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Our aim was to assess the cognitive and emotional state, as well as related-changes in the glucocorticoid receptor (GR), the corticotropin-releasing factor (CRF) and the brain-derived neurotrophic factor (BDNF) expression of adolescent C57BL/6J male mice after a 5-week two-bottle choice protocol (postnatal day [pd]21 to pd52). Additionally, we wanted to analyse whether the behavioural and neurobiological effects observed in late adolescence (pd62) lasted until adulthood (pd84). Behavioural testing revealed that alcohol during early adolescence increased anxiety-like and compulsive-related behaviours, which was maintained in adulthood. Concerning cognition, working memory was only altered in late adolescent mice, whereas object location test performance was impaired in both ages. In contrast, novel object recognition remained unaltered. Immunohistochemical analysis showed that alcohol during adolescence diminished BDNF+ cells in the cingulate cortex, the hippocampal CA1 layer and the central amygdala. Regarding hypothalamic-pituitary-adrenal axis (HPA) functioning, alcohol abuse increased the GR and CRF expression in the hypothalamic paraventricular nucleus and the central amygdala. Besides this, GR density was also higher in the prelimbic cortex and the basolateral amygdala, regardless of the animals' age. Our findings suggest that adolescent alcohol exposure led to long-term behavioural alterations, along with changes in BDNF, GR and CRF expression in limbic brain areas involved in stress response, emotional regulation and cognition. [ABSTRACT FROM AUTHOR]

Trace amine‐associated receptor 1 (Taar1) impacts methamphetamine (MA) intake. A mutant allele (Taar1m1J) derived from the DBA/2J mouse strain codes for a non‐functional receptor, and Taar1m1J/m1J mice consume more MA than mice possessing the reference Taar1+ allele. To study the impact of this mutation in a genetically diverse population, heterogeneous stock‐collaborative cross (HS‐CC) mice, the product of an eight‐way cross of standard and wild‐derived strains, were tested for MA intake. HS‐CC had low MA intake, so an HS‐CC by DBA/2J strain F2 intercross was created to transfer the mutant allele onto the diverse background, and used for selective breeding. To study residual variation in MA intake existing in Taar1m1J/m1J mice, selective breeding for higher (MAH) vs lower (MAL) MA intake was initiated from Taar1m1J/m1J F2 individuals; a control line of Taar1+/+ individuals (MAC) was retained. The lines were also examined for MA‐induced locomotor and thermal responses, and fluid and tastant consumption. Taar1m1J/m1J F2 mice consumed significantly more MA than Taar1+/+ F2 mice. Response to selection was significant by generation 2 and there were corresponding differences in fluid consumed. Fluid consumption was not different in non‐MA drinking studies. Taar1m1J/m1J genotype (MAL or MAH vs MAC mice) was associated with heighted MA locomotor and reduced hypothermic responses. MAL mice exhibited greater sensitization than MAH mice, but the selected lines did not consistently differ for thermal or tastant phenotypes. Residual variation among high‐risk Taar1m1J/m1J mice appears to involve mechanisms associated with neuroadaptation to MA, but not sensitivity to hypothermic effects of MA. [ABSTRACT FROM AUTHOR]

Background Alcohol binge drinking in humans is thought to increase the risk for alcohol use disorder (AUD). Unclear is whether drinking patterns (e.g., bingelike or stable drinking) differentially affect the transition to compulsive-like drinking in dependent individuals. We examined whether chronic bingelike drinking facilitates the transition to compulsive-like drinking in rats. Methods Male Wistar rats were given 5 months of intermittent access to ethanol (EtOH) (IAE) or continuous access to EtOH (CAE) in a 2-bottle choice paradigm. Then, rats were given chronic intermittent EtOH (CIE) vapor exposure. Escalation of EtOH intake and compulsive-like responding for EtOH, using a progressive-ratio schedule of reinforcement and quinine-adulterated EtOH, were measured. Results IAE rats escalated EtOH drinking after 2 weeks of 2-bottle choice, whereas CAE rats exhibited stable EtOH drinking for 5 months. After 8 weeks of CIE, both IAE + CIE and CAE + CIE rats escalated their EtOH intake. However, IAE rats escalated their EtOH intake weeks sooner than CAE rats and exhibited greater EtOH intake. No differences in compulsive-like responding were found between IAE + CIE and CAE + CIE rats. However, both IAE + CIE and CAE + CIE rats showed strong compulsive-like responding compared with rats without prior IAE or CAE. Conclusions Chronic EtOH drinking at stable or escalated levels for several months is associated with more compulsive-like responding for EtOH in rats that are exposed to CIE compared with rats without a prior history of EtOH drinking. Moreover, IAE facilitated the transition to compulsive-like responding for EtOH after CIE exposure, reflected by the escalation of EtOH intake. These results suggest that IAE may facilitate the transition to AUD. This study indicates that despite a moderate level of EtOH drinking, the IAE animal model is highly relevant to early stages of alcohol abuse and suggests that it may be associated with neuroadaptations that produce a faster transition to alcohol dependence. [ABSTRACT FROM AUTHOR]

The High Drinking in the Dark ( HDID) mice have been selectively bred for reaching high blood ethanol concentrations ( BECs) following the limited access Drinking in the Dark ( DID) test. We have shown previously that mice from the first HDID replicate line ( HDID-1) drink in larger, but not longer, ethanol drinking bouts than the low-drinking HS/Npt control mice when consuming modest amounts in the DID test. Here, we assessed drinking microstructure in HDID-1 mice during binge-like levels of ethanol intake using a lickometer system. Mice from both HDID replicates ( HDID-1 and -2) and HS mice were also given three DID tests (single-bottle ethanol, two-bottle choice and single-bottle saccharin) using a continuously recording BioDAQ system to determine whether there are selection-dependent changes in drinking microstructure. Larger ethanol bout size in the HDID-1 mice than the HS mice was found to be due to a larger lick volume in these mice. HDID-1 and HDID-2 mice were also seen to have different drinking microstructures that both resulted in high intake and high BECs. The HDID-1 mice drank in larger ethanol bouts than HS, whereas HDID-2 mice drank in more frequent bouts. This pattern was also seen in two-bottle choice DID. The HDID-2 mice had a high bout frequency for all fluid types tested, whereas the large bout size phenotype of the HDID-1 mice was specific to alcohol. These findings suggest that selection for drinking to intoxication has resulted in two distinct drinking microstructures, both of which lead to high BECs and high ethanol intake. [ABSTRACT FROM AUTHOR]

Background Peroxisome proliferator-activated receptor ( PPAR) agonists reduce voluntary ethanol (EtOH) consumption in rat models and are promising therapeutics in the treatment for drug addictions. We studied the effects of different classes of PPAR agonists on chronic EtOH intake and preference in mice with a genetic predisposition for high alcohol consumption and then examined human genomewide association data for polymorphisms in PPAR genes in alcohol-dependent subjects. Methods Two different behavioral tests were used to measure intake of 15% EtOH in C57 BL/6J male mice: 24-hour 2-bottle choice and limited access (3-hour) 2-bottle choice, drinking in the dark. We measured the effects of pioglitazone (10 and 30 mg/kg), fenofibrate (50 and 150 mg/kg), GW0742 (10 mg/kg), tesaglitazar (1.5 mg/kg), and bezafibrate (25 and 75 mg/kg) on EtOH intake and preference. Fenofibric acid, the active metabolite of fenofibrate, was quantified in mouse plasma, liver, and brain by liquid chromatography tandem mass spectrometry. Data from a human genome-wide association study ( GWAS) completed in the Collaborative Study on the Genetics of Alcoholism ( COGA) were then used to analyze the association of single nucleotide polymorphisms ( SNPs) in different PPAR genes ( PPARA, PPARD, PPARG, and PPARGC1A) with 2 phenotypes: DSM- IV alcohol dependence ( AD) and the DSM- IV criterion of withdrawal. Results Activation of 2 isoforms of PPARs, α and γ, reduced EtOH intake and preference in the 2 different consumption tests in mice. However, a selective PPAR δ agonist or a pan agonist for all 3 PPAR isoforms did not decrease EtOH consumption. Fenofibric acid, the active metabolite of the PPAR α agonist fenofibrate, was detected in liver, plasma, and brain after 1 or 8 days of oral treatment. The GWAS from COGA supported an association of SNPs in PPARA and PPARG with alcohol withdrawal and PPARGC1A with AD but found no association for PPARD with either phenotype. Conclusions We provide convergent evidence using both mouse and human data for specific PPARs in alcohol action. Reduced EtOH intake in mice and the genetic association between AD or withdrawal in humans highlight the potential for repurposing FDA-approved PPAR α or PPAR γ agonists for the treatment of AD. [ABSTRACT FROM AUTHOR]

Background Alcohol use and abuse patterns have created a need for novel treatment models. Current research has turned its focus on reward pathways associated with intrinsic necessities, such as feeding. Theories suggest that drugs of abuse seize control of natural reward pathways and dysregulate normal function, leading to chronic addiction. One such pathway involving the hunger stimulating peptide, ghrelin, is the focus of our study. Methods Male C57BL/6J mice were randomly assigned to groups and treated with vehicle or a ghrelin antagonist, either [D-Lys3]- GHRP-6 ( DLys) or JMV2959. Three experiments tested ghrelin antagonism using different doses; experiment 1 tested 12 mg/kg JMV2959; experiment 2 tested 15 mg/kg DLys; experiment 3 tested 9 mg/kg JMV2959. Using a 2-bottle choice 24-hour access paradigm, data were collected for ethanol intake, preference, water intake, and food intake at 4 and 24 hours after injection. Results Experiment 1 showed that 12 mg/kg of JMV2959 decreased ethanol, water, and food intake, without affecting preference. Experiment 2 showed that 15 mg/kg of DLys decreased ethanol intake, preference, and water intake only on the first day of treatment. Experiment 3 showed that 9 mg/kg of JMV2959 decreased only ethanol and food intake. No change was seen during deprivation, and JMV2959 was still effective at reducing ethanol intake upon reintroduction. Despite the change in food intake, there were no differences in body weight throughout the experiments. It should be noted that the majority of significant effects were only found 4 hours postinjection. Conclusions The results show that compounds that block ghrelin receptor activity are effective at decreasing ethanol intake. However, DLys was only effective at reducing intake and preference on the first day, suggesting a quick tolerance and selectivity for ethanol. JMV2959 consistently reduced ethanol intake, but at the higher dose also reduced all other consummatory behaviors. Thus, ghrelin antagonists provide a viable potential for treatment of alcohol abuse disorders, but further research is needed to determine an appropriate dose and administration paradigm. [ABSTRACT FROM AUTHOR]

Background It has been reported that dopamine D3 receptor (D3R) knockout mice display similar ethanol (EtOH) consumption compared to wild types. In addition, studies with D3R pharmacological targeting were inconclusive. Methods In the current study, we used both gain- and loss-of-function approaches to test the effects of central D3R manipulation on voluntary alcohol intake and EtOH-induced conditioned place preference (CPP) in rats. To this aim, we developed a lentiviral-mediated gene transfer approach to examine whether D3R knockdown (LV-siD3R) or overexpression (LV-D3R) in the nucleus accumbens (NAcc) is sufficient to modulate voluntary alcohol consumption and EtOH-CPP. Results Using the standard 2-bottle choice drinking paradigm and an unbiased CPP procedure, our results indicated that, like the D3R selective antagonist SB-277011-A, LV-siD3R attenuated voluntary alcohol consumption. In contrast, LV-D3R increased EtOH intake with no effect on total fluid intake. Similarly, the D3R agonist 7-OH-DPAT also exacerbated EtOH intake. Interestingly, neither pharmacological nor genetic manipulation of D3R activity affected saccharin and quinine consumption and preference. More importantly, we report that LV-siD3R blocked, whereas LV-D3R exacerbated, EtOH-CPP. Conclusions These results support the notion that the D3R plays an important role in alcohol reward in rats and suggest that a key threshold range of D3R levels is associated with impaired alcohol consumption. Taken together, these findings demonstrate that the D3R is an essential component of the molecular pathways underlying the reinforcing properties of alcohol. Thus, medications targeting the D3Rs may be beneficial to tackle EtOH abuse and alcoholism in humans. [ABSTRACT FROM AUTHOR]

Background Life-altering anxiety disorders, such as posttraumatic stress disorder ( PTSD), can co-occur at high rates with substance use disorders. Alcoholism, compared with other substance use disorders, is particularly common. Rodent studies of acute stress effects on alcohol consumption show that stress can alter ethanol ( Et OH) consumption. This study examined voluntary Et OH consumption in male Long- Evans rats that had undergone a stress-enhanced fear learning ( SEFL) procedure. Methods Adult Long- Evans rats were exposed to a stress that consisted of 15 inescapable foot-shocks (1 mA, 1 second) known to cause a long-lasting nonassociative enhancement of subsequent fear learning. Control animals received no shock. One day later, animals were placed in a novel and very different context and received a single foot-shock. On day 3, animals were returned to the single shock context and freezing was used as a measure of learned fear. The intermittent access 2-bottle choice (2 BC) regimen consisted of 1 bottle of water and 1 bottle of experimental solution, either 19% Et OH or 28.4% sucrose-0.08% quinine, for a 24-hour period, 3 days a week, and all other times 2 water bottles. This regimen lasted until stable levels of experimental solution drinking were reached, at which point the experimental solution was removed for 40 days and then returned to measure the resumption of consumption. Results Rats that received stress prior to Et OH consumed significantly more Et OH than control rats before and after reinstatement. Rats that received stress after drinking was established did not consume significantly more Et OH when the drug was returned. Stress had no significant effect on sucrose-quinine drinking, our calorie and taste control for Et OH. Conclusions A single traumatic event sufficient to produce long-lasting enhancement of fear learning increases voluntary Et OH consumption, but does not alter previously acquired Et OH drinking habits or alter the consumption of a calorically equivalent sweet-bitter-tasting solution. [ABSTRACT FROM AUTHOR]