Genetically selected alcohol preferring rats to model human alcoholism.
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ABSTRACT:
SUBMITTER: Ciccocioppo R
PROVIDER: S-EPMC5152912 | biostudies-literature | 2013
REPOSITORIES: biostudies-literature
Publications
Genetically selected alcohol preferring rats to model human alcoholism.
Current topics in behavioral neurosciences 20130101
Animal models have been successfully developed to mimic and study alcoholism. These models have the unique feature of allowing the researcher to control for the genetic characteristics of the animal, alcohol exposure and environment. Moreover, these animal models allow pharmacological, neurochemical and behavioral manipulations otherwise impossible. Unquestionably, one of the major contributions to the understanding of the neurobiological basis of alcoholism comes from data that have been obtain ...[more]
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Project description:The present article provides an up-to-date review summarizing almost 18 years of research in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. The results of this work demonstrate that msP rats have natural preference for ethanol characterized by a spontaneous binge-type of drinking that leads to pharmacologically significant blood ethanol levels. This rat line is highly vulnerable to relapse and presentation of stimuli predictive of alcohol availability or foot-shock stress can reinstate extinguished drug-seeking up to 8 months from the last alcohol experience. The msP rat is highly sensitive to stress, shows an anxious phenotype and has depressive-like symptoms that recover following ethanol drinking. Interestingly, these animals have an up-regulated corticotrophin releasing factor (CRF) receptor 1 system. Clinical studies have shown that alcoholic patients often drink ethanol in the attempt to self-medicate from negative affective states and to search for anxiety relief. We propose that msP rats represent an animal model that largely mimics the human alcoholic population that due to poor ability to engage in stress-coping strategies drink ethanol as a tension relief strategy and for self-medication purposes.
| S-EPMC3035824 | biostudies-literature
Project description:Urocortin 1 (Ucn 1) is an endogenous peptide related to the corticotropin-releasing factor (CRF). Ucn 1 is mainly expressed in the perioculomotor area (pIII), and its involvement in alcohol self-administration is well confirmed in mice. In other species, the relationship between the perioculomotor Ucn 1-containing population of neurons (pIIIu) and alcohol consumption needs further investigation. The pIII also has a significant subpopulation of dopaminergic neurons. Because of dopamine's (DA) role in addiction, it is important to evaluate whether this subpopulation of neurons contributes to addiction-related phenotypes. Furthermore, the effects of gender on the relationship between Ucn 1 and tyrosine hydroxylase (TH) in pIII and alcohol preference in rats have not been previously assessed.To address these issues, we compared 2 Sardinian alcohol-preferring sublines of rats, a population maintained at the Scripps Research Institute (Scr:sP) and a population maintained at University of Camerino-Marchigian Sardinian preferring rats (msP), to corresponding nonselectively bred Wistar rats of both sexes. Ucn 1- and TH-positive cells were detected on coronal midbrain sections from 6- to 8-week-old alcohol-naïve animals using brightfield and fluorescent immunohistochemistry. Ucn 1- and TH-positive cells in pIII were counted in the perioculomotor area, averaged across 2 to 3 sets, and binned into 3 bregma levels.Results demonstrated increased average counts of Ucn 1-positive cells in the middle bregma level in preferring male rats compared to Wistar controls and no difference in TH-positive cell counts in pIII. In addition, fluorescent double labeling revealed no colocalization of Ucn 1-positive and TH-positive neurons. Ucn 1 but not TH distribution was influenced by gender with female animals expressing more Ucn 1-positive cells than male animals in the peak bregma level.These findings extend previous reports of increased Ucn 1-positive cell distribution in preferring lines of animals. They indicate that Ucn1 contributes to increased alcohol consumption across different species and that this contribution could be gender specific. The results also suggest that Ucn1 regulates positive reinforcing rather than aversive properties of alcohol and that these effects could be mediated by CRF(2) receptors, independent of direct actions of DA.
| S-EPMC2813693 | biostudies-literature
Project description:For several decades, genetically selected alcohol-preferring rats have been successfully used to mimic and study alcohol use disorders (AUD). These rat lines have been instrumental in advancing our understanding of the neurobiology of alcoholism and enabling pharmacological studies to evaluate drug efficacy on alcohol drinking and relapse. Moreover, the results of these studies have identified genetic variables that are linked to AUD vulnerability. This is an up-to-date review that focuses on genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. To support the translational relevance of the findings that are obtained from msP rats and highlight important similarities to AUD patients, we also discuss the results of recent brain imaging studies. Finally, to demonstrate the importance of studying sex differences in animal models of AUD, we present original data that highlight behavioral differences in the response to alcohol in male and female rats. Female msP rats exhibited higher alcohol consumption compared with males. Furthermore, msP rats of both sexes exhibit higher anxiety- and depressive-like behaviors in the elevated plus maze and forced swim test, respectively, compared with unselected Wistar controls. Notably, voluntary alcohol drinking decreases foot-shock stress and depressive-like behavior in both sexes, whereas anxiety-like behavior in the elevated plus maze is attenuated only in males. These findings suggest that male and female msP rats both drink high amounts of alcohol to self-medicate negative affective symptoms. For females, this behavior may be driven by an attempt to treat stress and depressive-like conditions. For males, generalized anxiety appears to be an important additional factor in the motivation to drink alcohol. This article is part of the special issue on 'Vulnerabilities to Substance Abuse.'
| S-EPMC9261425 | biostudies-literature
Project description:BACKGROUND:Genetic deletion or antagonism of the neurokinin 1 receptor (NK1R) decreases alcohol intake, alcohol reward, and stress-induced alcohol relapse in rodents, while TACR1 variation is associated with alcoholism in humans. METHODS:We used L822429, a specific antagonist with high affinity for the rat NK1R, and examined whether sensitivity to NK1R blockade is altered in alcohol-preferring (P) rats. Operant alcohol self-administration and progressive ratio responding were analyzed in P-rats and their founder Wistar line. We also analyzed Tacr1 expression and binding and sequenced the Tacr1 promoter from both lines. RESULTS:Systemic L822429 decreased alcohol self-administration in P-rats but did not affect the lower rates of alcohol self-administration in Wistar rats. Tacr1 expression was elevated in the prefrontal cortex and the amygdala of P-rats. In central amygdala, elevated Tacr1 expression was accompanied by elevated NK1R binding. Central amygdala (but not prefrontal cortex) infusion of L822429 replicated the systemic antagonist effects on alcohol self-administration in P-rats. All P-rats, but only 18% of their founder Wistar population, were CC homozygous for a-1372G/C single nucleotide polymorphism. In silico analysis indicated that the Tacr1-1372 genotype could modulate binding of the transcription factors GATA-2 and E2F-1. Electromobility shift and luciferase reporter assays suggested that the-1372C allele confers increased transcription factor binding and transcription. CONCLUSIONS:Genetic variation at the Tacr1 locus may contribute to elevated rates of alcohol self-administration, while at the same time increasing sensitivity to NK1R antagonist treatment.
| S-EPMC3773538 | biostudies-literature
Project description:The goal of this study was to identify candidate genes that may influence alcohol consumption by comparing gene expression in 5 brain regions of alcohol-naïve iP and P.NP rats. Background: Selectively bred P (alcohol preferring) and NP (alcohol non-preferring) rats differ greatly in alcohol preference, in part due to a highly significant QTL on chromosome 4. Reciprocal congenic strains in which the iP chromosome 4 QTL interval was transferred to the iNP background (NP.P) and the iNP chromosome 4 QTL was transferred to the iP background (P.NP) exhibited alcohol consumption scores that correlated with the introgressed interval. The goal of this study was to identify candidate genes that may influence alcohol consumption by comparing gene expression in 5 brain regions of alcohol-naïve iP and P.NP rats. Methods: RNA from the amygdala, nucleus accumbens, hippocampus, caudate putamen, and frontal cortex from each of 8 iP and 8 P.NP rats was labeled and analyzed on Affymetrix Rat Genome 230 2.0 microarrays. Expression levels were normalized using robust multi-chip average (RMA), and differential gene expression was measured in individual brain regions and in the average of the five brain regions. Differential gene expression was validated using quantitative real-time PCR. Meta-analysis was applied to compare microarray data from this experiment with data from the reciprocal congenic strains NP.P vs. iNP (Carr et al, 2007). Results: We detected between 72 (nucleus accumbens) and 89 (hippocampus) cis-regulated probe sets within the QTL that significantly differed between the strains in the five brain regions. There was significant overlap among the regions; 157 cis-regulated probe sets were detected in at least one brain region, of which 104 showed differential expression in more than one region. Fewer trans-regulated probe sets were detected, ranging from 7 in the amygdala to 54 in the caudate putamen, and most of these differed in only one region; only 10 of the 85 trans-regulated probe sets differed in more than one region. To increase the power to detect differentially expressed genes, data from the five discrete brain regions of each animal were averaged; in this analysis we detected 141 cis-regulated probe sets and 207 trans-regulated probe sets. Meta-analysis comparing the present results from iP vs. P.NP rats with an earlier experiment that used the reciprocal congenic NP.P vs. iP demonstrated that 74 cis-regulated probe sets were differentially expressed in the same direction and with a consistent magnitude of difference in both experiments. No consistent trans-regulated probe sets were identified. Conclusions: Cis-regulated candidate genes for alcohol consumption that lie within the chromosome 4 QTL were identified and confirmed by meta-analysis with the reciprocal congenic NP.P vs iNP study. These genes are strong candidates for producing the difference in alcohol preference and consumption between the iP and iNP rats. There was little evidence for consistent trans-acting effects. Keywords: comparison of gene expression profiles for strain1 (P rat) vs. strain2 (P.NP rat)
2009-12-31 | GSE15415 | GEO
Project description:The alpha-synuclein (Snca) gene is expressed at higher levels in alcohol-naïve, inbred alcohol-preferring (iP) rats than in alcohol-non preferring (iNP) rats. Snca modulates dopamine transmission and the dopamineregic system, which play a role in mediating the rewarding properties of alcohol consumption. Thus, understanding regulation of Snca gene expression could provide insight into the relationship of Snca and alcohol consumption. To study regulation of rat Snca expression, 1,912 bp of the iP and iNP 5'-regions were cloned and sequenced. 5'-rapid amplification of cDNA ends (RACE), primer extension and RT-PCR mapped three transcription start site clusters (clusters TSS1, TSS2 and TSS3), suggesting that the Snca proximal promoter region has a complex architecture. This proximal promoter region has three TATA-less core promoters containing SP1 binding sites, initiator elements and downstream core promoter elements, which are often located in such promoters. Snca-luc constructs transiently transfected into SK-N-SH neuroblastoma cells showed that the region from - 1,912 to - 1,746 contained a strong core promoter, and that the entire approximately 2 kb region had significant promoter activity. Five polymorphisms identified between the iP and iNP in the proximal promoter region did not influence differential expression between the strains. In contrast, a single nucleotide polymorphism (SNP) at + 679 in the 3'-untranslated region (UTR) resulted in a 1.3-fold longer half-life of iP mRNA compared with iNP mRNA, which is consistent with the differential expression observed between the iP and iNP strains. These results suggest that regulation of rat Snca gene expression is complex and may contribute to alcohol preference in the iP rats.
| S-EPMC4455882 | biostudies-literature
Project description:The goal of this study was to identify candidate genes that may influence alcohol consumption by comparing gene expression in 5 brain regions of alcohol-naïve iP and P.NP rats. Background: Selectively bred P (alcohol preferring) and NP (alcohol non-preferring) rats differ greatly in alcohol preference, in part due to a highly significant QTL on chromosome 4. Reciprocal congenic strains in which the iP chromosome 4 QTL interval was transferred to the iNP background (NP.P) and the iNP chromosome 4 QTL was transferred to the iP background (P.NP) exhibited alcohol consumption scores that correlated with the introgressed interval. The goal of this study was to identify candidate genes that may influence alcohol consumption by comparing gene expression in 5 brain regions of alcohol-naïve iP and P.NP rats. Methods: RNA from the amygdala, nucleus accumbens, hippocampus, caudate putamen, and frontal cortex from each of 8 iP and 8 P.NP rats was labeled and analyzed on Affymetrix Rat Genome 230 2.0 microarrays. Expression levels were normalized using robust multi-chip average (RMA), and differential gene expression was measured in individual brain regions and in the average of the five brain regions. Differential gene expression was validated using quantitative real-time PCR. Meta-analysis was applied to compare microarray data from this experiment with data from the reciprocal congenic strains NP.P vs. iNP (Carr et al, 2007). Results: We detected between 72 (nucleus accumbens) and 89 (hippocampus) cis-regulated probe sets within the QTL that significantly differed between the strains in the five brain regions. There was significant overlap among the regions; 157 cis-regulated probe sets were detected in at least one brain region, of which 104 showed differential expression in more than one region. Fewer trans-regulated probe sets were detected, ranging from 7 in the amygdala to 54 in the caudate putamen, and most of these differed in only one region; only 10 of the 85 trans-regulated probe sets differed in more than one region. To increase the power to detect differentially expressed genes, data from the five discrete brain regions of each animal were averaged; in this analysis we detected 141 cis-regulated probe sets and 207 trans-regulated probe sets. Meta-analysis comparing the present results from iP vs. P.NP rats with an earlier experiment that used the reciprocal congenic NP.P vs. iP demonstrated that 74 cis-regulated probe sets were differentially expressed in the same direction and with a consistent magnitude of difference in both experiments. No consistent trans-regulated probe sets were identified. Conclusions: Cis-regulated candidate genes for alcohol consumption that lie within the chromosome 4 QTL were identified and confirmed by meta-analysis with the reciprocal congenic NP.P vs iNP study. These genes are strong candidates for producing the difference in alcohol preference and consumption between the iP and iNP rats. There was little evidence for consistent trans-acting effects. Keywords: comparison of gene expression profiles for strain1 (P rat) vs. strain2 (P.NP rat) 40 samples each of P and P.NP (8 animals each of P and P.NP. 5 brain regions)
2009-12-30 | E-GEOD-15415 | biostudies-arrayexpress
Project description:Alcohol addiction is regarded as a series of dynamic changes to neural circuitries. A comparison of the global network during different stages of alcohol addiction could provide an efficient way to understand the neurobiological basis of addiction. Two animal models (P-rats screened from an alcohol preference family, and NP-rats screened from an alcohol non-preference family) were trained for alcohol preference with a two-bottle free choice method for 4 weeks. To examine the changes in the neural response to alcohol during the development of alcohol preference and acute stimulation, different trials were studied with resting-state fMRI methods during different periods of alcohol preference. The correlation coefficients of 28 regions in the whole brain were calculated, and the results were compared for alcohol preference related to the genetic background/training association. The variety of coherence patterns was highly related to the state and development of alcohol preference. We observed significant special brain connectivity changes during alcohol preference in P-rats. The comparison between the P- and NP-rats highlighted the role of genetic background in alcohol preference. The results of this study support the alterations of the neural network connection during the formation of alcohol preference and confirm that alcohol preference is highly related to the genetic background. This study could provide an effective approach for understanding the neurobiological basis of alcohol addiction.
| S-EPMC8615902 | biostudies-literature
Project description:The objective of this study was to test the hypothesis that innate differences in gene expression in the brain could contribute to the differences in alcohol drinking or response to alcohol between adult male inbred alcohol-preferring (iP) and -non-preferring (iNP) rats. Gene expression was determined in the nucleus accumbens (ACB), amygdala (AMYG), frontal cortex (FC), caudate-putamen (CPU) and hippocampus (HIP) of alcohol-naïve adult male iP and iNP rats, using Affymetrix Rat Genome U34A microarrays (n = 6/strain). Significant differences between the two strains for each region were determined using Statistical Analysis of Microarrays (SAM). Using a false discovery rate threshold of 0.2, there were 46 genes with higher expression in iP rats and 61 genes with lower expression in the ACB, 111 genes with higher and 56 genes with lower expression in the AMYG, 61 genes with higher and 25 genes with lower expression in the FC, 39 genes with higher and 42 genes with lower expression in the CPU, and 35 genes with higher and 51 genes with lower expression in the HIP. In the AMYG, iP rats had higher expression of genes that are involved in neuronal growth and neurogenesis, e.g., brain derived neurotrophic factor, neuritin, etc. In contrast, in the ACB, iP rats had lower expression of genes involved in neurogenesis or cellular plasticity, e.g. cyclin E, vascular endothelial growth factor A. Many of the differences were in genes involved in intracellular signaling, cell membranes, extracellular matrix, and metabolism. These regional gene differences between the iP and iNP rat lines may contribute to the divergent alcohol drinking phenotypes of these rats. Keywords: alcohol, inbred, rat, gene expression, brain, nucleus accumbens, amygdala, frontal cortex, hippocampus, caudate-putamen
2007-07-28 | GSE4494 | GEO
Project description:Alcohol preference induced tolerance in humans and animals when their bodily functions adapt to compensate for the disruption caused by alcohol consumption. This was thought to be an important component of the genetic predisposition to alcoholism. To investigate the underlying mechanisms of hepatic metabolic tolerance during alcohol preference, the alcohol preferring and alcohol non-preferring rats were used in this study. The liver mitochondria were purified for comparative quantitative proteomics analysis, and the liver metabolite extracts were collected for metabolomics analysis. Our study identified 96 differentially expressed hepatic mitochondrial proteins that associated with alcohol preference, the further gene ontology and protein interaction network analysis suggest a down-regulation of amino acid metabolism and up-regulation of lipid metabolism. We found alcohol preference induced a series of enzymes decreased (e.g. SSADH and GABA-T) and several amino acids increased (e.g. glutamate and aspartate) in rat liver, indicating down-regulations of glutamate degradation occurred during alcohol preference. Most of these changes were due to the genetic differences between alcohol preferring and non-preferring animals. Furthermore, this study would provided new insights to further clarify the mechanisms of hepatic metabolic tolerance during alcohol preference.
| S-EPMC5731932 | biostudies-literature