When administered to rats in a cold environment, 3,4-methylenedioxymethamphetamine reduces brown adipose tissue thermogenesis and increases tail blood flow: effects of pretreatment with 5-HT1A and dopamine D2 antagonists.

When given in a warm environment MDMA (3,4-methylenedioxymethamphetamine, ecstasy) causes hyperthermia by increasing interscapular brown adipose tissue (iBAT) heat production and decreasing heat loss via cutaneous vasoconstriction. When given in a cold environment, however, MDMA causes hypothermia by an unknown mechanism. This paper addresses these mechanisms and in addition examines whether antagonists at 5-HT(1A) and D(2) receptors reduce the hypothermic action of MDMA. Male Sprague-Dawley rats instrumented with a Doppler probe for measuring tail blood flow, and probes for measuring core and iBAT temperatures, were placed in a temperature-controlled chamber. The chamber temperature was reduced to 10 degrees C and vehicle (0.5 ml Ringer), the 5-HT(1A) antagonist WAY 100635 (0.5 mg/kg), the D(2) antagonist spiperone (20 mug/kg), or the combination of Way 100635 and spiperone were injected s.c. Thirty minutes later the antagonists were injected again along with MDMA (10 mg/kg) or vehicle. MDMA reduced core body temperature by preventing cold-elicited iBAT thermogenesis and by transiently reversing cold-elicited cutaneous vasoconstriction. Pretreatment with WAY 100635 prevented MDMA induced increases in tail blood flow, and briefly attenuated MDMA's effects on iBAT and core temperature. While spiperone alone failed to affect any of the parameters, the combination of spiperone and WAY 100635 decreased MDMA-mediated hypothermia by attenuating both the effects on tail blood flow and iBAT thermogenesis. MDMA's prevention of cold-induced iBAT thermogenesis appears to have a central origin as it rapidly reverses cold-induced increases in iBAT sympathetic nerve discharge in anesthetized rats. Our results demonstrate that MDMA in a cold environment reduces core body temperature by inhibiting iBAT thermogenesis and tail artery vasoconstriction and suggest that mechanisms by which this occurs include the activation of 5-HT1A and dopamine D2 receptors.

Pearls and pitfalls in the approach to patients with neurotoxic syndromes.

Neurotoxins are an important cause of neurologic disorders. A vast number of potentially neurotoxic compounds exist, including prescription drugs, illicit substances, and exposures through the workplace, residence, hobbies, and the environment. Effects of neurotoxins can mimic neurologic illnesses; therefore, it is important to consider neurotoxins in the differential diagnosis of any patient with neurological dysfunction. Paramount to the diagnosis of a possible neurotoxic syndrome is establishing causation. This can be done by a systematic approach utilizing principles in epidemiology and applying them to the individual patient. This approach is discussed in the following article in an attempt to bring structure to solving problems in a complex area of medicine.

HIV-1 gp120-induced neurotoxicity to midbrain dopamine cultures.

HIV-1-associated cognitive/motor dysfunction is a frequent neurological complication of acquired immunodeficiency syndrome (AIDS) and has been termed AIDS dementia complex (ADC). The HIV-1 envelope glycoprotein gp120 has been implicated in producing brain injury associated with ADC. The purpose of the present study was to determine if gp120-induced neurotoxicity is associated with damage to dopaminergic systems. Exposure of rat midbrain dopamine cultures to gp120 for 3 days reduced the ability of dopaminergic cells to transport this amine and also resulted in a reduction in dopamine neuron process length while it did not alter either dopamine cell number or the total number of neuronal cells. These detrimental effects of gp120 were prevented by an NMDA receptor antagonist (MK-801) or by preincubation with anti-gp120 antibody. These results suggest that dopaminergic neuronal damage may contribute to the manifestations of AIDS dementia complex.

19F nuclear magnetic resonance analysis of trifluoroethanol metabolites in the urine of the Sprague-Dawley rat.

2,2,2-Trifluoroethanol (TFE) is a common industrial solvent and a known metabolite of the inhalation anesthetics fluroxene (2,2,2-trifluoroethyl vinyl ether) and halothane (2-bromo-2-chloro-1,1,1-trifluoroethane). The water-soluble metabolites of TFE were identified in the urine of Sprague-Dawley rats using 19F NMR spectroscopy. In rats dosed with 0.21 g TFE/kg body weight, approximately one-half of the administered TFE was excreted as the trifluoroethyl glucuronide. The remaining TFE was oxidized, primarily to trifluoroacetaldehyde hydrate, with a small percentage of the aldehyde oxidized further to trifluoroacetate. One additional fluorinated compound was found; after investigation, this was identified as a Schiff's base compound resulting from the addition of trifluoroacetaldehyde to urea. The time-dependent excretion of TFE metabolites was measured as a function of ethanol induction of hepatic enzymes. This study demonstrates the utility of 19F NMR for the analysis of drug metabolism in laboratory animals. In addition, the resistance of trifluoroacetaldehyde hydrate to further oxidation, coupled with its reactivity with common cellular amines, indicates the potential toxicity of this metabolite to mammalian tissues.