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Alcohol potentiates the psychostimulant and reinforcing effects of mephedrone in adolescent mice: role of D3 receptors and associated changes in gene expression

ABSTRACT: Mephedrone (Meph) is a novel psychostimulant whose recreational consumption is often associated to other drugs, especially alcohol (EtOH). This kind of drug consumption during adolescence is a matter of concern. We studied, in adolescent CD-1 mice, whether low-moderate doses of EtOH could enhance the psychostimulant (locomotor acivity) and reinforcing (conditioned place preference, CPP) effects of mephedrone. Simultaneously we also determined the most relevant transcriptional changes associated to a reinforcing treatment. A single dose of Meph (10 mg/kg, sc) induced an increase of about 100% in locomotor activity, which was a further enhanced by 40% when associated with a dose of EtOH (1 g/kg). The hyperlocomotion was partially antagonized by ketanserin and haloperidol, but only haloperidol blocked the potentiation induced by EtOH. Furthermore, Meph (25 mg/kg) induced significant positive conditioning, which increased by 70% when administered with 0.75 mg/kg EtOH. Microarray analysis of mRNA extracted from anterior striata of the mice used in CPP experiments reported significant modifications in genes related with neurotransmission and synaptic plasticity, which were further validated by Real-time PCR for all three drug-treated groups.

ORGANISM(S): Mus musculus

PROVIDER: GSE58279 | GEO | 2016/08/01

SECONDARY ACCESSION(S): PRJNA251885

REPOSITORIES: GEO

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Project description:Per- and polyfluoroalkyl substances (PFAS) are persistent pollutants known for their bio-accumulative properties and prevalence in water supplies and household products. Although legacy PFAS, such as perfluorooctanoic acid, are phased out in the U.S. due to public health concerns, a PFAS variant hexafluoropropylene oxide-dimer acid (HFPO-DA) is an emerging replacement. HFPO-DA is a potential neurotoxicant that has been shown to cause dopaminergic neurodegeneration. We investigated the bioaccumulative potential of HFPO-DA and its effects on lifespan, locomotor activity, and brain gene expression in female and male Drosophila melanogaster (fruit flies). Flies were collected less than 4 hours post-eclosion and exposed to 0, 10, 10^2, 10^3, or 10^4 mg/kg/day HFPO-DA. To measure the effect of HFPO-DA on lifespan, surviving flies from each exposure were recorded every 24 hours. Flies were subjected to a negative geotaxis assay at 3, 7, and 14 days of exposure to measure the effects of acute, sub-chronic, and chronic exposures on locomotor ability. To capture HFPO-DA-induced sexually dimorphic gene expression responses in the brain, we sequenced brain-specific mRNA from flies exposed for 3, 7, or 14 days. The Bioconcentration Factor was 0.031 for females, and 0.026 for males. Dose and median lifespan were negatively correlated in both female (R^2 adj = 0.77, p<0.0001) and male flies (R^2 adj = 0.77, p<0.0001). Log-rank Mantel-Cox tests and one-way ANOVAs revealed that median lifespan was reduced in females starting at 10 mg/kg/day and in males starting at 10^2 mg/kg/day (p< 0.01). Acute exposure at 10 mg/kg/day significantly decreased locomotor ability in females (p<0.0001) while acute exposures at 1 mg/kg/day decreased locomotor activity in males (p <0.0001). Among 7500 genes analyzed, pairwise gene expression comparison between controls and treatments identified 2496 differentially expressed genes. While HFPO-DA does not readily bioaccumulate in fruit fly bodies, high-dose exposures have sex-specific effects on lifespan, locomotor ability, and brain gene expression. LOAEL for median lifespan is 10 mg/kg/day in females, and 10^2 mg/kg/day in males. Both locomotor ability and brain gene expression exhibited non-conventional dose-response as seen in other endocrine disrupting chemical exposures.

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Alcohol potentiates the psychostimulant and reinforcing effects of mephedrone in adolescent mice: role of D3 receptors and associated changes in gene expression

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