William M. Doyon - US grants

DESCRIPTION (provided by applicant): The ventral and dorsal striatum are part of a neural network that is strongly implicated in the rewarding, reinforcing, and learning processes that occur with administration of addictive substances. The coordinated activation of dopamine and glutamate receptors within this system is thought to be a key mechanism by which these drugs (e.g., alcohol) produce their effects. The aim of this proposal is to monitor extracellular dopamine and glutamate in the nucleus accumbens and dorsal striatum concurrently during associative learning and operant self-administration of alcohol, with dual probe microdialysis. In this procedure, rats will be trained to respond operantly using ethanol + sucrose, sucrose, or water reinforcement. The microdialysis test will occur very early in training, after the animals initially acquire the capacity for operant self-administration. These experiments will distinguish between appetitive and consummatory behaviors and the accompanying neuronal responses. The overall hypothesis is that extracellular dopamine and glutamate are elevated during operant learning and ethanol self-administration.

[unreadable] DESCRIPTION (provided by applicant): PROJECT SUMMARY. The mechanisms involved in the development of ethanol reinforcement are not fully understood. Despite the broad action of ethanol in the brain, the activation of mesolimbic dopamine (DA) neurons may represent a key systems-level process involved in goal-directed behavior and adaptive responding to the environment. Although different paradigms show that ethanol directly stimulates mesolimbic DA neurons, the involvement of DA in ethanol-reinforced behavior remains controversial. We hypothesize that (1) DA neuron activity increases transiently during ethanol self-administration and that (2) the increase is related to ethanol stimulus cues and not to ethanol action upon the DA system. The major goal of the proposed study is to distinguish DA neuron activity in real time during operant responding, during the initial phase of ethanol consumption, and later after brain ethanol has reached pharmacological levels. During these specific periods of a self-administration session, we will monitor the firing activity of multiple DA neurons in the ventral tegmental area simultaneously with multiunit recording techniques. To determine the direct pharmacological effect of ethanol on DA signaling, we will administer ethanol in freely moving rats via an intraperitoneal catheter at a rate that approximates the pharmacokinetics of ethanol during self-administration. This approach will allow us to better understand the behavioral correlates involved in the DA response during self-administration. During these procedures, we will also quantify the DA concentration in the nucleus accumbens with microdialysis to better understand the relationship between DA neuron excitability and the release of DA at the terminal regions during ethanol administration. [unreadable] [unreadable] RELEVANCE. Alcohol abuse and dependence continue to cause major health and societal problems. [unreadable] However, the neuronal mechanisms that underlie this destructive behavior remain ambiguous. These experiments will provide important new insight into how brain regions that are implicated in drug addiction process information during motivated alcohol drinking. [unreadable] [unreadable] [unreadable]