MDMA (3,4-methylenedioxymethamphetamine) modulation of tactile sensory information processing

MDMA (ecstasy) is known to enhance tactile sensory perception, which has been reported to contribute to its abuse liability. To date no published literature exists that addresses the neurophysiological mechanisms underlying MDMA's effects on somatosensation; however MDMA interactions with the central serotonergic and noradrenergic systems via blockade of serotonin and norepinephrine transporter protein function (SERT & NET) are well known. The rat trigeminal somatosensory system has been well defined and receives serotonergic and noradrenergic afferents from the dorsal raphe and locus coeruleus, respectively. These fibers express SERT and NET, and are particularly vulnerable to MDMA-induced effects. We found that acute and chronic MDMA administration result in increased neurotransmitter efflux and alterations in neuronal responsiveness to sensory stimulation within the rat VPM thalamus. Theses findings, summarized below, begin to provide a neurochemical and neurophysiological basis for the alterations in tactile sensations that are reported by human recreational users of MDMA.; First, we found, using gas chromatography and mass spectrometry, that acute low-dose MDMA administration (3 mg/kg, i.p.) results in peak plasma blood levels that are similar to that seen in a human following a recreational dose of the drug.; Second, we demonstrated, through the use of immunohistochemical techniques, that both acute (3 and 10 mg/kg) MDMA injection and a challenge injection of MDMA (3 mg/kg) following chronic treatment (3 mg/kg once per day x 4 days) results in a reduction in the number of cell bodies in the ventral medial and lateral wing subdivisions of the DRN that double-label for 5-HT and SERT. In addition, we found that both acute and chronic MDMA administration leads to a reduction in 5-HT and SERT fiber density in the VPM thalamus. Therefore, both low and high dose MDMA administration leads to alterations in serotonergic function that are evident at least 7 hours after both an acute or challenge injection following chronic treatment.; Third, we found, using in vivo microdialysis and high performance liquid chromatography (HPLC), that acute MDMA administration (1, 3, and 10 mg/kg, i.p.) leads to a significant, rapid dose-dependent increase in 5-HT efflux in the VPM thalamus of awake rats. However, the same dose-dependent increase is not observed when measuring NE efflux. Acute MDMA administration causes increases in NE efflux in the VPM thalamus only at the highest dose tested (10 mg/kg). In contrast, we found that administration of a challenge injection (3 mg/kg i.p.) of MDMA following chronic MDMA treatment elicits both 5-HT and NE efflux in the VPM thalamus. Importantly, extracellular 5-HT levels remain elevated longer in the chronically treated rats. Furthermore, the observed increases in NE efflux following challenge injection in chronically treated animals were similar in time course and magnitude to an acute high dose injection of MDMA (10 mg/kg).; Fourth, we demonstrated, through the use of in vivo extracellular single-unit recording in VPM thalamus of the halothane anesthetized rat, that both acute and chronic MDMA administration leads to decreases in magnitude and timing of individual sensory neuron responses to whisker stimulation. Interestingly, MDMA's suppressant effects on whisker responsiveness to high intensity whisker stimulation are blunted following chronic treatment. Additionally, both acute and chronic MDMA administration leads to increases in the basal discharge of single neurons, followed by a return to control levels. However, following chronic MDMA administration the effects of the drug on spontaneous firing rate are blunted compared to acute treatment. The net effect of suppressed evoked discharge and increased spontaneous firing is a pronounced reduction in the signal to noise ratio for sensory signals. In addition, both acute and chronic MDMA administration decreases the duration of the whisker-evoked r...