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

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.

The Involvement of Secondary Neuronal Damage in the Development of Neuropsychiatric Disorders Following Brain Insults

“…This abnormally long presence and high concentration of neurotransmitters in the synapse will lead to brain dysfunction and damage in the particular parts of the brain such as the basal ganglia and the limbic system, thus causing psychiatric and behavioral problems including memory and cognitive deficits, dysphoria, depression, insomnia or hypersomnia, psychomotor retardation or agitation, elevated mood, supremacy feeling, irritability, paranoia, restlessness, anxiety, dilated pupils, excited and exuberant speech, etc. ( 45 – 47 ). Methamphetamine is a neurotoxin and potent psychostimulant of the phenethylamine and amphetamine classes.…”

Cannabidiol, a Cannabis sativa constituent, inhibits cocaine-induced seizures in mice: Possible role of the mTOR pathway and reduction in glutamate release

“…Cocaine intoxication in mice induces robust tonic-clonic seizures, which can be useful for understanding the neurobiological mechanisms as well as for developing new treatments. Although the mechanism is not fully elucidated, cocaine neurotoxicity seems to involve interactions with several neurotransmitters, including gamma-aminobutiric acid (GABA)-ergic, glutamatergic and serotoninergic systems, as well as certain intracellular signalling pathways (Lason, 2001;Planeta et al, 2013).…”

Single Low Dose of Cocaine–Structural Brain Injury Without Metabolic and Behavioral Changes

“…This drug inhibits the reuptake of monoamine neurotransmitters, including dopamine (DA) and noradrenaline (NA). The DA increase occurs in the mesocorticolimbic system (the brain reward system), which is responsible for the well-being sensation and euphoria, thus playing a major role in the addiction process (Planeta et al, 2013 ). DA auto-oxidation can lead to oxidative stress and apoptosis (Dias et al, 2008 ; Planeta et al, 2013 ).…”

“…The DA increase occurs in the mesocorticolimbic system (the brain reward system), which is responsible for the well-being sensation and euphoria, thus playing a major role in the addiction process (Planeta et al, 2013 ). DA auto-oxidation can lead to oxidative stress and apoptosis (Dias et al, 2008 ; Planeta et al, 2013 ). There is evidence that oxidative stress contributes to cocaine neurotoxicity (Dietrich et al, 2005 ; Pereira et al, 2015 ).…”