Neurobiology of cocaine's addiction | Neurobiología de la cocaína

Abstract

Objective. Cocaine is an indirect dopaminergic agonists that blocks the dopamine transporter, DAT, increasing dopamine concentration in the synapse. Cocaine produces its psychoactive and addictive effects by acting on the brain's limbic system, composed of the dopaminergic neurons of the ventral tegmental area (VTA) that projects to the NAc, ventral striatum and the prefrontal cortex. We have studied the short and long term molecular changes of cocaine and the phenotype of striatal and N. Accumbens neurons that are activated by cocaine. dopamine receptor subtype in the effects of cocaine. Material and methods. We have used inmunocytochemistry to study the pattern of gene expression in the dorsal and ventral striatum induced by acute and chronic cocaine. To determine the molecular phenotype of the neurons that are activated by cocaine we have used a double in situ hybridization combining a riboprobe for c-Fos with riboprobes for selective markers of each striatal neuronal types. Finally we have use dopamine D1 receptor knock out mice to determine the role of D1 receptors in the behavioural and molecular responses to cocaine. Results. We found that cocaine dose-dependently activates cAMP-dependent gene expression in the striatum and in the nucleus accumbens and phosphorylates CREB and ERK. The genes that are activated included c-fos, fos B, jun B, NGFI-A, NGFI-B, NFkB, Akt and Cdk5, etc. These genes are called immediate early genes because its activation is rapid and does not need protein synthesis. The pattern of gene expression changes from acute to chronic cocaine, while acute cocaine induce DFos B homogeneously in the striatum, chronic cocaine primarily activates the striosomes. We also found that cocaine activates the striatal direct pathway neurons (striatonigral) neurons whose specific marker is the neuropeptide dynorphine and specifically expressed the dopamine D1 receptors. Finally, we found that inactivation of D1 receptors blocks cocaine-induced locomotor activity and cocaine-induced gene expression in the striatum and nucleus accumbens. Conclusions. Our results emphasize a principal role of D1 receptors in the responses to cocaine. Cocaine induced cAMP-dependent genes expression, inducing c-fos, fos B, jun B, NGFI-A etc in the striatum and specifically activates the striatal direct pathway neurons. Inactivation of D1 receptors blocks cocaine's behavioural and molecular responses.