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Recent in vivo microdialysis studies have indicated that presynaptic deficits occur in brain 5-HT neurochemistry during cocaine withdrawal. The purpose of the present study was to utilize the head-twitch response (HTR) produced by 5-hydroxytryptophan (5-HTP) to investigate the dose- and time-response effects of this deficit. The HTR is considered to be a sensitive model for activation of central postsynaptic 5-HT2A receptors in rodents. Thus, different groups of mice were injected with cocaine twice daily (0, 0.1, 0.5, 2.5, 5 or 10 mg/kg, i.p.) for 7 or 13 days. During HTR testing, at 24 h following last injection, the treated mice received either 1) no cocaine; 2) their corresponding daily dose as challenge injection; or 3) a 10 mg/kg challenge dose. In a second series of experiments, extended abstinence studies were performed under the conditions of experimental protocols 1 and 2 for both 7- and 13-day cocaine (0, 0.5 and 5 mg/kg, twice daily) exposure regimens at 24, 48, 72 and 96 h following last cocaine injection. In protocol 3, the effects of a 10 mg/kg challenge dose of cocaine were studied following prolonged withdrawal from chronic cocaine exposure (0, 0.5, 5 and 10 mg/kg, twice daily for 7 and 13 days) at 24, 96 and 240 h abstinence. In experimental protocol 1 at 24 h abstinence in the 7 day exposure group, only lower doses of cocaine (0.5-2.5 mg/kg) significantly attenuated the 5-HTP-induced HTR. The deficit in 0.5 mg/kg group persisted up to 72 h abstinence. Although in the 13 day cocaine exposure groups (experimental paradigm 1) mean HTRs were generally reduced, they however failed to attain statistical significance throughout the 96 h abstinence. In protocol 2 very low challenge doses of cocaine (0.1-0.5 mg/kg) in their corresponding pretreatment groups significantly reduced the behavior at diverse abstinence intervals in both 7- and 13-day exposure regimens relative to their chronically vehicle-treated controls which had received a vehicle challenge injection during HTR testing. Unlike small doses of cocaine, larger challenge doses (5-10 mg/kg) of the stimulant potentiated the HTR score at various abstinence periods. However, the degree of the potentiations are considerably less than the ability of acute cocaine administration in enhancing the 5-HTP-induced HTR. The 10 mg/kg challenge injection in experimental protocol 3 at 24 h abstinence in the 7-day exposed mice attenuated the 5-HTP-induced HTR in 0.5, 5 and 10 mg/kg cocaine-treated groups relative to their chronic vehicle-treated controls receiving a 10 mg/kg challenge cocaine injection. The deficit in chronic 10 mg/kg cocaine-exposed mice persisted up to 240 h postcocaine abstinence. On the other hand, in the 13-day regimen, the challenge 10 mg/kg dose exhibited significant potentiations at 24 h and at 96 h for 5 and 0.5 mg/kg chronic cocaine doses respectively, but it also produced significant deficits in 0.5 and 10 mg/kg chronic doses of cocaine at 240 h abstinence. Overall, the present results suggest that enduring deficits occur in presyna...

Shrews are abundant in most areas of toxic chemical contamination and bioaccumulate pollutants at much higher rates than sympatric rodent species. As a part of studies to provide information concerning the toxicity of 1,3-dinitrobenzene (DNB) in least shrews (Cryptotis parva), groups of 10 females and 10 males received DNB at 0 (control), 0.7, 2.9, 11.6, and 46.3 microl/L (equivalent mean daily dosage of 0, 0.26, 1.06, 4.26, and 17.0 mg/kg body wt in each sex) in their diet for 14 d. Leukocytosis present at the 0.26 mg/kg body weight/d dosage established the lowest-observed-adverse effect level (LOAEL). Adrenal enlargement was noted at the 1.06 mg/kg body weight/d level. Splenic enlargement and reductions in hematocrit and hemoglobin values occurred at the 4.26 mg/kg body weight/d treatment. Enlargements in the liver and heart and reductions in brown fat weight, granulocyte numbers, and alanine aminotransferase levels were present at high dose levels. Histopathologic examinations showed Kupffer's cell hemosiderosis and suggested testicular damage at the two highest tested doses but failed to confirm brain lesions. Least shrews do not follow standard scaling estimates for lifespan or metabolic rates. The LOAEL calculated from the standard terrestrial screening benchmark equation was higher than our findings, suggesting that these estimates must be viewed with caution.

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