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Role of D1, NMDA receptors and DARPP-32 protein of nucleus accumbens in the expression of behavioral sensitization to ethanol

Grant number: 08/01819-5
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): July 01, 2008
Effective date (End): March 31, 2012
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Maria Lucia Oliveira de Souza Formigoni
Grantee:Karina Possa Abrahão
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Behavioral sensitization to the stimulant effect of ethanol is characterized by an increased locomotor activity observed after repeated exposure to that drug. However, there is a great variability in its development among different species and even among animals from the same strain. This variability is related to differences in dopaminergic and glutamatergic receptors, mainly in the nucleus accumbens. Intracellular biochemical pathways appear to critically contribute to long-term changes in the level of synaptic activation of the medium spiny neurons of nucleus accumbens. These alterations have been implicated in ethanol dependence and in the effects of ethanol on locomotor activity. The medium spiny neurons have an intracellular phosphoprotein that is regulated by a prior activated of D1-signaling cascade through the cAMP-PKA phosphorilation: DARPP-32. When activated, DARPP-32 protein gets an indirect potent activator of NMDA phosphorilation, decreasing its sensibility to the inhibition caused by ethanol. In the present project, we intend to evaluate the influence of the variability in the development of ethanol behavioral sensitization on the activity of dopaminergic D1 receptors, glutamatergic NMDA receptors and the phosphorilation of DARPP-32 protein of the nucleus accumbens. Swiss Albinos male mice will receive repeated administration of ethanol (2.2 g/kg) or saline, every other day, during 10 days. According to their locomotor response in the last day of treatment, ethanol-pretreated animals will be classified into two groups: sensitized mice or non-sensitized mice. After that, animals will be submitted to the surgery procedure to implanted bilateral cannula on nucleus accumbens. The goal of the first part of this work is to evaluate the role of D1 and NMDA receptors in the expression of behavioral sensitization to ethanol. The animals will receive D1 or NMDA receptors agonists intra-accumbens and, after 48 hours, they will receive D1 or NMDA receptors antagonists. Considering that there is a modulation between D1 and NMDA receptors, in the second part of challenges, the animals will received first a D1 or NMDA antagonists (to isolated the role of each receptor on expression of behavioral sensitization) followed by the NMDA or D1 agonists or antagonists, respectively. In every test days the animals will be tested in the locomotor activity cages. Besides, we intend to evaluate the DARPP-32 phosphorilation state, central protein in D1/PKA/NMDA regulation, among ethanol sensitized, non-sensitized and saline groups by immunohistochemistry and western-blotting techniques. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
ABRAHAO, KARINA POSSA; GOELDNER, FRANCINE OLIVEIRA; OLIVEIRA SOUZA-FORMIGONI, MARIA LUCIA. Individual Differences in Ethanol Locomotor Sensitization Are Associated with Dopamine D1 Receptor Intra-Cellular Signaling of DARPP-32 in the Nucleus Accumbens. PLoS One, v. 9, n. 6 JUN 11 2014. Web of Science Citations: 6.
ABRAHAO, KARINA POSSA; ARIWODOLA, OLUSEGUN J.; BUTLER, TRACY R.; RAU, ANDREW R.; SKELLY, MARY JANE; CARTER, EUGENIA; ALEXANDER, NANCY P.; MCCOOL, BRIAN A.; SOUZA-FORMIGONI, MARIA LUCIA O.; WEINER, JEFFREY L. Locomotor Sensitization to Ethanol Impairs NMDA Receptor-Dependent Synaptic Plasticity in the Nucleus Accumbens and Increases Ethanol Self-Administration. JOURNAL OF NEUROSCIENCE, v. 33, n. 11, p. 4834-4842, MAR 13 2013. Web of Science Citations: 48.
ABRAHAO, KARINA POSSA; OLIVEIRA SOUZA-FORMIGONI, MARIA LUCIA. Behavioral sensitization to ethanol results in cross-sensitization to MK-801 but not to NMDA administered intra-accumbens. Behavioural Brain Research, v. 235, n. 2, p. 218-224, DEC 1 2012. Web of Science Citations: 10.

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