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Region‐specific tolerance to cocaine‐regulated cAMP‐dependent protein phosphorylation following chronic self‐administration
Author(s) -
Edwards Scott,
Graham Danielle L.,
Bachtell Ryan K.,
Self David W.
Publication year - 2007
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2007.05473.x
Subject(s) - phosphorylation , sensitization , synapsin i , dopamine , creb , synapsin , protein phosphorylation , protein kinase a , pharmacology , neuroscience , psychology , medicine , chemistry , endocrinology , biochemistry , transcription factor , vesicle , membrane , synaptic vesicle , gene
Chronic cocaine self‐administration can produce either tolerance or sensitization to certain cocaine‐regulated behaviours, but whether differential alterations develop in the biochemical response to cocaine is less clear. We measured cocaine‐induced phosphorylation of multiple cAMP‐dependent and ‐independent protein substrates in mesolimbic dopamine terminal regions following chronic self‐administration. Changes in self‐administering rats were compared to changes produced by passive yoked injection to identify reinforcement‐related regulation, whereas acute and chronic yoked groups were compared to identify the development tolerance or sensitization in the biochemical response to cocaine. Microwave‐fixed brain tissue was collected immediately following 4 h of intravenous cocaine administration, and subjected to Western blot analysis of phosphorylated and total protein substrates. Chronic cocaine produced region‐ and substrate‐specific tolerance to cAMP‐dependent protein phosphorylation, including phosphorylation in striatal and amygdala subregions and phosphorylation in the CA1 subregion of the hippocampus. Tolerance also developed to cAMP‐independent phosphorylation in the prefrontal cortex. In contrast, sensitization to presynaptic regulation of synapsin S9 phosphorylation developed in the hippocampal CA3 subregion while cAMP‐dependent tyrosine hydroxylase S40 phosphorylation decreased in striatal dopamine terminals. Cocaine‐induced ERK and CREB S133 phosphorylation were dissociated in many brain regions and failed to develop either tolerance or sensitization with chronic administration. Positive reinforcement‐related correlations between cocaine intake and protein phosphorylation were found only in self‐administering animals, while negative dose‐related correlations were found primarily with yoked administration. These regional‐ and substrate‐specific adaptations in cocaine‐induced protein phosphorylation are discussed in view of their potential impact on the development of cocaine addiction.