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 journalArticle

54 Citations (Scopus)

Abstract

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
Volume25
Issue number7
DOIs
StatePublished - Apr 2007

Fingerprint

Self Administration
Cocaine
Phosphorylation
Proteins
Corpus Striatum
Dopamine
Synapsins
Cocaine-Related Disorders
Brain
Microwaves
Amygdala
Prefrontal Cortex
Intravenous Administration
Tyrosine
Hippocampus
Western Blotting
Injections

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Region-specific tolerance to cocaine-regulated cAMP-dependent protein phosphorylation following chronic self-administration. / Edwards, Scott; Graham, Danielle L.; Bachtell, Ryan K.; Self, David W.

In: European Journal of Neuroscience, Vol. 25, No. 7, 04.2007, p. 2201-2213.

Research output: Contribution to journalArticle

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