Nrf2 deletion gene does not sensitize mice to acute and repeated cocaine

A.M. PACCHIONI,; J. VALLONE,; R.I. MELENDEZ,; A. SHIH,; T.H. MURPHY,; P.W. KALIVAS.

Washington DC, USA

Congreso; 35th Annual Meeting of Neurosciences; 2005

Society for Neuroscience

<!-- /* Font Definitions */ @font-face {font-family:"Cambria Math"; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:roman; mso-font-pitch:variable; mso-font-signature:-1610611985 1107304683 0 0 159 0;} @font-face {font-family:Times; panose-1:2 2 6 3 5 4 5 2 3 4; mso-font-charset:0; mso-generic-font-family:auto; mso-font-pitch:variable; mso-font-signature:50331648 0 0 0 1 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; mso-bidi-font-size:10.0pt; font-family:Times; mso-fareast-font-family:Times; mso-hansi-font-family:Times; mso-bidi-font-family:"Times New Roman";} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-size:10.0pt; mso-ansi-font-size:10.0pt; mso-bidi-font-size:10.0pt; mso-ascii-font-family:Times; mso-fareast-font-family:Times; mso-hansi-font-family:Times;} @page Section1 {size:8.5in 11.0in; margin:1.0in 1.0in 1.0in 1.0in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.Section1 {page:Section1;} --> Repeated cocaine treatment produces persistent neuroadaptations in the concentration of extracellular glutamate in the nucleus accumbens, including a reduction in basal extracellular levels of glutamate and an increased extracellular glutamate response to cocaine. Both changes are associated with a reduced affinity and/or synthesis of the cystine/glutamate exchanger (xCT). xCT transcription is regulated by Nrf2 (transcription factor NF-E2-related factor) binding to an antioxidant response element (ARE). The deletion of Nrf2 gene will decrease transcriptional regulation of xCT expression which was hypothesized to produce a behavioral and neurochemical phenotype similar to that produced by chronic cocaine administration. Therefore, we compared cocaine effects in mice with a homozygous deletion of the Nrf2 gene (Nrf2 KO) to their respective wild type (Nrf2 WT) littermates. The cocaine injections (10 mg/kg IP) were given during a conditioning place preference (CPP) paradigm where locomotor activity was simultaneously measured. We employed both female and male mice, and, regarding place conditioning, gender differences were found. While both female Nrf2 KO and WT displayed place conditioning, only the Nrf2 KO male showed CPP. The Nrf2 KO mice also showed a higher locomotor response to an acute cocaine injection compared with Nfr2 WT. However, after repeated injection of cocaine all genotypes developed locomotor sensitization. These data indicate that modulation of xCT expression by Nrf2 can regulate the behavioral effects of acute and repeated  cocaine.  Nota: los resultados finales fueron diferentes de los preliminares (descriptos en el resumen) por lo cual tuvimos que cambiar el titulo.