PARC 2013 Pilot Projects

Project funding period:  January 1, 2013 - December 31, 2013

Awarded projects:

Ethanol Effects on Retinoid Signaling in the Zebra Finch Brain
PI: Claudio V. Mello, M.D., Ph.D., Department of Behavioral Neuroscience, OHSU

Abstract: Ethanol consumption is associated with long-term cognitive deficits, yet the specific action of ethanol on the brain is poorly understood. Recently retinoic acid, a molecule with potent effects on nervous system phenotype, has been found to be elevated in the brains of mice following acute and chronic ethanol exposure. Here we will investigate how ethanol and retinoid signaling in the brains of the zebra finch interact to affect song, a complex learned behavior. Song is easily quantifiable and easy to induce as birds are highly motivated to sing. Finches learn song from a vocal tutor, and perfect their song by a process of auditory-motor feedback, akin to human infant babbling. In preliminary tests we find that finches are voluntary consumers of ethanol in their water, and that their relatively slow metabolic clearance of ethanol makes them a highly suitable organism for ethanol studies. Here we propose two aims to examine ethanol effects at two life-stages: (1) the mature cognitive decline of song with ethanol, and (2) ethanol effects on the development of juvenile vocal learning. In Aim 1 we will expose adult male finches to chronic ethanol and examine the effects of song structure, motivation to sing, and underlying neuroanatomy of the song system (song nuclei volume, cell soma size) and gene expression of a number of enzymes that regulate levels of retinoic acid in tissues. In a separate part of Aim 1 we will directly measure levels of retinoic acid and and its precursors in subregions of the finch brain to test hypotheses regarding the location of retinoid signaling in the finch song system. In Aim 2 we will use the zebra finch model to examine the effects ethanol may have on juvenile (adolescent) song development, as well as the development of the song system neuroanatomy and on gene expression during development. In a parallel experiment in Aim 2 we will also directly measure retinoids in subregions of the brain, as in Aim 1. This proposal will introduce a well-understood and powerful model organism for studies of neurogeneis and genomics to the field of ethanol research. Furthermore it inquires into a specific mechanism that links ethanol consumption to retinoic acid-linked gene expression and cognitive decline.

Effects of Exercise on Ethanol Drinking in 6 Inbred Strains of Rat
PI: Suzanne H. Mitchell, Ph.D., Department of Behavioral Neuroscience, OHSU

Abstract: Recent research suggests that adults who regularly engage in exercise are less likely to engage in drug use and consume alcohol. There has also been research using rodent models that indicated rats with the opportunity to exercise (wheel running) self-administer cocaine. The overall goal of the proposed current research aims to extend these findings to alcohol drinking, but also to examine whether there is a genetic contribution to this negative relationship between exercise and consumption. To accomplish this goal, male rats from 6 inbred strains will be examined: Brown Norway, Copenhagen, Fisher 344, Lewis, Wistar Furth, Wistar Kyoto. In a simple ABA design, rats will choose between bottles containing 10% ethanol and water in their home cages for 2 weeks prior to being randomly assigned to one of two exercise groups: home-cage with no wheel (no exercise group) and home-cage with access to a wheel (exercise group). After 4-weeks, access to the wheel will be blocked for the following 2 weeks. Consumption of the ethanol solution and preference relative to water, as well as time spent exercising and distance travelled in the exercise group, will be assessed daily throughout this period. We hypothesize that animals in the exercise group will consume less ethanol solution when the wheel is available, and that this cannot be accounted for the reduced time in home cage, when not exercising. When the exercise option is removed we expect that ethanol consumption will solely return to baseline levels. Further, we expect that there will be pronounced strain differences in consumption and preference at baseline, which are maintained in the no exercise group but diminished during the exercise condition for the exercise group. It is possible that some strains will be more sensitive to the effects of exercise than others, for example, resulting in a larger proportional decline in consumption when expressed as a function of baseline consumption. It is also possible that strains will return to baseline levels of consumption at different rates, once access to the exercise wheel is blocked. The data collected in this study will provide a foundation for future studies examining the genes and speak to neural mechanisms underlying the relationship between ethanol consumption and exercise.

Effects of Nicotine and Varenicline on Ethanol Behaviors
PI: Tamara J. Phillips, Ph.D., Department of Behavioral Neuroscience, OHSU, and Portland VA Medical Center

Abstract: Alcohol (ethanol) and nicotine, when excessively used, are associated with high rates of morbidity and mortality. Their co-abuse is common, but mechanisms leading to co-use are not well defined. One possibility is that nicotinic acetylcholine receptors (nAChR) are a common site of action for ethanol and nicotine, and that co-use results in greater reward compared to that produced by either drug alone. Our preliminary and published data show that the non-selective nAChR antagonist mecamylamine attenuates, while nicotine enhances, locomotor stimulation to ethanol in mice selectively bred for high locomotor stimulation to ethanol. The first goal of this proposal is to determine if nicotine potentiates the development of two ethanol-related behaviors: conditioned place preference (CPP), a measure of drug reward, and behavioral sensitization, a measure of drug-induced neural changes. Secondly, RT-PCR and autoradiography will be used to measure gene expression and levels of certain nAChR subtypes in mice treated with chronic nicotine, ethanol and both drugs. We hypothesize that nicotine will enhance the rewarding and sensitizing effects of ethanol and that group differences in nAChR levels, and perhaps expression, will correspond with behavioral effects. Our third aim is focused on treatment, using the FDA-approved smoking cessation drug varenicline. There is limited research focused on how varenicline affects behaviors that could impact consumption. For example, varenicline could influence ethanol consumption by reducing the rewarding effects of ethanol, or varenicline could increase the rewarding effects of ethanol and shift the dose response curve to the left, reducing the amount of alcohol needed to achieve the same level of reward. It could also accentuate behavioral effects that interfere with drinking. Here, we have started with examination of the effects of varenicline on alcohol induced behaviors alone, but we also propose a study examining effects of varenicline on combined alcoholnicotine CPP. These data could be informative with regard to the clinical use of varenicline for the treatment of alcohol dependence and combined alcohol-nicotine dependence.

PARC Pilot Project Application Information

Each year, the Portland Alcohol Research Center (PARC) aims to fund three pilot research projects (up to $35K each). The PARC is especially interested in encouraging investigators new to alcohol research to submit applications. Pilot proposals that focus on the neuroadaptation to ethanol exposure and those with relevance to behavioral genomics are especially welcome.

The call for pilot project applications generally is made each year on this website June 1st, with an application due date in late August, for funding to commence for selected projects the following January.

Each proposal is reviewed by at least two members of our external scientific advisory board. Based on these reviews and their own reviews, Center Director John Crabbe and Scientific Director Robert Hitzemann make recommendations to the PARC Executive Committee for funding.

Please contact the PARC Scientific Director, Robert Hitzemann, with questions at hitzeman@ohsu.edu or 503-402-2858.

 

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