Susan M. Brasser, Ph.D. - US grants

The proposed research is designed to investigate age-related differences in sensitivity to anxiolytic effects of alcohol between the time of weaning and young adulthood. The immediate objectives are to understand the conditions under which alcohol may act as an effective anxiolytic unconditioned stimulus during different stages on ontogeny, and to identify specific developmental periods during which an organism may be more vulnerable to consequences of the drug. This information will provide a critical basis for subsequently examining how the timing of exposure to and learning about ethanol's anxiolytic effects early in life may control later alcohol-drinking patterns and contribute to the development of alcohol dependence. Toward achievement of these aims, two experimental paradigms used to measure anxiety that may be easily adapted for use with subjects of various ages were selected to assess potential ontogenetic differences in 1) initial sensitivity to any anxiolytic effects of alcohol, and 2) tolerance/sensitization to such effects with repeated drug exposure. Experiments 1 and 2 will examine the influence of a single acute administration of various mild doses of ethanol on the fear-potentiated startle response and elevated-plus maze performance of weanling (P23), periadolescent (P35), and adult (P75) rats. Using either of these two tasks, the third experiment will then examine how experience with alcohol via a sequence of prior daily administrations influences the anxiolytic action of the drug at the aforementioned ages.

[unreadable] DESCRIPTION (provided by applicant): The present proposal represents a collaborative effort between investigators in the fields of alcohol pharmacology and gustatory neurobiology to systematically examine the contribution of gustatory receptor and central neural circuits processing appetitive oral alcohol information to genetically-mediated alcohol preference. Although significant progress has been made in identifying the biological mechanisms that mediate alcohol reinforcement and contribute to its consumption, our understanding of the complex neuroanatomical circuits that control initiation and maintenance of oral alcohol ingestion is far from complete. A substantial body of evidence from animal and human studies over the last decade has supported a robust genetically-influenced relationship between the ingestion of alcohol and consumption of naturally-reinforcing sweet substances, but the mechanisms underlying inherited co-variation in alcohol and sweet intake are presently unknown. Recent findings from our laboratory have shown that oral alcohol stimulation potently activates sweet-responsive gustatory circuits in the nucleus of the solitary tract and that alcohol-induced activity in these pathways is directly inhibited by pharmacological blockade of oral sweet receptors. New preliminary behavioral data indicate that genetic deletion of the T1r3 sweet taste receptor in mice produces indifference to alcohol in long-term intake tests at concentrations that are normally highly preferred. Experiments under Specific Aim 1 will measure the neurophysiological processing of ethanol gustatory information in the NST across multiple selectively bred alcohol-preferring/-nonpreferring rat lines and their nonselected progenitor lines to test the hypothesis that enhanced alcohol-induced activation of central sweet taste circuits is a consistent biological phenotype associated with genetically-mediated alcohol preference. Experiments under Specific Aim 2 will examine the effects of gustatory sweet receptor blockade on psychophysical orosensory responses to ethanol in alcohol- and sweet-preferring P, HAD1, HAD2, and C57BL lines/strains and their respective nonpreferring/nonselected lines to test the hypothesis that reduction of oral alcohol stimulation of sweet taste pathways will decrease orosensory-mediated ethanol preference. At the conclusion of this project, we will have produced a body of valuable data addressing the specific contribution of gustatory receptor and central neural pathways conveying appetitive oral alcohol information to genetically-influenced ethanol preference. More generally, these studies will enhance our understanding of the central nervous system processing of alcohol sensory information, an area that is currently not well understood. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Alcohol addiction is a chronic disorder involving neuroplastic changes in the brain that contribute both to the maintenance of ongoing drug use and relapse to drug seeking after periods of abstinence. Although substantial progress has been made in identifying neurobiological mechanisms that mediate excessive alcohol seeking and consumption, enduring susceptibility to relapse remains a major obstacle in the treatment of alcohol addiction. A key factor known to maintain drug taking and to precipitate relapse are learned responses elicited by sensory stimuli that have been repeatedly paired with drug administration and thus become salient cues predictive of impending drug reinforcement. Given its oral route of administration, the chemosensory cues accompanying alcohol consumption are among the most intimate and consistent stimuli immediately predictive of the drug's postabsorptive effects. Ethanol chemosensory stimuli induce urges to drink and corresponding physiologic changes in alcoholics and promote relapse to ethanol seeking in rodent models, yet the underlying neural substrates mediating learned responses to ethanol sensory cues in chronically exposed organisms are not well established. The present proposal aims to investigate alterations in the neural processing of ethanol orosensory signals within the insular cortex following chronic experience with the drug and the effects of inactivation of candidate subregions of the insula in reducing learned reactivity to ethanol chemosensory cues and their ability to induce ethanol-seeking responses. Experiments under Specific Aim 1 will measure alterations in central neural response to ethanol chemosensory signals within the insula in chronically ethanol- exposed animals and the effects of direct pharmacological silencing of primary gustatory and visceral subregions of the insular cortex in suppressing heightened behavioral reactivity to ethanol chemosensory cues. Experiments under Aim 2 will measure neural response within the insula elicited by re-exposure to ethanol chemosensory cues following extinction of self-administration and the ability of inactivation of gustatory and interoceptive regions of the insula to disrupt cue-induced reinstatement of ethanol seeking. At the conclusion of this project, we will have produced valuable data regarding neural mechanisms underlying established alcohol- seeking responses elicited by exposure alcohol sensory cues, essential to identifying targets for treatment to reduce compulsive drug seeking and persistent vulnerability to relapse. More broadly, these studies will continue to enhance our understanding of the central nervous system processing of alcohol sensory information, an understudied but important area of research.