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NIAAA P01

Project 2: Non-Human Primate Studies

Translational Model Development for Non-Human Primate Studies of Risk Factors Linking Anxiety-Like Behaviors and Alcohol Consumption

Principal Investigator: Paul Czoty, PhD
Co-Investigator:
James Daunais, PhD

While the original focus of this project was directed at the association between early life stress and AUD vulnerability, the unexpected departure of the original PIs of this project led to what proved to be a very positive shift in experimental focus. Due to budgetary limitations, the original non-human primate project focused solely on behavioral studies. However, we had always recognized the need to integrate neurobiological methods and approaches into these studies to establish a translational research platform directed at the neural substrates underlying vulnerability to alcohol use disorder. Fortunately, through other means, including a one-year supplement awarded to Dr. Daunais, this project was able to integrate neuroimaging and behavioral approaches. Importantly, the expanded focus of these projects allowed us to think more broadly about vulnerability and to begin to develop models to explore other factors, in addition to early life stress, that may be associated with increased risk of AUD. Examples include adolescent alcohol exposure, social status, and high levels of alcohol craving. Behavioral studies, led by Dr. Czoty, established a well-validated non-human primate model of voluntary ethanol drinking (based on the pioneering work of Dr. Kathleen Grant) along with newly developed NHP measures of behavioral risk factors of alcohol addiction (e.g. anxiety-like behaviors). The findings from these studies confirmed and extended other work demonstrating the interaction between ethanol consumption and anxiety-like behavioral measures. Dr. Czoty also established a new drinking procedure optimized to assess potential pharmacotherapies for excessive ethanol drinking in NHPs.

Dr. Czoty also established a new drinking procedure optimized to assess potential pharmacotherapies for excessive ethanol drinking in NHPs. Using this procedure, his lab has already shown that a novel nocicepton/orphanin FQ peptide (NOP) receptor agonist, BU08028, significantly decreased ethanol drinking in NHPs (Fig. 2). This procedure is currently being used to rapidly translate therapeutic discoveries in rodent models to non-human primates.

Proj2Fig2

Brain imaging studies directed by Dr. Daunais have used magnetoencephalography (MEG) to identify how brain function changes after 3 months of induction and over 6 months of voluntary ethanol consumption in a self-administration paradigm. Preliminary comparisons of heavy and moderate drinkers' power spectral densities suggest individual differences in resting state activity may relate to the speed at which monkeys initially consume ethanol. This may be important given that early drinking typologies are related to subsequent drinking phenotypes in this NHP ethanol self-administration procedure (Grant et al., 2008). Initial findings revealed that monkeys differed markedly in their rate of ethanol consumption during the final phase of the induction procedure used to initiate ethanol drinking. Some animals consumed 1.5 g/kg in less than 20 min (fast drinkers), while others took 60 minutes or more to drink the same amount (slow drinkers). In the slow drinkers, power spectral densities after 3 months of voluntary ethanol drinking increased from baseline in both cortical and subcortical regions (e.g. medial and lateral orbital frontal cortex, dorsolateral PFC, lateral amygdala, and nucleus accumbens). In contrast, fast drinkers exhibited decreased power in most of the same brain regions. Together, these novel neurobehavioral findings are beginning to identify structural and functional changes that may underlie vulnerability to alcohol use disorder.

References Cited

Grant KA, Leng X, Green HL, Szeliga KT, Rogers LS, Gonzales SW (2008) Drinking typography established by scheduled induction predicts chronic heavy drinking in a monkey model of ethanol self-administration. Alcoholism, clinical and experimental research 32:1824-1838.


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