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Linking addiction-related behavior to synaptic efficacy and network activity in the prefrontal-accumbal pathway of behaving rats

Pais Gomes Luís, Catarina

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Abstract

Addiction is a chronically relapsing brain disorder, involving compulsive drug seeking and taking. Enduring vulnerability to relapse is a challenging feature to manage in substance use disorder, with devastating effects to those who suffer from it, as well as at familial and public health levels. Incubation of drug craving characterized by gradual increases in cue-induced drug craving following halting of drug use, may contribute to heightened relapse risk, even after prolonged abstinence. Addictive drugs act upon and usurp the mesolimbic circuit, with long-term drug abuse leads to reward processing, cognitive and decision-making deficits. Drug-driven neuronal plasticity within the Prefrontal cortex (PFC) to Nucleus Accumbens (NAc) pathway is a known key substrate and mediator of addictive behavior. Here we performed longitudinal in vivo local field potential (LFP) recordings in freely behaving rats throughout an incubation of drug seeking paradigm. This approach proved suitable to assess both evoked and spontaneous LFP activity at distinct behavioral stages of the addiction cycle, in a within subject manner. Chronic cocaine self-administration induced strengthening of the PFC-NAc pathway, accompanied by enhanced glutamate release, when compared to drug naïve conditions. Compellingly, the degree of synaptic adaptation correlated with the cocaine intake and incubation severity of individual rats. At the network level, accumbal oscillatory profile of rats that underwent CSA was also altered, with suppression of high gamma and enhanced alpha and beta waves. Throughout withdrawal, persistent pre-synaptic release subsisted, while network changes proved to be transient. Yet, rats with history of cocaine intake did showed altered LFP patterns, upon a cocaine challenge, when compared to saline yoked counterparts, suggesting impaired corticostriatal network dynamics that endures after long-term abstinence. During reinstatement, i.e. relapse-like conditions, distinct frequency components were found to be differentially modulated by drug seeking behavior. Drug-driven adaptations to synaptic transmission and concomitant alterations of oscillatory landscape of functionally connected areas, such as the PFC and NAc, represent multiple-leveled dysregulation exerted by addictive drugs. Concerted maladaptive changes may contribute to the development of a de novo homeostatic threshold that is both driven by and drives drug abuse, craving and relapse in a spiraling cycle of addiction.

Item Type: Dissertation
Supervisor: Köhr, PD Dr. Georg
Date of thesis defense: 28 February 2018
Date Deposited: 19 Jun 2018 06:02
Date: 2019
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Service facilities > Interdisziplinäres Zentrum für Neurowissenschaften
Service facilities > Zentralinstitut für Seelische Gesundheit
Subjects: 500 Natural sciences and mathematics
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