PubMed · 8659758
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S E Metzger, L A Fleisher. 1996. Cost-effective modeling.. https://doi.org/10.1097/00000539-199607000-00066
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Life-threatening hyperthermia occurs in some individuals taking 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). In rabbits, sympathetically mediated vasoconstriction in heat-exchanging cutaneous beds (ear pinnae) contributes to MDMA-elicited hyperthermia. We investigated whether MDMA-elicited cutaneous vasoconstriction and hyperthermia are reversed by clozapine and olanzapine, atypical antipsychotic agents. Ear pinna blood flow and body temperature were measured in conscious rabbits; MDMA (6 mg/kg, i.v.) was administered; and clozapine (0.1-5 mg/kg, i.v.) or olanzapine (0.5 mg/kg, i.v.) was administered 15 min later. One hour after MDMA, temperature was 38.7 +/- 0.5 degrees C in 5 mg/kg clozapine-treated rabbits and 39.0 +/- 0.2 degrees C in olanzapine-treated rabbits, less than untreated animals (41.5 +/- 0.3 degrees C) and unchanged from pre-MDMA values. Ear pinna blood flow increased from the MDMA-induced near zero level within 5 min of clozapine or olanzapine administration. Clozapine-induced temperature and flow responses were dose-dependent. In urethane-anesthetized rabbits, MDMA (6 mg/kg, i.v.) increased ear pinna postganglionic sympathetic nerve discharge to 217 +/- 33% of the pre-MDMA baseline. Five minutes after clozapine (1 mg/kg, i.v.) discharge was reduced to 10 +/- 4% of the MDMA-elicited level. In conscious rats made hyperthermic by MDMA (10 mg/kg, s.c.), body temperature 1 hr after clozapine (3 mg/kg, s.c.) was 36.9 +/- 0.5 degrees C, <38.6 +/- 0.3 degrees C (Ringer's solution-treated) and not different from the pre-MDMA level. One hour after clozapine, rat tail blood flow was 24 +/- 3 cm/sec, greater than both flow in Ringer's solution-treated rats (8 +/- 1 cm/sec) and the pre-MDMA level (17 +/- 1 cm/sec). Clozapine and olanzapine, by interactions with 5-HT receptors or by other mechanisms, could reverse potentially fatal hyperthermia and cutaneous vasoconstriction occurring in some humans after ingestion of MDMA.
A series of (+/-)-2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinolines were prepared and their bradycardic activities were examined in isolated guinea-pigs' right atria and in anesthetized rats. Modifications on the benzyl moiety of the parent compound, 1, led to the identification of compound 11e as a potent and specific bradycardic agent.
The parabrachial nucleus (PBN), an integration site for autonomic regulation in the mesopontine brainstem, receives sensory information about cold temperatures from the skin. Here we investigated the role of the PBN in thermoregulation. Unilateral stimulation of the PBN (10-40 microA, 5 min) immediately increased the rate of O(2) consumption ( VO(2)) and heart rate, and the magnitude of these responses increased with the intensity of the stimulus in urethane-anesthetized rats. High-intensity (40 microA) stimulation of the PBN increased the temperature of the interscapular brown adipose tissue and that of the colon but had no effect on that of the tail skin, although weaker stimulation was without effect on these temperatures. Next, we examined the effects of bilateral lesioning of the PBN on environmental cooling-induced thermogenesis in conscious rats. Exposure of PBN-lesioned rats to a cool (16.6 degrees C) environment induced a significantly smaller increase in VO(2) than did that of rats with a sham operation or with lesions made outside of the PBN, and resulted in a marked decrease in body temperature in PBN-lesioned rats but not in other rats. Both frequency and duration of gross motor activity in the cool environment were similar between PBN-lesioned and sham-operated rats. These results suggest that the PBN is involved in the central mechanisms of cooling-induced thermogenesis.