Influence of the dopaminergic system, CREB, and transcription factor-κB on cocaine neurotoxicity

C.S Planeta,C Scavone,L.B Lepsch,R Alves

doi:10.1590/1414-431x20133379

Abstract

Cocaine is a widely used drug and its abuse is associated with physical, psychiatric and social problems. Abnormalities in newborns have been demonstrated to be due to the toxic effects of cocaine during fetal development. The mechanism by which cocaine causes neurological damage is complex and involves interactions of the drug with several neurotransmitter systems, such as the increase of extracellular levels of dopamine and free radicals, and modulation of transcription factors. The aim of this review was to evaluate the importance of the dopaminergic system and the participation of inflammatory signaling in cocaine neurotoxicity. Our study showed that cocaine activates the transcription factors NF-κB and CREB, which regulate genes involved in cellular death. GBR 12909 (an inhibitor of dopamine reuptake), lidocaine (a local anesthetic), and dopamine did not activate NF-κB in the same way as cocaine. However, the attenuation of NF-κB activity after the pretreatment of the cells with SCH 23390, a D1 receptor antagonist, suggests that the activation of NF-κB by cocaine is, at least partially, due to activation of D1 receptors. NF-κB seems to have a protective role in these cells because its inhibition increased cellular death caused by cocaine. The increase in BDNF (brain-derived neurotrophic factor) mRNA can also be related to the protective role of both CREB and NF-κB transcription factors. An understanding of the mechanisms by which cocaine induces cell death in the brain will contribute to the development of new therapies for drug abusers, which can help to slow down the progress of degenerative processes.

Highlights

Drug abuse and addiction constitute a public health problem of great importance: both affect many people and cause a wide variety of consequences to society
This system originates in the ventral tegmental area (VTA) and projects mainly to the nucleus accumbens (NAc) and prefrontal cortex (PFC)
The results showed that concentrations of cocaine comparable to the concentration that has been reported in plasma levels (0.3 mM to 1 mM) of subjects who use this drug [60,68] can induce changes in transcription factors that are important to the inflammatory response and innate immune response [69] and to cell death and the cell protection response

Summary

Introduction

Drug abuse and addiction constitute a public health problem of great importance: both affect many people and cause a wide variety of consequences to society. Activation of dopamine transmission in the mesocorticolimbic system is a common characteristic of all addictive drugs. This system originates in the ventral tegmental area (VTA) and projects mainly to the nucleus accumbens (NAc) and prefrontal cortex (PFC). Addiction is a chronic relapsing disease [3] and its treatment is the most expensive of the neuropsychiatric disorders [4], mainly owing to the costs of health care, productivity loss, and crime (UNODC, 2011)

Cocaine Toxicity

Cell Death and Cocaine