An optical fibre point temperature sensor for investigation of 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) induced hyperthermia in the rat brain

Abstract

3,4-methylenedioxymehtamphetamine (MDMA, ‘ecstasy’) is an illegal stimulant drug that can produce life-threatening hyperthermia following consumption in humans. Administration of MDMA also produces similar effects in experimental animals and it can lead to death usually through multi-organ failure, and vasogenic brain oedema. Despite the danger acute MDMA-induced hyperthermia poses, current treatments for these adverse effects in a clinical setting are limited and do not address hyperthermia’s central origins. Due to ethical reasons, the investigation of these MDMA-induced changes in humans are restricted, therefore animal models are relied on to investigate the real-time thermoregulatory effects of MDMA and their underlying pharmacological mechanisms. This being considered, it is important to investigate MDMAs adverse effects in animals and potential pharmacological therapeutics using advantageous techniques in order to effectively relate these findings from animals to humans. The aim of this thesis was to develop a novel portable optical fibre temperature sensor for the monitoring of brain temperature in awake freely-moving rats, and to use this sensor in conjunction with radiotelemetry to investigate the effects of MDMA on thermoregulation and its related physiological parameters. We also aimed to investigate the brain hyperthermia-attenuating effects of the tetracycline antibiotic drug minocycline, as well as its effects on body temperature, heart rate, and locomotor activity. The first part of this thesis aimed at optimizing a portable optical fibre temperature sensor based on rare-earth thermometry for long-term temperature measurements in vivo. Initial in vitro tests revealed measurement instabilities in the original configuration and therefore changes were made to the optical equipment aimed at increasing its long-term stability. The susceptibility of the previous probe to signal bend-loss and breakage during animal movement following MDMA administration was also reduced through numerous physical changes to the sensor design. The second study aimed to provide proof-of-concept for this portable optical fibre-tip sensor capable of recording brain temperature in conscious freely-moving rats. This study was successful in demonstrating that accurate and spatially precise brain temperature recordings could be performed by the probe while utilising a portable optical setup. These brain temperature measurements also showed a good correlation with body temperature recorded with radiotelemetry throughout the experiment. The third study made further improvements to the probe structure which increased probe durability, reusability and ease of use for in vivo experiments. These changes significantly increased experimental throughput and reduced time and resource costs associated with probe fabrication. Brain temperature measurements made with this probe showed that MDMA (10 mg/kg) induced a significant hyperthermia in the brains of Sprague-Dawley rats. The fourth study looked at the effects of MDMA administered at differing ambient temperatures, as well as the hyperthermia attenuating effects of minocycline. Administration of MDMA (10 mg/kg) induced both a significant hypothermia and hyperthermia when administered at normal, and high ambient temperature respectively, and significantly increased heart rate, and locomotor activity irrespective of environmental conditions. Pretreatment with minocycline (50 mg/kg) was able to significantly attenuate MDMA-induced brain and body hyperthermia at high ambient temperature and reduce MDMA-induced increases in heart rate and locomotor activity. In conclusion, we have developed and validated an optical fibre point temperature sensor based on rare-earth thermometry that accurately records rat brain temperature in vivo. We also combined optical fibre brain temperature measurements with body temperature monitoring to investigate the thermoregulatory, and physiological effects of MDMA and minocycline in freely-moving rats.