Role of nucleus accumbens dopamine receptor subtypes in the learning and expression of alcohol-seeking behavior.

These studies examined the roles of dopamine D1- and D2-like receptors within the nucleus accumbens (Acb) in the acquisition and expression of ethanol-induced (2g/kg) conditioned place preference (CPP) in adult male DBA/2J mice. Bilateral intra-Acb infusions of the D1-like dopamine receptor antagonist SCH23390 (0.05, 0.5µg/side) or the D2-like dopamine receptor antagonist raclopride (0.5-5.0µg/side) were administered 30min before each ethanol conditioning trial (acquisition studies) or before preference tests (expression studies). CPP was conditioned to tactile cues using an unbiased apparatus and procedure. Intra-Acb infusion of SCH23390 prevented CPP acquisition, whereas intra-Acb infusion of raclopride did not. Intra-Acb infusion of both antagonists, however, dose-dependently reduced ethanol-stimulated locomotor activity during conditioning. In contrast, intra-Acb antagonist infusion had no effect on ethanol CPP expression, suggesting that dopamine's role in the Acb is limited to neurobiological processes engaged during the learning of the relationship between contextual cues and ethanol reward. Control experiments showed that intra-Acb injection of SCH23390 alone produced no place conditioning and did not interfere with the acquisition of conditioned place aversion induced by lithium chloride, suggesting that the antagonist's effect on ethanol CPP was not due to a more general detrimental effect on associative learning. Overall, these data suggest that D1-like (but not D2-like) dopamine Acb receptors play an important role in the learning of context-ethanol associations, either by modulating the magnitude of ethanol reward or the rate of learning about ethanol reward.

Impact of breeding for reduced methane emissions in New Zealand sheep on maternal and health traits.

Enteric methane emissions from ruminants account for ∼35% of New Zealand's greenhouse gas emissions. This poses a significant threat to the pastoral sector. Breeding has been shown to successfully lower methane emissions, and genomic prediction for lowered methane emissions has been introduced at the national level. The long-term genetic impacts of including low methane in ruminant breeding programs, however, are unknown. The success of the New Zealand sheep industry is currently heavily reliant on the prolificacy, fecundity and survival of adult ewes. The objective of this study was to determine genetic and phenotypic correlations between adult maternal ewe traits (live weight, body condition score, number of lambs born, litter survival to weaning, pregnancy scanning and fleece weight), faecal and Nematodirus egg counts and measures of methane in respiration chambers. More than 9,000 records for methane from over 2,200 sheep measured in respiration chambers were collected over 10 years. Sheep were fed on a restricted diet calculated as approximately twice the maintenance. Methane measures were converted to absolute daily emissions of methane measured in g per day (CH4/day). Two measures of methane yield were recorded: the ratio of CH4 to dry matter intake (g CH4/kg DMI; CH4/DMI) and the ratio of CH4 to total gas emissions (CH4/(CH4 + CO2)). Ewes were maintained in the flocks for at least two parities. Non-methane trait data from over 8,000 female relatives were collated to estimate genetic correlations. Results suggest that breeding for low CH4/DMI is unlikely to negatively affect faecal egg counts, adult ewe fertility and litter survival traits, with no evidence for significant genetic correlations. Fleece weight was unfavourably (favourably) correlated with CH4/DMI (rg = -0.21 ± 0.09). Live weight (rg = 0.3 ± 0.1) and body condition score (rg = 0.2 ± 0.1) were positively correlated with methane yield. Comparing the two estimates of methane yield, CH4/DMI had lower heritability and repeatability. However, correlations of both measures with adult ewe traits were similar. This suggests that breeding is a suitable mitigation strategy for lowering methane yield, but wool, live weight and fat deposition traits may be affected over time and should be monitored.

Morphine and ethanol pretreatment effects on expression and extinction of ethanol-induced conditioned place preference and aversion in mice.

RATIONALE: Opioid receptor antagonists reliably alter the expression or extinction of ethanol's conditioned motivational effects as indexed by the place conditioning procedure, suggesting endogenous opioids are normally involved. These studies examined how exogenous stimulation of opioid receptors alters ethanol's conditioned rewarding and aversive effects. OBJECTIVES: Drugs that either directly (morphine) or indirectly (ethanol) stimulate opioid receptors were tested for their effects on the expression and extinction of ethanol-induced conditioned place preference (CPP) and conditioned place aversion (CPA). METHODS: Male DBA/2J mice were exposed to unbiased ethanol (2 g/kg) conditioning procedures that produced either CPP (experiments 1-2) or CPA (experiments 3-4). Morphine (0, 2.5, 5, or 10 mg/kg) was injected before three post-conditioning tests in experiments 1 and 3, whereas ethanol (0, 1, 2, or 3 g/kg) was injected before tests in experiments 2 and 4. All groups received vehicle on test 4 to determine whether the drug pretreatments altered the course of extinction. RESULTS: Morphine dose-dependently enhanced CPP expression (experiment 1), but ethanol dose-dependently reduced CPP expression (experiment 2). Test 4 showed no differences between drug-treated mice and mice given vehicle on all tests. Morphine had no effect on expression or extinction of ethanol-induced CPA (experiment 3). The highest ethanol dose (3 g/kg) interfered with CPA expression, but not extinction (experiment 4). CONCLUSIONS: Pretreatment drug effects on ethanol CPP and CPA expression were most likely a byproduct of their activity altering effects rather than opioid-receptor mediated modulation of ethanol's conditioned motivational effects. Neither drug affected the course of extinction.

The bed nucleus of the stria terminalis regulates ethanol-seeking behavior in mice.

Drug-associated stimuli are considered important factors in relapse to drug use. In the absence of drug, these cues can trigger drug craving and drive subsequent drug seeking. One structure that has been implicated in this process is the bed nucleus of the stria terminalis (BNST), a chief component of the extended amygdala. Previous studies have established a role for the BNST in cue-induced cocaine seeking. However, it is unclear if the BNST underlies cue-induced seeking of other abused drugs such as ethanol. In the present set of experiments, BNST involvement in ethanol-seeking behavior was assessed in male DBA/2J mice using the conditioned place preference procedure (CPP). The BNST was inhibited during CPP expression using electrolytic lesions (Experiment 1), co-infusion of GABAA and GABAB receptor agonists muscimol and baclofen (M+B; Experiment 2), and activation of inhibitory designer receptors exclusively activated by designer drugs (hM4Di-DREADD) with clozapine-N-oxide (CNO; Experiment 3). The magnitude of ethanol CPP was reduced significantly by each of these techniques. Notably, infusion of M+B (Exp. 2) abolished CPP altogether. Follow-up studies to Exp. 3 showed that ethanol cue-induced c-Fos immunoreactivity in the BNST was reduced by hM4Di activation (Experiment 4) and in the absence of hM4Di, CNO did not affect ethanol CPP (Experiment 5). Combined, these findings demonstrate that the BNST is involved in the modulation of cue-induced ethanol-seeking behavior.

Differential effects of ghrelin antagonists on alcohol drinking and reinforcement in mouse and rat models of alcohol dependence.

An effort has been mounted to understand the mechanisms of alcohol dependence in a way that may allow for greater efficacy in treatment. It has long been suggested that drugs of abuse seize fundamental reward pathways and disrupt homeostasis to produce compulsive drug seeking behaviors. Ghrelin, an endogenous hormone that affects hunger state and release of growth hormone, has been shown to increase alcohol intake following administration, while antagonists decrease intake. Using rodent models of dependence, the current study examined the effects of two ghrelin receptor antagonists, [DLys3]-GHRP-6 (DLys) and JMV2959, on dependence-induced alcohol self-administration. In two experiments adult male C57BL/6J mice and Wistar rats were made dependent via intermittent ethanol vapor exposure. In another experiment, adult male C57BL/6J mice were made dependent using the intragastric alcohol consumption (IGAC) procedure. Ghrelin receptor antagonists were given prior to voluntary ethanol drinking. Ghrelin antagonists reduced ethanol intake, preference, and operant self-administration of ethanol and sucrose across these models, but did not decrease food consumption in mice. In experiments 1 and 2, voluntary drinking was reduced by ghrelin receptor antagonists, however this reduction did not persist across days. Despite the transient effects of ghrelin antagonists, the drugs had renewed effectiveness following a break in administration as seen in experiment 1. The results show the ghrelin system as a potential target for studies of alcohol abuse. Further research is needed to determine the central mechanisms of these drugs and their influence on addiction in order to design effective pharmacotherapies.

Perfectionism, low self-esteem, and family factors as predictors of bulimic behavior.

A previous study found that self-reported body dissatisfaction, depression, and peer pressure to maintain a thin body shape were significant predictors of bulimic behavior in college women, but that family functioning was not a significant predictor [Eat. Behav. 2 (2001) 323]. The current study examined whether perfectionism, low self-esteem, and a more specific family variable--perceived pressure from the family to be thin--predicted any additional variance in eating-disordered behavior after significant variables from the previous study had been taken into account. As in the previous study, self-reported body dissatisfaction, depression, and peer pressure to maintain a thin body shape were significant predictors of bulimic behavior. Perceived weight-related pressure from the family was also a significant predictor. In contrast, high parental expectations were found to predict lower levels of bulimic behavior and to moderate the effects of peer influence on bulimic behavior. The variables found in this study to be related to bulimic behavior may be useful targets for clinical intervention for women with disturbed eating patterns.

Blockade of opioid receptors in anterior cingulate cortex disrupts ethanol-seeking behavior in mice.

The anterior cingulate cortex (ACC) and opioid receptors have been suggested to play a role in attributing incentive motivational properties to drug-related cues. We examined whether blockade of ACC opioid receptors would reduce cue-induced ethanol-seeking behavior in mice. We show that intra-ACC opioid receptor blockade disrupted expression of an ethanol-induced conditioned place preference, suggesting that endogenous opioid modulation in the ACC may be critical for maintaining the cue's conditioned rewarding effects.