ΔFosB: A Molecular Mechanism of MDMA Dependence

<p>Rationale. 3,4-methylenedioxymethamphetamine (MDMA) is a widely used illicit substance and some users show signs of abuse and dependence. It has been suggested that addiction reflects persistent neuroplasticity and one proposed mechanism has been a change in the expression of the transcription factor, ΔFosB.  Objectives. This study determined whether ΔFosB expression in reward-relevant brain areas was altered as a function of MDMA self-administration.  Methods. Rats were separated into triads. One rat self-administered MDMA (master rat) and the other 2 rats received either MDMA (yoked MDMA) or saline (yoked saline) infusions contingent on the behaviour of the master rat. Testing continued until a total intake of 350 mg/kg of MDMA was delivered. Two days following the final self-administration session, rats were sacrificed and perfused transcardially. Brains were removed, and ΔFosB immunohistochemistry was conducted. ΔFosB expression in striatum and medial prefrontal cortex was compared across groups.  Results. Unfortunately the tissue from many of the yoked MDMA rats was compromised and therefore data from this group were not included in any analyses. MDMA self-administration produced a significantly greater expression of ΔFosB in the ventromedial and ventrolateral portions of the caudate putamen when compared to expression produced following yoked saline exposure. Within the infralimbic cortex, accumbens shell and dorsolateral caudate putamen differences approached significance. A significant correlation between ΔFosB expression in the ventromedial caudate putamen and cumulative active lever presses across the final 5 days of self-administration was also found.  Conclusions. These findings provide the first evidence of MDMA-induced expression of ΔFosB. Increased expression of ΔFosB was observed in regions associated with the development and maintenance of drug addiction. These data support the idea that induction of ΔFosB may present a mechanism by which MDMA can induce alterations in genetic transcription, which may underlie the development of MDMA dependence.  Future studies should utilise antagonism of ΔFosB via region-selective administration of Δc-jun in order to further elucidate the role of these transcriptional changes in the development and maintenance of self-administration.</p>