3,4-methylenedioxymethamphetamine (MDMA/ 'ecstasy') is a popular """"""""recreational"""""""" drug with considerable abuse liability including potential neurotoxicities directed toward the central serotonergic system. Although much attention has focused on MDMA's neurotoxic effects and its' ability to promote release of monoamine transmitters, little is known about how the drug affects the operation of neural circuits and brain function either at high neurotoxic doses or doses considered to be in the """"""""recreational"""""""" range. For example, MDMA users report that one of the major pleasurable outcomes of ecstasy self-administration is enhanced tactile sensation, but there is no explanation for how the drug produces this desirable and much sought after sensory experience. Because of the potential for long term damage to the nervous system after MDMA ingestion, there is a pressing need to understand the neural substrates underlying the motivation for human self-administration of this agent. The long-term goal of the proposed research is to better understand the neurophysiology underlying ecstasy's effects. The immediate goal of the present proposal is to develop and validate procedures for evaluating the impact of MDMA on sensory signal processing in the VPM thalamus of intact rats. The project employs plasma level analysis of drug concentrations, and electrophysiological determination of VPM cellular function in intact anesthetized or waking rats. Multi-channel, multi-neuron extracellular recording, systemic drug administration, activation of afferent trigeminal somatosensory pathways, and computer based analysis of spike train data are used to assess the impact of MDMA on sensory signal processing. A significant feature of this multi-dimensional approach is that drug effects will be determined at acute and chronic doses that: 1) approximate human self-administration regimens, 2) produce known plasma levels of the drug, and 3) elicit measurable changes in monoamine efflux within sensory circuits of the brain. Understanding the relationship between MDMA administration, monoamine transmitter efflux, and the operation of the somatosensory system will provide a basis for understanding the neurophysiological mechanisms underlying the drugs' effects on tactile sensory perception, in particular; and neural circuit functions, in general. A detailed knowledge of MDMA's effects on cellular and neural circuit function including its effects on sensory neurophysiology is essential in order to provide the public with accurate information regarding the risks associated with recreational use of this popular compound and its derivatives. Furthermore, once established, these methods will be used in future studies to characterize MDMA actions in other brain networks (prefrontal cortex, limbic) and more sophisticated behavioral assays (sensory discrimination, self-administration, craving and re-instatement) as a means of further clarifying its abuse liability. Waterhouse, Barry D. PROJECT NARRATIVE ()3,4-methylenedioxymethamphetamine (MDMA/ 'ecstasy') is an increasingly popular """"""""recreational"""""""" drug that poses a significant threat to the nation's health because of its: 1) adverse acute and chronic effects on behavior and physiological functions, 2) neurotoxicity toward selected neurotransmitter systems in the brain, and 3) overall addictive potential. Although much attention has focused on MDMA's neurotoxic effects and its' ability to promote release of endogenous transmitters, little is known about how the drug affects the operation of neural circuits and brain function either at high neurotoxic doses or doses considered to be in the """"""""recreational"""""""" range. Because of the potential for addiction and long term damage to the nervous system after MDMA ingestion, there is a pressing need to understand the neural substrates underlying the motivation for human self-administration of this agent. The goal of the proposed project is to develop and validate procedures that will help us better comprehend the neurophysiological basis for ecstasy's effects in human drug users. ? ? ?
| Vasudeva, Rani K; Waterhouse, Barry D (2014) Cellular profile of the dorsal raphe lateral wing sub-region: relationship to the lateral dorsal tegmental nucleus. J Chem Neuroanat 57-58:15-23 |
| Starr, M A; Page, M E; Waterhouse, B D (2012) Effects of repeated 3,4-methylenedioxymethamphetamine administration on neurotransmitter efflux and sensory-evoked discharge in the ventral posterior medial thalamus. J Pharmacol Exp Ther 340:73-82 |
