion injury; (2) physiological saline at 2 h post-SCI; or (3) physiological saline without injury. Statin-treated rats showed significant (p < 0.05) improvement in locomotion at week 4 post-SCI compared to vehicle-treated animals. Explaining this outcome, caspase-3 activity decreased by 50% (p < 0.05), and the histological TUNEL method revealed a decrease of approximately 20% in apoptotic cells at the injury site (p < 0.01) at 4 h post-SCI in atorvastatin-treated rats in comparison to vehicle-treated controls. These data demonstrate that atorvastatin is effective after experimental spinal cord contusion injury in preventing early apoptosis at the injury site within 2 h post-administration.     

The delayed phase of cisplatin-induced emesis is mediated by the area postrema and not the abdominal visceral innervation in the ferret

The anti-cancer chemotherapeutic agent cisplatin induces an acute (∼24 h) and delayed (∼24–72 h+) emetic response in humans; whereas the mechanism mediating the acute phase has been characterised, the delayed phase is relatively poorly understood. We have used nerve lesions (abdominal vagus, VX; greater splanchnic nerve, GSNX) and area postrema ablation (APX) in the ferret model of cisplatin (5 mg/kg, i.p.) delayed emesis and demonstrated that VX and VX + GSNX did not significantly modify the delayed emetic response (24–72 h), which consisted of 276.0 ± 62.8 retches + vomits (R + V) in sham-operated ferrets and 167.2 ± 34.0 R + V and 214.8 ± 40.2 R + V, in the VX and VX + GSNX groups, respectively. APX virtually abolished the delayed phase of emesis and sham-operated ferrets had 93.0 ± 22.9 R + V whilst only 6.0 ± 3.6 R + V (p = 0.009) were observed in APX animals. These data suggest that, in contrast to the acute emetic response triggered by cisplatin, the delayed phase does not rely on abdominal visceral afferents but is mediated via the area postrema.     

The FAAH inhibitor URB-597 interferes with cisplatin- and nicotine-induced vomiting in the Suncus murinus (house musk shrew)

Considerable evidence implicates the endocannabinoid system as a neuromodulator of nausea and vomiting. The action of anandamide (AEA) can be prolonged by inhibiting its degradation, through the use of URB597 (URB), a Fatty Acid Amide Hydrolase (FAAH) enzyme inhibitor. Here we present evidence that the FAAH inhibitor, URB, interferes with cisplatin- and nicotine-induced vomiting in the Suncus murinus. In Experiment 1, shrews were injected with URB (0.9 mg/kg) or vehicle 120 min prior to the behavioral testing. They received a second injection of AEA (5 mg/kg) or vehicle 15 min prior to being injected with cisplatin (20 mg/kg) or saline and the number of vomiting episodes were counted for 60 min. In Experiment 2, shrews were injected with vehicle or URB (0.9 mg/kg) 120 min prior to receiving an injection of nicotine (5 mg/kg) or saline and the number of vomiting episodes were counted for 15 min. Experiment 3 evaluated the potential of the CB₁ antagonist, SR141716, to reverse the effect of URB on nicotine-induced vomiting. URB attenuated vomiting produced by cisplatin and nicotine and the combination of URB + AEA suppressed vomiting produced by cisplatin. The effect of URB on nicotine-induced vomiting was reversed by SR141716. These data suggest that the EC system plays a tonic role in the regulation of toxin-induced vomiting.     

Multi-hormonal weight loss combinations in diet-induced obese rats: Therapeutic potential of cholecystokinin?

Cholecystokinin (CCK) acutely synergizes with amylin to suppress food intake in lean mice. To extend on these findings, the present studies sought to identify neural correlates for the interaction of amylin and CCK, as well as further understand the therapeutic potential of CCK-based combinations in obesity. First, c-Fos activation was assessed in various brain nuclei after a single intraperitoneal injection of amylin (5 µg/kg) and/or CCK (5 µg/kg). Amylin and CCK additively increased c-Fos within the area postrema (AP), predominantly in noradrenergic (e.g., dopamine-β-hydroxylase-containing) cells. Next, amylin (100 or 300 μg/kg/d) and/or CCK (100 or 300 μg/kg/d) were subcutaneously infused for 7 days in diet-induced obese (DIO) rats. Amylin treatment of DIO rats for 7 days induced significant body weight loss. CCK, while ineffective alone, significantly enhanced body weight loss when co-administered with the higher dose of amylin. Finally, the addition of CCK (300 μg/kg/d) to leptin (125 µg/kg/d), and to the combination of amylin (50 μg/kg/d) and leptin (125 μg/kg/d), was also explored in DIO rats via sustained subcutaneous infusion for 14 days. Infusion of amylin/leptin/CCK for 14 days exerted significantly greater body weight loss, inhibition of food intake, and reduction in adiposity compared to amylin/leptin treatment alone in DIO rats. However, co-infusion of CCK and leptin was an ineffective weight loss regimen in this model. Whereas CCK agonism alone is ineffective at eliciting or maintaining weight loss, it durably augmented the food intake and body weight-lowering effects of amylin and amylin/leptin in a relevant disease model, and when combined with amylin, cooperatively activated neurons within the caudal brainstem.     

The study of ISO induced heart failure rat model

Objective

To find a more excellent large-dose isoproterenol (ISO) induced heart failure (HF) rat model.

Methods

166 male Wistar rats were divided into four groups, normal group (n = 10), 85/85 mg/kg group (n = 50), 85/340 mg/kg group (n = 50) and 340/340 mg/kg group (n = 56). HF was induced by two subcutaneous injections of homologous ISO on 2 consecutive days. We calculated death rate of each ISO group on different time points. And all the survival ISO rats were examined by echocardiography separately on 2 weeks, 3 weeks and 4 weeks. We defined the EF < 45% rats as heart failure, and calculated EF < 45% rate of three ISO groups. 4 weeks after the last injection, all of the rats were sacrificed. H&E and Masson staining were used to evaluate inflammatory infiltration and myocardial fibrosis, and immunohistochemistry was used to measure the levels of IL-1, IL-6 and IL-17. We also treated adult rat cardiac fibroblasts with IL-1, IL-6, IL-17, or PBS for 24 h, and real-time PCR was used to measure the expressions of MMP-2 and MMP-9 in treated fibroblasts.

Results

Through 4-week observation, we found that the period within 2 days after the last injection was the most dangerous one for all the ISO rats, regardless of injection dose. Then, the death rate increased slowly. 4 weeks later, the death rates were respectively 30% in 85/85 mg/kg group, 60% in 85/340 mg/kg group, and 68% in 340/340 mg/kg group, and there were statistical differences among three experimental groups. Moreover, the EF < 45% rate and cardiac fibrosis rate were 100% in 85/340 mg/kg group as same as 340/340 mg/kg group, and much higher than 85/85 mg/kg group. Furthermore, we also found that pro-inflammatory cytokines (IL-1, IL-6 and IL-17) increased in 85/340 mg/kg group compared with normal group, and above cytokines could induce MMP-2 and MMP-9 expression in cardiac fibroblasts.

Conclusion

85/340 mg/kg ISO induced HF rat model was superior to the other two dose ISO induced HF rat models. Pro-inflammatory cytokines might contribute to HF and myocardial fibrosis through promotion of MMPs expression in cardiac fibroblasts.     

The effect of systemic injection of cyclosporin A on the phosphorylation of the PKC substrates MARCKS and GAP43 in the rat hippocampus

Cyclosporin A (CsA) is an inhibitor of calcineurin, a calcium/calmodulin dependent serine/threonine phosphatase. Protein kinase C (PKC) is a family of serine/threonine kinases. Both calcineurin and PKC are implicated in psychiatric diseases and the therapeutic mechanisms of treatment agents. It has been reported that calcineurin interacts with components of PKC signaling pathways. We administrated 50 mg/kg CsA into rats by intraperitoneal injection and examined the acute effect of single systemic CsA on the locomotor activity of rats and the phosphorylation of PKC and its substrates GAP43 and MARCKS. Systemic CsA increased locomotor activity beginning 1 h after injection. The immunoreactivity of p-MARCKS(S152/156) was higher in the CsA group 1 h after injection, whereas p-GAP43(S41) immunoreactivity was increased by CsA after 5 h. The immunoreactivity of p-PKC pan was increased by CsA at both 1 and 5 h after administration. Our data suggest that activation of the PKC pathway might be related to CsA-induced hyperlocomotion.     

Perception of empathy in the therapeutic encounter: effects on the common cold

Objective

To evaluate the effects of patient-practitioner interaction on the severity and duration of the common cold.

Methods

We conducted a randomized controlled trial of 719 patients with new cold onset. Participants were randomized to three groups: no patient-practitioner interaction, “standard” interaction or an “enhanced” interaction. Cold severity was assessed twice daily. Patients randomized to practitioner visits used the Consultation and Relational Empathy (CARE) measure to rate clinician empathy. Interleukin-8 (IL-8) and neutrophil counts were obtained from nasal wash at baseline and 48 h later.

Results

Patients’ perceptions of the clinical encounter were associated with reduced cold severity and duration. Encounters rated perfect on the CARE score had reduced severity (perfect: 223, sub-perfect: 271, p = 0.04) and duration (perfect: 5.89 days, sub-perfect: 7.00 days, p = 0.003). CARE scores were also associated with a more significant change in IL-8 (perfect: mean IL-8 change 1586, sub-perfect: 72, p = 0.02) and neutrophil count (perfect: 49, sub-perfect: 12, p = 0.09).

Conclusions

When patients perceive clinicians as empathetic, rating them perfect on the CARE tool, the severity, duration and objective measures (IL-8 and neutrophils) of the common cold significantly change.

Practice implications

This study helps us to understand the importance of the perception of empathy in a therapeutic encounter.     

Augmented breaths (‘sighs’) are suppressed by morphine in a dose-dependent fashion via naloxone-sensitive pathways in adult rats

Morphine treatment can eliminate augmented breaths (ABs; ‘sighs’) during spontaneous breathing. In the present study, unanesthetized rats were studied to: (1) determine the involvement of naloxone-sensitive receptor pathways, and (2) establish the dose–response relationship of this side effect. At a dosage of 5 mg/kg (2–10 mg/kg is recommended range for analgesia) morphine eliminated ABs from the breathing rhythm across nearly 100 min post-administration (vs. 6.2 ± 1.6 ABs in 15 min, control condition, p < 0.001). This occurred despite no apparent effect on indices of ventilation. By contrast, when naloxone was co-administered with morphine, the occurrence of ABs was not different compared to control. The suppression of ABs by morphine followed a sigmoidal pattern across the low–mid dosage range (R² = 0.83), whereas tidal volume and breathing frequency were unaffected. We conclude that the opioid-induced suppression of ABs is mediated by naloxone-sensitive opioid receptor pathways, and that this side effect is potent across the low–mid dosage range, and cannot be simply avoided by restricting dosage.     

Pica--a model of nausea? Species differences in response to cisplatin

Rats lack the emetic reflex but exhibit pica in response to stimuli that induce emesis in species with an emetic reflex, hence it has been proposed that pica may be analogous to emesis in species lacking the reflex. In the present study, we investigated whether pica was present in Suncus murinus (with an emetic reflex) as well as in rats and mice (without emetic reflex) to provide a further insight to the validity of pica as a model for nausea/vomiting. Cisplatin (6 mg/kg, i.p.) induced pica in rats, indicated by a significant increase in kaolin consumption at 24 h (but not 48 h) post-treatment whereas we failed to demonstrate this effect in mice (inbred or outbred strain, 6 or 20 mg/kg i.p.) and whilst cisplatin (20 mg/kg, i.p.) induced emesis in Suncus, kaolin intake was not significantly affected. Furthermore, cisplatin significantly increased the weight of gastric contents at 48 h post-injection in rats and mice indicating delayed gastric emptying whereas this effect was not present in Suncus. These results show that Suncus and two strains of mice, unlike rats, do not develop pica in response to cisplatin which suggests that the consumption of kaolin induced by cisplatin may not be associated with whether or not an emetic reflex is present. The differences in ingestive behaviour and gastric response between species with and without an emetic reflex in response to cisplatin treatment as well as the difference between mice and rats, is discussed in relation to the selection of models for the study of nausea and vomiting.     

Further antinociceptive effects of myricitrin in chemical models of overt nociception in mice

The present work explored the antinociceptive effects of the flavonoid myricitrin in models of overt nociception triggered by intraplantar injection of chemical algogens into the hind paw of mice. The nociception induced by bradykinin (3 nmol/paw i.pl.) was abolished by prior treatment with myricitrin (10–100 mg/kg, i.p.) with ID₅₀ of 12.4 (8.5–18.1) mg/kg. In sharp contrast, myricitrin failed to affect the nociception elicited by prostaglandin E₂ (3 nmol/paw i.pl.). Cinnamaldehyde (10 nmol/paw i.pl.)-induced nociception was reduced by myricitrin (100 mg/kg, i.p.) and camphor (7.6 mg/kg, s.c.) in 43 ± 10% and 57 ± 8%, respectively. Myricitrin (30–100 mg/kg, i.p.) and amiloride (100 mg/kg, i.p.) inhibited nociceptive responses induced by acidified saline (pH 5/paw i.pl.), with ID₅₀ of 22.0 (16.1–30.0) mg/kg and inhibition of 71 ± 6% and 64 ± 5%, respectively. Moreover, myricitrin (10–30 mg/kg, i.p.) and ruthenium red (3 mg/kg, i.p.) significantly reduced the nociception induced by menthol (1.2 μmol/paw i.pl.) with the mean ID₅₀ of 2.4 (1.5–3.7) mg/kg and inhibition of 95 ± 3% and 51 ± 7%, respectively. In addition, myricitrin administration (30 and 100 mg/kg, i.p.) markedly reduced menthol-induced mechanical allodynia. However, myricitrin (100 mg/kg, i.p.) prevented (only in time of 60 min) cold allodynia induced by menthol. Collectively, the present results extend prior data and show that myricitrin promotes potent antinociception, an action that is likely mediated by an inhibition of the activation of nociceptors by bradykinin and TRPs agonist (i.e. cinnamaldehyde, acidified saline and menthol), probably via inhibition of PKC pathways. Thus, myricitrin could constitute an attractive molecule of interest for the development of new analgesic drugs.     

Whole genome association scan for genetic polymorphisms influencing information processing speed

Processing speed is an important cognitive function that is compromised in psychiatric illness (e.g., schizophrenia, depression) and old age; it shares genetic background with complex cognition (e.g., working memory, reasoning). To find genes influencing speed we performed a genome-wide association scan in up to three cohorts: Brisbane (mean age 16 years; N = 1659); LBC1936 (mean age 70 years, N = 992); LBC1921 (mean age 82 years, N = 307), and; HBCS (mean age 64 years, N = 1080). Meta-analysis of the common measures highlighted various suggestively significant (p < 1.21 × 10⁻⁵) SNPs and plausible candidate genes (e.g., TRIB3). A biological pathways analysis of the speed factor identified two common pathways from the KEGG database (cell junction, focal adhesion) in two cohorts, while a pathway analysis linked to the GO database revealed common pathways across pairs of speed measures (e.g., receptor binding, cellular metabolic process). These highlighted genes and pathways will be able to inform future research, including results for psychiatric disease.     

Deletion of the GluR5 subunit of kainate receptors affects cocaine sensitivity and preference

We have demonstrated previously that mice expressing a constitutive deletion of the kainate receptor subunit GluR5 (GluR5 KO) do not differ from wildtype (WT) littermates of a congenic C57BL/6 background with regard to both the development of morphine physical dependence as measured by naloxone-precipitated withdrawal signs and to morphine reward as revealed by the expression of conditioned place preference (CPP). However, unlike WT, GluR5 KO mice fail to develop antinociceptive tolerance following repeated systemic morphine administration. In this report, we examined the impact of GluR5 deletion on cocaine-mediated CPP and locomotor sensitization. Expression of CPP was evident in WT mice following repeated daily administration of 20 mg/kg (but not 10 mg/kg) i.p. cocaine. Interestingly, GluR5 KO mice exhibited enhanced cocaine preference as compared with WT mice at both 10 and 20 mg/kg doses. In addition, while GluR5 KO mice did not differ from WT with respect to baseline locomotor activity, mutant mice demonstrated increased locomotor hyperactivity versus WT mice after repeated injection of 15 mg/kg i.p. cocaine. Collectively, these data indicate that GluR5 appears to negatively modulate some psychostimulant and rewarding properties of cocaine, as demonstrated by heightened sensitization and salience in mutant mice.     

Effectiveness of riluzole in suppressing spasticity in the spinal cord injured rat

Spasticity poses a major detrimental impact on the quality of life in a significant number of people with spinal cord injury (SCI). Recent observations in our laboratory suggest that spinal transection at the sacral S₂ level induces a significant increase in glutamatergic input to sacrocaudal motoneurons during the time spasticity is present in the tail muscles. The present study examined the effectiveness of riluzole, an agent that has been shown to reduce glutamate release, in managing spasticity within the tail musculature. In this blinded, cross-over study animals with S₂ spinal transections were tested behaviorally for the progression of spasticity in the tail musculature using our established system. When the animals demonstrated a significant level of spastic behavior (e.g. increased response to quick stretch, noxious and non-noxious cutaneous stimuli), they received either saline or riluzole (8 or 10 mg/kg i.p.) and assessed behaviorally at 1, 3, 6, and 12 post-injection. Results: riluzole at 8 mg/kg significantly decreased the response of the tail muscle to noxious and non-noxious cutaneous stimuli for the first 3 h post-administration, while administration of riluzole at 10 mg/kg significantly decreased the responsiveness of the tail to all of the behavioral assessments. However, a significant percentage of the animals displayed motor impairments at this higher dosage. Conclusion: suppression of glutamate release by the administration of riluzole can reduce several, but not all, aspects of spastic activity in the tail muscles at concentrations that do not elicit negative side-effects.     

Differential activity of drugs to induce emesis and pica behavior in Suncus murinus (house musk shrew) and rats

We have previously reported that emetic stimuli induce kaolin ingestion behavior (pica behavior) in rats and mice (i.e., species that do not have the emetic reflex) and that the behavior may be analogous to gastrointestinal discomfort, such as nausea and emesis. We hypothesized that pica behavior may also occur in species capable of vomiting and that it may serve as an additional index of discomfort relevant to antiemetic drug development. The present experiments were conduced using Suncus murinus and rats and kaolin consumption was measured at 24 h after the administration of nicotine (1.25-5 mg/kg, s.c.), copper sulfate (10-120 mg/kg, p.o.), lithium chloride (50-200 mg/kg, i.p.) and cisplatin (1-30 mg/kg, i.p.). In S. murinus, all treatments, excepting lithium chloride, were emetic but none induce kaolin consumption. Conversely, all treatments induced kaolin consumption in rats without inducing emesis. The results indicate that pica behavior is not likely to be useful to assess gastrointestinal discomfort in S. murinus.