All ETDs from UAB

Advisory Committee Chair

Robin A J Lester

Advisory Committee Members

John J Hablitz

Lori L McMahon

Harald W Sontheimer

J Michael Wyss

Document Type

Dissertation

Date of Award

2008

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

seeking behavior following chronic drug use lasts for many months or even years. Short-term withdrawal experiments have suggested that the neuroadaptations thought to underlie learning and memory may also contribute to addictive behavior. However, there is little information about the physiological mechanisms that participate in craving and relapse following long-term withdrawal. Here I show in hippocampal slices from rats treated with nicotine for 1 week that there is a change in the excitability of CA1 pyramidal cells that persists for up to 9 months following the cessation of drug treatment. The expression of this enhanced excitability is dependent on different mechanisms immediately after cessation of the drug compared to following longer withdrawal. After short-term withdrawal (1 day), the enhanced excitability is dependent on spontaneous activity upstream of CA1 that results in a depolarization of the CA1 pyramidal cells. Following longer withdrawal (> 4 weeks) the enhanced excitability is localized to the CA1 region and mediated via an increase in the intrinsic excitability of the CA1 pyramidal cells. Re-exposure to nicotine in vitro restores hippocampal function to normal after 1 day of withdrawal, but not at withdrawal times later than 4 weeks suggesting a homeostatic induction mechanism followed by long-lasting neuroadaptations downstream of nicotinic receptors that may contribute to the expression of nicotine craving and relapse.

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