C.J. Malanga, MD, PhD - US grants

DESCRIPTION (provided by applicant): Prenatal exposure to drugs of abuse such as cocaine and alcohol is the single largest preventable cause of developmental compromise of infants in America today. Clinical and preclinical data suggest that cocaine may act as a behavioral teratogen, a drug capable of altering fetal brain development and subsequent function. Animal models of gestational cocaine exposure have been able to identify and separate the role of cocaine and cocaine-induced malnutrition in impairing fetal brain growth and development from the myriad of confounding co-variables encountered in human subjects from the clinical setting. There is a convergence of preclinical data suggesting persistent compromise in brain systems involved in drug self-administration, which have been linked to alterations in brain reward, in animals exposed to cocaine in utero. Specifically, alterations in dopamine responses at the dopamine D1 receptor in limbic forebrain structures have been observed. A series of experiments is proposed to investigate a well-characterized mouse model using brain-stimulation reward (BSR) techniques to ascertain differences in reward pathways resulting from gestational cocaine exposure. Rate-frequency functions for BSR will be determined for mice exposed to cocaine in utero and for their pair-fed controls. The effects of acute cocaine administration on rewarding self-stimulation will be compared between cocaine-exposed offspring and controls. It is hypothesized that mice exposed to cocaine in utero will be less responsive to the effects of acute cocaine administration on reinforcing self-stimulation demonstrated by a rightward shift of the dose-response curve. In addition to models of gestational cocaine exposure, experiments are described to investigate the effect of cocaine on brain-stimulation reward in mice lacking the dopamine-1A (D1a) receptor. It is hypothesized that as in cocaine-exposed mice, these animals will show decreased potency of acute cocaine compared to their genetic controls. Further in vitro electrophysiological and pharmacological experiments are proposed to investigate the cellular mechanisms underlying these changes. Data identifying the role of gestational drug exposure in altering brain development with specific consequences on subsequent drug seeking behaviors independent of other medical, social and economic variables must be considered when weighing the factors that impact on the developing human brain, and which contribute to adverse outcomes in such exposed children. Research identifying specific pharmacological changes and their cellular mechanisms in animal models will yield insights into both the basic functions of brain reward systems underlying actions of drugs of abuse and their role in behavioral development. It is hoped that this preclinical work may ultimately lead to further translational research identifying potentially relevant, selective therapeutic targets, which can be explored in appropriate preclinical and clinical research models, to blunt the toxicity of or to augment function in specific pathways that demonstrate persistent developmental compromise in children following gestational cocaine exposure.

DESCRIPTION (provided by applicant): Alcohol use disorders and alcoholism are complex behavioral and biological endpoints that begin with the pleasurable, rewarding effects of initial alcohol use. Although many overlapping brain mechanisms contribute to addiction, mechanisms of reward and motivation are among the most salient targets of all addictive or compulsive disorders. To better understand what motivates excessive alcohol consumption, and thereby develop more effective strategies for intervention, a more thorough understanding of the relationship between alcohol and biological mechanisms of reward is important. This proposal will focus on the rewarding properties of alcohol in mouse models. Intracranial self-stimulation (ICSS) is a behavioral method used in animal studies that has made major contributions to our understanding of cocaine, amphetamine, opiate and nicotine reward. However, the application of ICSS to the study of alcohol reward has been comparatively limited, and the effects of alcohol on brain stimulation-reward (BSR) have not been studied in mouse models where genetic differences can more easily be evaluated. The main advantage of ICSS over other operant behavioral methods in which the animal must perform a task in order to receive a drug reinforcer (action->outcome) is that the rewarding effect of a drug is measured independent of the motivation of the animal to seek or consume the drug. Alcohol self-administration in rodent models may be complicated by factors such as taste aversion and thirst that are avoided with ICSS, which allows a unique and novel approach to investigate the genetic and pharmacological regulation of alcohol reward. Preliminary studies in our laboratory have shown that alcohol potentiates the rewarding value of BSR after acute administration by oral gavage in both C57BL6/J and DBA/2 mice. Genetic factors represent about half of the risk for alcohol dependence, and our preliminary data have established clear genetic differences in alcohol reward between these two mouse strains: alcohol doses lower than 1 g/kg potentiate BSR while doses higher than 1 g/kg depreciate BSR in C57BL6/J mice, a strain that voluntarily consumes alcohol. In contrast, DBA/2 mice show a robust, dose-dependent potentiation of BSR at doses up to 2.4 g/kg but do not voluntarily consume alcohol. The rewarding effect of alcohol is greatest at early time points (15-30 minutes) and coincides with the peak blood alcohol concentration (BAC) after oral administration in both strains, supporting the idea that animals find the rising phase of the BAC curve more pleasurable or rewarding than the falling phase. Experiments are proposed to further elucidate the pharmacokinetics and pharmacological effects of acute alcohol administration;to investigate adaptations to alcohol reward with intermittent or chronic alcohol exposure;and to determine the contribution of dopaminergic mechanisms to alcohol reward. Understanding the role of reward in alcohol dependence will clarify mechanisms of increased drinking liability and lead to insights into novel therapeutic targets that modify consumption by changing alcohol reward. PUBLIC HEALTH RELEVANCE: The behavioral and biological problems of alcohol abuse begin with the pleasurable or rewarding effects of alcohol use. Alcohol use disorders are a major public health problem, costing American taxpayers almost $200 billion each year. The development of new and effective treatments based on sound neuroscientific evidence is critical to address the pain and impairment these disorders bring to the nearly 10 million people who suffer from them in the United States of America.