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Repeated ethanol administration modifies the temporal structure of sucrose intake patterns in mice: effects associated with behavioral sensitization.

ABSTRACT: Neuroadaptations supporting behavioral sensitization to abused drugs are suggested to underlie pathological, excessive motivation toward drugs and drug-associated stimuli. Drug-induced sensitization has also been linked to increased appetitive responses for non-drug, natural reinforcers. The present research investigated whether ethanol (EtOH)-induced neural changes, inferred from psychomotor sensitization, can modify consumption and intake dynamics for the natural reinforcer, sucrose. The effects of EtOH-induced sensitization in mice on the temporal structure of sucrose intake patterns were measured using a lickometer system. After sensitization, sucrose intake dynamics were measured for 1 hour daily for 7 days and indicated more rapid initial approach and consumption of sucrose in EtOH-sensitized groups; animals showed a shorter latency to the first intake bout and an increased number of sucrose bottle licks during the initial 15 minutes of the 1-hour sessions. This effect was associated with increased frequency and size of bouts. For the total 1-hour session, sucrose intake and bout dynamics were not different between groups, indicating a change in patterns of sucrose intake but not total consumption. When sensitization was prevented by the gamma-aminobutyric acid B receptor agonist, baclofen, the increased rate of approach and consumption of sucrose were also prevented. Thus, EtOH-induced sensitization, and not the mere exposure to EtOH, was associated with changes in sucrose intake patterns. These data are consistent with current literature suggesting an enhancing effect of drug-induced sensitization on motivational processes involved in reinforcement.

SUBMITTER: Pastor R

PROVIDER: S-EPMC2904994 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Repeated ethanol administration modifies the temporal structure of sucrose intake patterns in mice: effects associated with behavioral sensitization.

Pastor Raúl R Kamens Helen M HM McKinnon Carrie S CS Ford Matthew M MM Phillips Tamara J TJ

Addiction biology 20100701 3

Neuroadaptations supporting behavioral sensitization to abused drugs are suggested to underlie pathological, excessive motivation toward drugs and drug-associated stimuli. Drug-induced sensitization has also been linked to increased appetitive responses for non-drug, natural reinforcers. The present research investigated whether ethanol (EtOH)-induced neural changes, inferred from psychomotor sensitization, can modify consumption and intake dynamics for the natural reinforcer, sucrose. The effec ...[more]

PMID: 20624153

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Project description:BackgroundThe N-methyl-D-aspartate (NMDA) receptors play a role in behavioral abnormalities observed after administration of the psychostimulant, methamphetamine (METH). Serine racemase (SRR) is an enzyme which synthesizes D-serine, an endogenous co-agonist of NMDA receptors. Using Srr knock-out (KO) mice, we investigated the role of SRR on METH-induced behavioral abnormalities in mice.Methodology/principal findingsEvaluations of behavior in acute hyperlocomotion, behavioral sensitization, and conditioned place preference (CPP) were performed. The role of SRR on the release of dopamine (DA) in the nucleus accumbens after administration of METH was examined using in vivo microdialysis technique. Additionally, phosphorylation levels of ERK1/2 proteins in the striatum, frontal cortex and hippocampus were examined using Western blot analysis. Acute hyperlocomotion after a single administration of METH (3 mg/kg) was comparable between wild-type (WT) and Srr-KO mice. However, repeated administration of METH (3 mg/kg/day, once daily for 5 days) resulted in behavioral sensitization in WT, but not Srr-KO mice. Pretreatment with D-serine (900 mg/kg, 30 min prior to each METH treatment) did not affect the development of behavioral sensitization after repeated METH administration. In the CPP paradigm, METH-induced rewarding effects were demonstrable in both WT and Srr-KO mice. In vivo microdialysis study showed that METH (1 mg/kg)-induced DA release in the nucleus accumbens of Srr-KO mice previously treated with METH was significantly lower than that of the WT mice previously treated with METH. Interestingly, a single administration of METH (3 mg/kg) significantly increased the phosphorylation status of ERK1/2 in the striatum of WT, but not Srr-KO mice.Conclusions/significanceThese findings suggest first, that SRR plays a role in the development of behavioral sensitization in mice after repeated administration of METH, and second that phosphorylation of ERK1/2 by METH may contribute to the development of this sensitization as seen in WT but not Srr-KO mice.

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Project description:Alcoholism is a complex behavioral disorder characterized by loss of control in limiting intake, and progressive compulsion to seek and consume ethanol. Prior studies have suggested that the characteristic behaviors associated with escalation of drug use are caused, at least in part, by ethanol-evoked changes in gene expression affecting synaptic plasticity. Implicit in this hypothesis is a dependence on new protein synthesis and remodeling at the synapse. It is well established that mRNA can be transported to distal dendritic processes, where it can undergo localized translation. It is unknown whether such modulation of the synaptic transcriptome might contribute to ethanol-induced synaptic plasticity. Using ethanol-induced behavioral sensitization as a model of neuroplasticity, we investigated whether repeated exposure to ethanol altered the synaptic transcriptome, contributing to mechanisms underlying subsequent increases in ethanol-evoked locomotor activity. RNAseq profiling of DBA/2J mice subjected to acute ethanol or ethanol-induced behavioral sensitization was performed on frontal pole synaptoneurosomes to enrich for synaptic mRNA. Genomic profiling showed distinct functional classes of mRNA enriched in the synaptic vs. cytosolic fractions, consistent with their role in synaptic function. Ethanol sensitization regulated more than twice the number of synaptic localized genes compared to acute ethanol exposure. Synaptic biological processes selectively perturbed by ethanol sensitization included protein folding and modification as well as and mitochondrial respiratory function, suggesting repeated ethanol exposure alters synaptic energy production and the processing of newly translated proteins. Additionally, marked differential exon usage followed ethanol sensitization in both synaptic and non-synaptic cellular fractions, with little to no perturbation following acute ethanol exposure. Altered synaptic exon usage following ethanol sensitization strongly affected genes related to RNA processing and stability, translational regulation, and synaptic function. These genes were also enriched for targets of the FMRP RNA-binding protein and contained consensus sequence motifs related to other known RNA binding proteins, suggesting that ethanol sensitization altered selective mRNA trafficking mechanisms. This study provides a foundation for investigating the role of ethanol in modifying the synaptic transcriptome and inducing changes in synaptic plasticity.

Dataset Information

Repeated ethanol administration modifies the temporal structure of sucrose intake patterns in mice: effects associated with behavioral sensitization.

Publications

Repeated ethanol administration modifies the temporal structure of sucrose intake patterns in mice: effects associated with behavioral sensitization.

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