Role of Wnt/β-catenin pathway in the Nucleus Accumbens in long-term cocaine-induced neuroplasticity: a possible novel target for addiction treatment.

CUESTA, SANTIAGO; BATUECAS, JORGELINA A.; SEVERIN, MA. JULIA; FUNES, ALEJANDRINA; ROSSO, SILVANA B; PACCHIONI, ALEJANDRA M

JOURNAL OF NEUROCHEMISTRY

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2017 vol. 140 p. 114 - 125

0022-3042

Cocaine addiction is a chronic relapsing disorder characterized by the loss of control over drug-seeking and taking, and continued drug use regardless of adverse consequences. Despite years of research, effective treatments for psychostimulant addiction have not been identified. Persistent vulnerability to relapse arises from a number of long lasting adaptations in the reward circuitry that mediate the enduring response to the drug. Recently, we reported that the activity of the canonical or Wnt/β-catenin pathway in the Prefrontal Cortex (PFC) is very important in the early stages of cocaine-induced neuroadaptations. In the present work, our main goal was to elucidate the relevance of this pathway in cocaine-induced long-term neuroadaptations that may underlie relapse. We found that a cocaine challenge, after a period of abstinence, induced an increase in the activity of the pathway which is revealed as an increase in the total and nuclear levels of β-catenin (final effector of the pathway) in the Nucleus Accumbens (NAcc), together with a decrease in the activity of Glycogen synthase kinase 3β (GSK3β). Moreover, we found that the pharmacological modulation of the activity of the pathway has long-term effects on the cocaine-induced neuroplasticity at behavioral and molecular levels. All the results imply that changes in the Wnt/β-catenin pathway effectors are long-term neuroadaptations necessary for the behavioral response to cocaine. Even though more research is needed, the present results introduce the Wnt canonical pathway as a possible target to manage cocaine long-term neuroadaptations.