A long hangover from party drugs: Residual proteomic changes in the hippocampus of rats 8 weeks after γ-hydroxybutyrate (GHB), 3,4-methylenedioxymethamphetamine (MDMA) or their combination

Abstract

3,4-Methylenedioxymethamphetamine (MDMA) and γ-hydroxybutyrate (GHB) are popular party drugs that are used for their euphoric and prosocial effects, and sometimes in combination. Both drugs increase markers of oxidative stress in the hippocampus and can cause lasting impairments in hippocampal-dependent forms of memory. To gain further information on the biochemical mechanisms underlying these effects, the current study examined residual changes in hippocampal protein expression measured 8 weeks after chronic administration of GHB (500mg/kg), MDMA (5mg/kg) or their combination (GHB/MDMA). The drugs were administered once a day for 10 days in an environment with an elevated ambient temperature of 28°C. Results showed significant changes in protein expression, relative to controls, in all three groups: MDMA and GHB given alone caused residual changes in 8 and 5 proteins respectively, while the GHB/MDMA combination significantly changed 6 proteins. The altered proteins had roles in neuroplasticity, neuroprotection, intracellular signalling and cytoskeletal function. The largest change (−4.3-fold) was seen in the MDMA group with the protein C-crk: a protein implicated in learning-related neuroplasticity. The second largest change (3.0-fold) was seen in the GHB group in Glutathione-S-transferase (GST), a protein that protects against oxidative stress. Two cytoskeletal proteins (Tubulin Folding Cofactor B and Tropomyosin-alpha-3 chain) and one plasticity related protein (Neuronal Pentraxin-1 NP1) were similarly changed in both the MDMA and the GHB groups, while two intracellular signalling proteins (alpha-soluble NSF-attachment protein and subunits of the V-type proton ATPase) were changed in both the MDMA/GHB and the MDMA groups. These results provide some insight into the molecular pathways possibly underlying the lasting cognitive deficits arising from GHB and/or MDMA use.