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Role of hypothermia in the mechanism of protection against serotonergic toxicity. II. Experiments with methamphetamine, p-chloroamphetamine, fenfluramine, dizocilpine and dextromethorphan.
J Pharmacol Exp Ther. 1995 Feb; 272(2):868-75.JP

Abstract

Several amphetamine analogs, when administered in high-dose regimens, have been shown to cause long-lasting depletions of central serotonin (5-HT), which are indicative of neuronal toxicity. These depletions and the resulting toxicity can be attenuated pharmacologically or by lowering ambient temperature. The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (DZ) blocks depletion of 5-HT induced by methamphetamine (METH) and p-chloroamphetamine (PCA), but not fenfluramine (FEN). This study investigated whether the effects of DZ and another calcium channel antagonist, dextromethorphan (DEX), are due to induction of hypothermia. Male Sprague-Dawley rats were injected with either saline (SAL), DZ (1 or 2 injections of 2.5 mg/kg), or DEX (75.0 mg/kg) followed by either SAL, METH (4 injections of 10.0 mg/kg), PCA (1 injection of 10.0 mg/kg) or FEN (2 or 4 injections of 12.5 mg/kg). Core body temperature (TEMP) was monitored for 4 h or longer with radiotelemetry. Base-line TEMP was between 37.0 and 37.6 degrees C. SAL/METH caused a significant increase in TEMP which peaked at 40.8 +/- 0.50 degrees C after the last injection. Coadministration of DZ with METH caused TEMP to decrease to 33.8 +/- 0.30 degrees C within 2 h of the first injection and lasting more than 3 h, and protected against depletion of 5-HT. SAL/PCA caused a small increase in TEMP to 37.7 +/- 0.36 degrees C, whereas coadministration of DZ with PCA decreased TEMP to 35.2 +/- 0.50 degrees C, lasting 2 h, in a dose regimen which has been shown to be neuroprotective.(

ABSTRACT

TRUNCATED AT 250 WORDS)

Authors+Show Affiliations

University of Chicago, Department of Pharmacological and Physiological Sciences, Illinois.No affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

7853205

Citation

Farfel, G M., and L S. Seiden. "Role of Hypothermia in the Mechanism of Protection Against Serotonergic Toxicity. II. Experiments With Methamphetamine, P-chloroamphetamine, Fenfluramine, Dizocilpine and Dextromethorphan." The Journal of Pharmacology and Experimental Therapeutics, vol. 272, no. 2, 1995, pp. 868-75.
Farfel GM, Seiden LS. Role of hypothermia in the mechanism of protection against serotonergic toxicity. II. Experiments with methamphetamine, p-chloroamphetamine, fenfluramine, dizocilpine and dextromethorphan. J Pharmacol Exp Ther. 1995;272(2):868-75.
Farfel, G. M., & Seiden, L. S. (1995). Role of hypothermia in the mechanism of protection against serotonergic toxicity. II. Experiments with methamphetamine, p-chloroamphetamine, fenfluramine, dizocilpine and dextromethorphan. The Journal of Pharmacology and Experimental Therapeutics, 272(2), 868-75.
Farfel GM, Seiden LS. Role of Hypothermia in the Mechanism of Protection Against Serotonergic Toxicity. II. Experiments With Methamphetamine, P-chloroamphetamine, Fenfluramine, Dizocilpine and Dextromethorphan. J Pharmacol Exp Ther. 1995;272(2):868-75. PubMed PMID: 7853205.
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TY - JOUR T1 - Role of hypothermia in the mechanism of protection against serotonergic toxicity. II. Experiments with methamphetamine, p-chloroamphetamine, fenfluramine, dizocilpine and dextromethorphan. AU - Farfel,G M, AU - Seiden,L S, PY - 1995/2/1/pubmed PY - 1995/2/1/medline PY - 1995/2/1/entrez SP - 868 EP - 75 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 272 IS - 2 N2 - Several amphetamine analogs, when administered in high-dose regimens, have been shown to cause long-lasting depletions of central serotonin (5-HT), which are indicative of neuronal toxicity. These depletions and the resulting toxicity can be attenuated pharmacologically or by lowering ambient temperature. The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (DZ) blocks depletion of 5-HT induced by methamphetamine (METH) and p-chloroamphetamine (PCA), but not fenfluramine (FEN). This study investigated whether the effects of DZ and another calcium channel antagonist, dextromethorphan (DEX), are due to induction of hypothermia. Male Sprague-Dawley rats were injected with either saline (SAL), DZ (1 or 2 injections of 2.5 mg/kg), or DEX (75.0 mg/kg) followed by either SAL, METH (4 injections of 10.0 mg/kg), PCA (1 injection of 10.0 mg/kg) or FEN (2 or 4 injections of 12.5 mg/kg). Core body temperature (TEMP) was monitored for 4 h or longer with radiotelemetry. Base-line TEMP was between 37.0 and 37.6 degrees C. SAL/METH caused a significant increase in TEMP which peaked at 40.8 +/- 0.50 degrees C after the last injection. Coadministration of DZ with METH caused TEMP to decrease to 33.8 +/- 0.30 degrees C within 2 h of the first injection and lasting more than 3 h, and protected against depletion of 5-HT. SAL/PCA caused a small increase in TEMP to 37.7 +/- 0.36 degrees C, whereas coadministration of DZ with PCA decreased TEMP to 35.2 +/- 0.50 degrees C, lasting 2 h, in a dose regimen which has been shown to be neuroprotective.(ABSTRACT TRUNCATED AT 250 WORDS) SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/7853205/Role_of_hypothermia_in_the_mechanism_of_protection_against_serotonergic_toxicity__II__Experiments_with_methamphetamine_p_chloroamphetamine_fenfluramine_dizocilpine_and_dextromethorphan_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=7853205 DB - PRIME DP - Unbound Medicine ER -