MDMA ELICITS DIFFERENT BEHAVIORS, GENE EXPRESSION IN ADOLESCENT, ADULT MICE

Harvard Medical School, Boston MA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. AIMS: MDMA methylene-dioxymethamphetamine or ecstasy is a widely abused psychoactive drug, considered to produce its empathic effects primarily by modulating serotonin transporter SERT function and brain serotonin activity. MDMA is also a mild psychomotor stimulant in humans and nonhuman primates, an effect reportedly mediated by dopaminergic activity. We previously demonstrated that MDMA is an effective substrate for the dopamine DAT transporter. Based on these findings, we hypothesized that an acute dose of MDMA would occupy the DAT in vivo, as manifest by reduced DAT binding potential. METHODS: In rhesus monkeys n=5, we used PET imaging and the DAT ligand (11C)CFT to measure DAT binding potential. PET imaging was performed over 60 min, with regions of interest drawn over striatum and cerebellum and binding potential calculated using the SSRT method. Following generation of baseline DAT binding potential, MDMA (1.5 mg/kg was injected intravenously and imaging was repeated 1 hour after drug injection. RESULTS: Contrary to expectations, DAT binding potential measured with (11C)CFT was consistently higher, 121 percent (n=5, than baseline values, following an acute dose of MDMA. Intramuscular MDMA and the DAT ligand (11C)altropane yielded inconsistent changes, confirming our previous findings that METH effects are sensitive to route of administration and time. CONCLUSIONS: These unanticipated findings are conceivably attributable to neurochemical properties of METH or technical reasons. MDMA may alter DAT regulatory mechanisms acutely to increase DAT availability or alternately, MDMA blockade of striatal SERT could prevent SERT occupancy by (11C)CFT to increase PET ligand availability for the DAT.AIMS: The undeveloped adolescent brain is particularly susceptible to addiction. Risk analyses show early onset of drug use results in a much higher prevalence of addiction to alcohol, nicotine, cocaine, opioids, and MDMA, than initiation of drug use in adulthood. Our focus on MDMA (3, 4-methylenedioxymethamphetamine, ecstasy) is driven by a recent surge in use among youth combined with declining perception of harm. We explored the hypothesis that MDMA exposure during brain development alters the trajectory of normal neurodevelopment by modifying expression of genes designated axonal guidance molecules (AGMs). AGMs are critical for neurodevelopment, neurogenesis and neuroadaptation. METHODS: 14 peri-adolescent mice and 14 adult mice were administered either a low dose of MDMA (3 mg/kg) daily for 6 non-sequential days, or saline, with locomotor activity measured daily. Real-time quantitative PCR measured mRNA expression of 22 genes implicated in MDMA effects in post-mortem brain regions. RESULTS: MDMA suppressed locomotor activity in adolescent mice and increased activity in adult mice. Locomotor effects occurred at earlier times and declined faster in adolescent than adult mice. In striatum and hippocampus, MDMA produced different changes in expression of genes implicated in activity, neurodevelopment and neuroadaptation. CONCLUSIONS: MDMA produces marked differences in adolescent and adult mice, in locomotor activity and in gene expression levels, conceivably contributing to the higher susceptibility of adolescents to MDMA-induced addiction and cognitive impairment. This novel approach may clarify the role of these and other critical genes in mediating the heightened adverse consequences of MDMA, other psychostimulant drugs of abuse in adolescents.