Region-specific tolerance to cocaine-regulated cAMP-dependent protein phosphorylation following chronic self-administration

Scott Edwards, Danielle L. Graham, Ryan K. Bachtell, David W. Self

Research output: Contribution to journalArticlepeer-review

59 Scopus citations


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 hydroxylaseS40 phosphorylation decreased in striatal dopamine terminals. Cocaine-induced ERK and CREBS133 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.

Original languageEnglish (US)
Pages (from-to)2201-2213
Number of pages13
JournalEuropean Journal of Neuroscience
Issue number7
StatePublished - Apr 2007


  • Amygdala
  • Nucleus accumbens
  • Prefrontal cortex
  • Protein kinase A
  • Rats

ASJC Scopus subject areas

  • Neuroscience(all)


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