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Increased Response to 3,4-Methylenedioxymethamphetamine (MDMA) Reward and Altered Gene Expression in Zebrafish During Short- and Long-Term Nicotine Withdrawal.

ABSTRACT: An interactive effect between nicotine and 3,4-methylenedioxymethamphetamine (MDMA) has been reported but the mechanism underlying such interaction is not completely understood. This study used zebrafish to explore gene expression changes associated with altered sensitivity to the rewarding effects of MDMA following 2-week exposure to nicotine and 2-60 days of nicotine withdrawal. Reward responses to MDMA were assessed using a conditioned place preference (CPP) paradigm and gene expression was evaluated using quantitative real-time PCR of mRNA from whole brain samples from drug-treated and control adult zebrafish. Zebrafish pre-exposed for 2 weeks to nicotine showed increased conditioned place preference in response to low-dose, 0.1 mg/kg, MDMA compared to un-exposed fish at 2, 7, 30 and 60 days withdrawal. Pre-exposure to nicotine for 2 weeks induced a significant increase of c-Fos and vasopressin receptor expression but a decrease of D₃ dopaminergic and oxytocin receptor expression at 2 days of withdrawal. C-Fos mRNA increased also at 7, 30, 60 days of withdrawal. Nicotine pre-exposed zebrafish submitted to MDMA-induced CPP showed an increase in expression of p35 at day 2, α4 at day 30, vasopressin at day 7 and D₃ dopaminergic receptor at day 7, 30 and 60. These gene alterations could account for the altered sensitivity to the rewarding effects of MDMA in nicotine pre-exposed fish, suggesting that zebrafish have an altered ability to modulate behaviour as a function of reward during nicotine withdrawal.

SUBMITTER: Ponzoni L

PROVIDER: S-EPMC8170707 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:3,4-Methylenedioxymethamphetamine (MDMA) is an illicit phenethylamine ingested for entactogenic and euphoric effects. Although blood is more commonly submitted for forensic analysis, previous human MDMA pharmacokinetics research focused on plasma data; no direct blood-plasma comparisons were drawn. Blood and plasma specimens from 50 healthy adult volunteers (33 males, 17 females, 36 African-American) who ingested recreational 1.0 and 1.6 mg/kg MDMA doses were quantified for MDMA and metabolites 4-hydroxy-3-methoxymethamphetamine (HMMA), 3,4-methylenedioxyamphetamine (MDA), and 4-hydroxy-3-methoxyamphetamine (HMA) by two-dimensional gas chromatography-mass spectrometry. Specimens were collected up to 3 h post-dose and evaluated for maximum concentration (C max), first detection time (t first), time of C max (t max), and 3-h area under the curve (AUC0-3 h); as well as blood metabolite ratios and blood/plasma ratios. Median blood MDMA and MDA C max were significantly greater (p?<?0.0005) than in plasma, but HMMA was significantly less (p?<?0.0005). HMA was detected in few blood specimens, at low concentrations. Nonlinear pharmacokinetics were not observed for MDMA or MDA in this absorptive phase, but HMMA C max and AUC0-3 h were similar for both doses despite the 1.6-fold dose difference. Blood MDA/MDMA and MDA/HMMA significantly increased (p?<?0.0001) over the 3-h time course, and HMMA/MDMA significantly decreased (p?<?0.0001). Blood MDMA C max was significantly greater in females (p?=?0.010) after the low dose only. Low-dose HMMA AUC0-3 h was significantly decreased in females' blood and plasma (p?=?0.027) and in African-Americans' plasma (p?=?0.035). These data provide valuable insight into MDMA blood-plasma relationships for forensic interpretation and evidence of sex- and race-based differential metabolism and risk profiles. Figure Median (interquartile range) blood/plasma 3,4-methylenedioxymethamphetamine (MDMA) (a), 4-hydroxy-3-methoxymethamphetamine (HMMA) (b), and 3,4-methylenedioxyamphetamine (MDA) (c) ratios for 3 h after controlled MDMA administration. Changes over time were significant after the 1.6 mg/kg dose for HMMA and MDA (p?=?0.013 and p?=?0.021), but not for MDMA. No changes over time were significant after the 1.0 mg/kg dose. Note: y-axes do not begin at 0. *p ?<?0.05 (low vs. high).

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Increased Response to 3,4-Methylenedioxymethamphetamine (MDMA) Reward and Altered Gene Expression in Zebrafish During Short- and Long-Term Nicotine Withdrawal.

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