Synapse density and dendritic complexity are reduced in the prefrontal cortex following seven days of forced abstinence from cocaine self-administration.

Khampaseuth Rasakham,Kevin Kay,Megan N. Huizenga,Tara L. Spires-Jones,R. Christopher Pierce,Heath D. Schmidt,Narghes Calcagno,Ghazaleh Sadri-Vakili,Ryan K. Bachtell

doi:10.1371/journal.pone.0102524

Abstract

Chronic cocaine exposure in both human addicts and in rodent models of addiction reduces prefrontal cortical activity, which subsequently dysregulates reward processing and higher order executive function. The net effect of this impaired gating of behavior is enhanced vulnerability to relapse. Previously we have shown that cocaine-induced increases in brain-derived neurotrophic factor (BDNF) expression in the medial prefrontal cortex (PFC) is a neuroadaptive mechanism that blunts the reinforcing efficacy of cocaine. As BDNF is known to affect neuronal survival and synaptic plasticity, we tested the hypothesis that abstinence from cocaine self-administration would lead to alterations in neuronal morphology and synaptic density in the PFC. Using a novel technique, array tomography and Golgi staining, morphological changes in the rat PFC were analyzed following 14 days of cocaine self-administration and 7 days of forced abstinence. Our results indicate that overall dendritic branching and total synaptic density are significantly reduced in the rat PFC. In contrast, the density of thin dendritic spines are significantly increased on layer V pyramidal neurons of the PFC. These findings indicate that dynamic structural changes occur during cocaine abstinence that may contribute to the observed hypo-activity of the PFC in cocaine-addicted individuals.

Highlights

Alterations in structural plasticity within the reward circuitry are proposed to be key mechanisms contributing to cocaine’s powerful ability to maintain drug-seeking behavior
While most studies have focused on structural changes associated with the dysfunctional activity of the nucleus accumbens (NAc), considerably fewer studies have examined the alterations in the prefrontal cortex (PFC)
In the present study we demonstrate that there are pronounced structural and synaptic changes in layer V of the PFC following 7 days of forced abstinence from cocaine self-administration

Summary

Introduction

Alterations in structural plasticity within the reward circuitry are proposed to be key mechanisms contributing to cocaine’s powerful ability to maintain drug-seeking behavior (reviewed in [1]). In rodents, increased neuronal activity in the PFC is associated with cocaine intake [9,10], compulsive drug-seeking behavior [12], and cocaine reinstatement after withdrawal [13,14,15]. Druginduced metabolic activity in the PFC is blunted in rats administered a challenge injection during withdrawal from cocaine self-administration [9,17]. Together, these studies indicate that chronic cocaine induces profound functional changes in PFC that may be associated with an increase in the number of inhibitory synapses and/or a reduction in excitatory synapses in the PFC. The morphological alterations that occur in the PFC following chronic drug use have not been elucidated

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Conclusion