期刊
EUROPEAN JOURNAL OF NEUROSCIENCE
卷 25, 期 7, 页码 2201-2213出版社
BLACKWELL PUBLISHING
DOI: 10.1111/j.1460-9568.2007.05473.x
关键词
amygdala; nucleus accumbens; prefrontal cortex; protein kinase A; rats
资金
- NIDA NIH HHS [F31 DA016472-02, DA 008227, F31 DA016472-03, F31 DA016472, DA 016472, DA 016587, DA 010460, F31 DA016472-01] Funding Source: Medline
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 GluR(1)(S845) phosphorylation in striatal and amygdala subregions and NR1S897 phosphorylation in the CA1 subregion of the hippocampus. Tolerance also developed to cAMP-independent GluR(1)(S831) 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 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.
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