The chronic effects of cocaine abuse on brain structure and function

The chronic effects of cocaine abuse on brain structure and function are blamed for the inability of most addicts to remain abstinent. regulated by cocaine that code for proteins involved in the remodeling of the cytomatrix and synaptic connections and the inhibition of blood vessel proliferation (PCDH8, LAMB1, ITGB6, CTGF and EphB4). The observed microarray phenotype in the human hippocampus recognized RECK and other region-specific genes that may promote long-lasting structural changes with repeated cocaine abuse. Extracellular matrix remodeling in the hippocampus may be a persisting effect of 64043-42-1 manufacture chronic abuse that Rabbit Polyclonal to EDG4 contributes to the compulsive and relapsing nature of cocaine dependency. Introduction A major goal in drug abuse research is to identify key molecular mechanisms that underlie the development of compulsive drug use. The persisting urges for cocaine that remain after a protracted period of withdrawal may be due to long-lasting structural changes in certain brain regions. Recent observations suggest that hippocampal learning and memory of the drug euphoria may drive the maladaptive behaviors that increase the risk of relapse to cocaine use [1]C[3]. The hippocampus is usually involved in short and long-term memory processing [4] and one important target of hippocampal projections is the nucleus accumbens (NAC), a region involved in drug incentive circuitry [for review, 5]. Synchronous activity in the hippocampus and nucleus accumbens may be a motivation-to-action interface [6]. Recent behavioral data demonstrate that hippocampal theta activation is sufficient to drive reinstatement of cocaine intake in rats extinguished from self-administration [7]. Long-term potentiation (LTP) in the rat hippocampus is usually modulated by cocaine exposure, suggesting further that drug-induced changes in the hippocampal formation may have some role in the addictive state [8]. By using high density genome-wide arrays, we profiled hippocampal gene expression in cocaine abusers to identify new targets that may play a role in cocaine dependence. Target validation and protein steps were carried out for selected genes to further confirm functional relevance. This transcriptome survey in the human hippocampus identified an unexpected elevation in RECK (reversion-inducing-cysteine-rich protein with kazal motifs), an endogenous inhibitor of matrix metalloproteinases (MMPs). MMPs remodel the pericellular environment, primarily through cleavage of extracellular matrix (ECM) proteins and receptors [9]C[11]. Brain ECM proteins form the scaffolding for neurons and glia to cling to and make up approximately 20% of 64043-42-1 manufacture the brain. The balance in endogenous tissue inhibitors of MMP activity sustain or break down existing cell adhesion molecules, permitting the reconfiguration of synaptic connections. Gene expression recognized hippocampal transcripts involved in angiogenesis, cell adhesion, synaptic formation and cell communication that were regulated by cocaine 64043-42-1 manufacture exposure. Regional gene expression results 64043-42-1 manufacture shown here provide evidence for active transcripts that function to remodel the hippocampal extracellular matrix in human cocaine addiction. Results Brain tissues were taken from autopsy cases according to criteria described by the National Association of Medical Examiners (NAME) Committee on Cocaine-related Deaths for documenting, interpreting and certifying potential cocaine-related fatalities [12], [13]. The investigation of any 64043-42-1 manufacture drug-related death requires knowledge of the circumstances of death, the death scene, and past medical history. It is also necessary to have the results of the forensic toxicologic analysis and those of a forensic autopsy examination prior to classifying that a cause and manner of death is usually associated with acute cocaine exposure or chronic cocaine use that leads ultimately to a fatal pathologic process. The cocaine users experienced.

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