Roberto I. Melendez, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): Alcohol addiction continues to be a substantial medical, social, and financial problem in the United States. The dynamic process of alcohol addiction involves a transition from recreational alcohol use and deteriorates over time into excessive or compulsive drinking. Given that alcoholism is a chronic relapsing disease, it is not uncommon for many alcoholics to experience periods of drinking followed by periods of abstinence. This cyclic pattern of alcohol intake and deprivation may have severe consequnces on drinking behavior, including excessive or 'binge-like' consumption. There is very little pre-clinical information on the environmental and biological factors that mediate relapse-like alcohol drinking. Most basic reasearch using animal models has concentrated on the initiation and maintenance phases of alcohol intake. However, alcohol cosumption data (limited or continous access) by such approaches shows little variation over time (i.e., stable patterns of alcohol intake), thus fails to capture a fundamental characteristic of the addiction process. Thus, a goal has been to develop behavioral models that reflect the transition from controlled alcohol use to excessive consumption. A primary experimental approach to study relapse-like drinking has [unreadable] been through the expression of the alcohol deprivation effect (ADE), which is measured by an increase in alcohol intake and preference over baseline drinking conditions after a period of abstinence. The focus and overall objective of this proposal is to is employ a C57BL/6 model of repeated alcohol deprivations and relapse-like drinking to identify the neurobiological events that contribute to relapse. Conceivably, changes in extracellular glutamate levels the prefrontal cortex and ventral striatum may represent key neural substrates and neurochemical events critical in mediating relapse drinking behavior. To date, there is very little information available about changes in glutamatergic transmission that may relate to alcohol relapse. Therefore, a unique and novel feature of this proposal is to combine a robust C57BL/6 model of alcohol relapse drinking with in vivo microdialysis and site specific microinjections to validate the relevance of glutamatergic alterations in the prefrontal-ventral striatal pathway. Research to this end could potentially lead to pharmacotherapies that might reduce relapse risk and craving states. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Excessive alcohol drinking among human adolescents is a major social and biomedical problem in the United States and Puerto Rico. Moreover, early initiation of alcohol use or misuse leads to greater risk of lifetime alcohol use disorders. Recent human brain imaging studies clearly show that the prefrontal cortex (PFC), which underlies various executive cognitive functions, undergoes extensive structural and functional re- organization from adolescence to adulthood. This is consistent with the notion that heightened synaptic plasticity is a cardinal feature of adolescent brain development. Although usually adaptive and beneficial, heightened plasticity may lead to greater vulnerability to substance abuse. Indeed, the mechanisms underlying synaptic plasticity are similar to the mechanisms mediating ethanol dependence. Research performed in animal models is needed because studies involving the administration of alcohol to human adolescents are illegal. We have recently developed an adolescent C57BL/6J (B6) mouse model that shows greater propensity for ethanol drinking behavior. The use of the B6 strain may be especially valuable given its wealth of available genetic information (i.e., Mouse Genome Project). Studies proposed in this application are to combine our B6 adolescent drinking model with in-vivo neurochemical and pharmacological approaches that have never been employed during the adolescent period. Our primary objective is to determine the role of extracellular glutamate homeostasis in the PFC and its projections to the nucleus accumbens (NAC). Our working hypothesis is that elevated glutamatergic transmission in the PFC-NAC circuit leads to greater propensity for alcohol drinking during adolescence. We also propose to study the effects of adolescent drinking on dendritic spines in the PFC, which are the major postsynaptic components of glutamatergic synapses. It is anticipated that prefrontal spine plasticity will be severely altered following adolescent alcohol drinking experience. Collectively, these studies will generate new and novel information regarding the role of synaptic glutamate transmission in the PFC-NAC circuitry in mediating adolescent alcohol drinking. This will provide valuable insight into this crucial clinical and social issue, as well as facilitate development of new glutamate- an neuroplasticity-based pharmacotherapies that reduce harmful consequences of alcohol abuse.

DESCRIPTION (provided by applicant): Excessive alcohol drinking among human adolescents is a major social and biomedical problem in the United States and Puerto Rico. Moreover, early initiation of alcohol use or misuse leads to greater risk of lifetime alcohol use disorders. Recent human brain imaging studies clearly show that the prefrontal cortex (PFC), which underlies various executive cognitive functions, undergoes extensive structural and functional re- organization from adolescence to adulthood. This is consistent with the notion that heightened synaptic plasticity is a cardinal feature of adolescent brain development. Although usually adaptive and beneficial, heightened plasticity may lead to greater vulnerability to substance abuse. Indeed, the mechanisms underlying synaptic plasticity are similar to the mechanisms mediating ethanol dependence. Research performed in animal models is needed because studies involving the administration of alcohol to human adolescents are illegal. We have recently developed an adolescent C57BL/6J (B6) mouse model that shows greater propensity for ethanol drinking behavior. The use of the B6 strain may be especially valuable given its wealth of available genetic information (i.e., Mouse Genome Project). Studies proposed in this application are to combine our B6 adolescent drinking model with in-vivo neurochemical and pharmacological approaches that have never been employed during the adolescent period. Our primary objective is to determine the role of extracellular glutamate homeostasis in the PFC and its projections to the nucleus accumbens (NAC). Our working hypothesis is that elevated glutamatergic transmission in the PFC-NAC circuit leads to greater propensity for alcohol drinking during adolescence. We also propose to study the effects of adolescent drinking on dendritic spines in the PFC, which are the major postsynaptic components of glutamatergic synapses. It is anticipated that prefrontal spine plasticity will be severely altered following adolescent alcohol drinking experience. Collectively, these studies will generate new and novel information regarding the role of synaptic glutamate transmission in the PFC-NAC circuitry in mediating adolescent alcohol drinking. This will provide valuable insight into this crucial clinical and social issue, as well as facilitate development of new glutamate- an neuroplasticity-based pharmacotherapies that reduce harmful consequences of alcohol abuse.