Genetic factors involved in risk for methamphetamine intake and sensitization.

Lines of mice were created by selective breeding for the purpose of identifying genetic mechanisms that influence the magnitude of the selected trait and to explore genetic correlations for additional traits thought to be influenced by shared mechanisms. DNA samples from high and low methamphetamine-drinking (MADR) and high and low methamphetamine-sensitization lines were used for quantitative trait locus (QTL) mapping. Significant additive genetic correlations between the two traits indicated a common genetic influence, and a QTL on chromosome X was detected for both traits, suggesting one source of this commonality.

Ethanol concentration-dependent effects and the role of stress on ethanol drinking in corticotropin-releasing factor type 1 and double type 1 and 2 receptor knockout mice.

Rationale: Exposure to stressors promotes ethanol (EtOH) consumption and enhances drug craving during abstinence. Corticotropin-releasing factor (CRF), and in particular, CRF actions via type 1 CRF receptors (CRF(1)) are critical in behavioral responses to stressors. CRF(1) play a role in EtOH-induced behavioral neuroadaptation, in binge-like EtOH consumption, and in heightened EtOH consumption in dependent animals.

Selective breeding for magnitude of methamphetamine-induced sensitization alters methamphetamine consumption.

Rationale: Genetically determined differences in susceptibility to drug-induced sensitization could be related to risk for drug consumption.

Objectives: Studies were performed to determine whether selective breeding could be used to create lines of mice with different magnitudes of locomotor sensitization to methamphetamine (MA). MA sensitization (MASENS) lines were also examined for genetically correlated responses to MA.

A method for mapping intralocus interactions influencing excessive alcohol drinking.

Excessive alcohol (ethanol) consumption is the hallmark of alcohol use disorders. The F1 hybrid cross between the C57BL/6J (B6) and FVB/NJ (FVB) inbred mouse strains consumes more ethanol than either progenitor strain. The purpose of this study was to utilize ethanol-drinking data and genetic information to map genes that result in overdominant (or heterotic) ethanol drinking.

Corticotropin-releasing factor-1 receptor involvement in behavioral neuroadaptation to ethanol: a urocortin1-independent mechanism.

A common expression of neuroadaptations induced by repeated exposure to addictive drugs is a persistent sensitized behavioral response to their stimulant properties. Neuroplasticity underlying drug-induced sensitization has been proposed to explain compulsive drug pursuit and consumption characteristic of addiction. The hypothalamic-pituitary-adrenal (HPA) axis-activating neuropeptide, corticotropin-releasing factor (CRF), may be the keystone in drug-induced neuroadaptation.

Ethanol-related traits in mice selectively bred for differential sensitivity to methamphetamine-induced activation.

Acute drug stimulation has been proposed to be an endophenotype for drug abuse. The authors previously reported the short-term selective breeding of lines of mice for low (LMACT) and high (HMACT) stimulation to methamphetamine (MA). These mice were used to examine whether common genes influence the locomotor response to MA and ethanol.

The effect of fostering on the genetic expression of locomotor sensitivity to alcohol.

Steps were taken to eradicate endemic mouse coronavirus from a colony that was part of a behavioral project characterizing the genetics of alcohol sensitivity. This behavioral study was conducted to determine whether changing the uterine or rearing environment (as is integral to common rederivation methods) would have a significant effect on the expression of the behavioral traits in question. Selected breeding pairs of the affected lines were divided into four treatment groups: 1) transfer of embryos to pseudopregnant B6D2F1 female mice, 2) fostering offspring to B6D2F1 dams, 3) fostering offspring to a different dam of the same line, and 4) offspring raised by the birth dam.

Mice deficient in corticotropin-releasing factor receptor type 2 exhibit normal ethanol-associated behaviors.

Background: Stress is believed to influence alcohol use and relapse in alcoholics. Animal studies suggest an interaction between corticotropin-releasing factor (CRF) and its receptors and the behavioral effects and consumption of alcohol. The objective of these studies was to examine the effect of corticotropin-releasing factor receptor type 2 (CRF2) on ethanol consumption, conditioned taste aversion, sedation, and hypothermia.

Genetic correlational analyses of ethanol reward and aversion phenotypes in short-term selected mouse lines bred for ethanol drinking or ethanol-induced conditioned taste aversion.

Short-term selective breeding created mouse lines divergent for ethanol drinking (high drinking short-term selected line [STDRHI], low drinking [STDRLO]) or ethanol-induced conditioned taste aversion (CTA; high [HTA], low [LTA]). Compared with STDRLO, STDRHI mice consumed more saccharin and less quinine, exhibited greater ethanol-induced conditioned place preference (CPP), and showed reduced ethanol stimulation and sensitization under some conditions; a line difference in ethanol-induced CTA was not consistently found. Compared with LTA, HTA mice consumed less ethanol but were similar in saccharin consumption, sensitivity to ethanol-induced CPP, and ethanol-induced locomotor stimulation and sensitization.

Gene expression differences in mice divergently selected for methamphetamine sensitivity.

In an effort to identify genes that may be important for drug-abuse liability, we mapped behavioral quantitative trait loci (bQTL) for sensitivity to the locomotor stimulant effect of methamphetamine (MA) using two mouse lines that were selectively bred for high MA-induced activity (HMACT) or low MA-induced activity (LMACT). We then examined gene expression differences between these lines in the nucleus accumbens, using 20 U74Av2 Affymetrix microarrays and quantitative polymerase chain reaction (qPCR). Expression differences were detected for several genes, including Casein Kinase 1 Epsilon (Csnkle), glutamate receptor, ionotropic, AMPA1 (GluR1), GABA B1 receptor (Gabbr1), and dopamine- and cAMP-regulated phosphoprotein of 32 kDa (Darpp-32).

Corticotropin-releasing factor overexpression decreases ethanol drinking and increases sensitivity to the sedative effects of ethanol.

Rationale: Corticotropin-releasing factor (CRF) may play a significant role in drug and alcohol abuse.

Objective: To evaluate the role of CRF in these processes, we examined several ethanol (EtOH) related behaviors in mice that carry a transgene that causes overexpression of CRF.

Methods: We examined voluntary EtOH drinking, loss of the righting reflex (LORR), EtOH-induced conditioned taste aversion (CTA), and EtOH clearance in littermate transgenic (TG) and non-transgenic (non-TG) mice.

Reverse selection for differential response to the locomotor stimulant effects of ethanol provides evidence for pleiotropic genetic influence on locomotor response to other drugs of abuse.

Background: Addictive drugs share the ability to induce euphoria, which may be associated with their potential for abuse. Replicate mouse lines with high (FAST-1, FAST-2) and low (SLOW-1, SLOW-2) sensitivity to ethanol-induced psychomotor stimulation (a possible animal model for the euphoria experienced by humans) have provided evidence for common genetic influences (pleiotropy) on sensitivity to the effects of ethanol and of GABA-A receptor acting compounds on locomotor activity. Differences between FAST and SLOW mice in locomotor response to certain other drugs were found later in selection.

Different data from different labs: lessons from studies of gene-environment interaction.

It is sometimes supposed that standardizing tests of mouse behavior will ensure similar results in different laboratories. We evaluated this supposition by conducting behavioral tests with identical apparatus and test protocols in independent laboratories. Eight genetic groups of mice, including equal numbers of males and females, were either bred locally or shipped from the supplier and then tested on six behaviors simultaneously in three laboratories (Albany, NY; Edmonton, AB; Portland, OR).

Forward, relaxed, and reverse selection for reduced and enhanced sensitivity to ethanol's locomotor stimulant effects in mice.

Background: Rarely have trait markers for alcoholism risk been identified. However, relative sensitivity to the arousing effects of ethanol and sensitivity to ethanol's sedative effects have been distinguished as potentially valuable behavioral risk factors. Both traits are genetically influenced and have been modeled in mice by measuring sensitivity to ethanol-induced locomotor stimulation and hypnosis.