Date of Award

2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Antonieta Lavin

Second Advisor

Carmela M. Reichel

Third Advisor

John J. Woodward

Fourth Advisor

Arthur C. Riegel

Fifth Advisor

Kuei Y. Tseng

Abstract

The medial prefrontal cortex (mPFC) is an important node in the brain’s reward-seeking circuit and neuronal activity within this region is modulated by exposure to discrete cues and contexts previously associated with a drug experience. The mPFC is anatomically divided into the dorsal mPFC (dmPFC: containing the cingulate and dorsal prelimbic areas) and ventral mPFC (vmPFC: ventral prelimbic and infralimbic areas). Several studies have explored the functional distinctions between the dorsal and ventral mPFC with pharmacologic or genetic manipulations of its afferent glutamatergic projections to the ventral striatum. This line of research has uncovered opposing roles between these two mPFC subregions. Specifically, increases in activity within the prelimbic area (PLmPFC) have been shown to drive drug-seeking behavior while excitatory drive of the infralimbic area (IL-mPFC) inhibits this behavior following extinction training. However, the basal features of glutamatergic synaptic transmission that underlie this functional distinction and the synaptic plasticity generated by drug experience or exposure to drug-associated stimuli in PL- and IL-mPFC pyramidal projection neurons are not known. This dissertation addresses the hypothesis that glutamate synaptic transmission in deep layer 5/6 pyramidal neurons of the mPFC exhibits basal differences between mPFC subregions that are altered in response to drug-related cues and context, and that drug-seeking behavior, specifically psychostimulants such as cocaine and methamphetamine, is in part regulated by these plastic changes in ionotropic excitatory synaptic transmission. To test this, we made brain slice recordings in two widely used models of drug addiction in rats: the conditioned place preference paradigm (CPP) and the reinstatement model of drug self-administration. Following self-administration or experimenter administration (in the CPP paradigm) of psychostimulants (i.e. cocaine or methamphetamine), we tested whether exposure to discrete cues (reinstatement model) or the context (CPP) previously associated with the drug, produced alterations in synaptic excitatory ionotropic glutamate receptor transmission that could account for the following behavioral responses: retention of CPP after different abstinence intervals or cue-induced reinstatement of drug seeking. Our results suggest that cocaine produces different effects on PL and IL neurons that are dependent on the behavioral paradigm that is utilized. Specifically, cocaine self-administration followed by extinction alone, or cue-induced reinstatement did not produce any measurable differences in glutamate transmission compared to saline yoked rats. Cocaine-CPP on the other hand, produced several changes in glutamate transmission in both PL and IL neurons. These neuroadaptations were dependent on the length of abstinence and were reversed by context re-exposure. Lastly, contrary to the effects of cocaine self-administration, methamphetamine self-administration followed by 8 days of abstinence produced pre- and postsynaptic changes in glutamate transmission in mPFC neurons. In summary, these results provide evidence that general changes in mPFC synaptic glutamate transmission account for aspects of drug-seeking behavior that are not responsive to exposure to drug-associated cues or context, while other alterations in synaptic transmission that meet the functional distinction between mPFC subregions are sensitive to drug cue- or context-associations.

Rights

All rights reserved. Copyright is held by the author.

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