Abstract
Several studies have reported a role for the nucleus accumbens (NAcc) in learning and memory. Specifically, NAcc seems to function as a neural bridge for the translation of corticolimbic information to the motor system mediating locomotor learning, but the signaling mechanisms involved in this striatal learning await further investigation. The present experiments investigated the role of the mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) cascades within the NAcc of Long-Evans rats in a food-search spatial learning task (FSSLT). First, we used immunoblotting to examine changes in MAPK p42/p44 phosphorylation within the NAcc in the acquisition phase of the FSSLT. Second, we examined the effect on the acquisition and retention phases in the FSSLT of pretraining intra-accumbal microinjections of the MAPK [U0126; 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophynyltio)butadiene, 1 μg/side] or PKC [GF109203X; bisindolylmaleimide or 1-(3-dimethylaminopropyl)-indol-3-yl]-3-(indol-3-yl) maleimide, 0.5 ng/side] inhibitors (four training sessions; one session/day). Third, the potential coupling of PKC and MAPK signaling pathways in the NAcc in spatial learning was studied using microinjections of GF109203X, radioactive activity assays, and immunoblotting. Results showed that 1) MAPK p42/p44 phosphorylation is augmented within the NAcc after spatial learning, 2) MAPK and PKC inhibition caused differential deficits in the acquisition and formation of spatial memories, and 3) inhibition of PKC activity by GF109203X caused a reduction in MAPKs phosphorylation in the NAcc in an early stage of the acquisition phase. Overall, these findings suggest that NAcc-PKC and -MAPK play important roles in spatial learning and that MAPKs phosphorylation seems to be mediated through the activation of the PKC signaling pathway.
Footnotes
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This work was supported by Centers of Biomedical Research Excellence/National Center for Research Resources/National Institutes of Health Grants P20 RR15565 02 (Center for Molecular, Developmental, and Behavioral Neuroscience), Minority Biomedical Research Support/Support for Continuous Research Excellence/National Institutes of Health 1 GM5s06GM08103, and Research Initiative for Scientific Enhancement R25 GM6-1151-01 (to L.A.J. and M.F.R.).
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doi:10.1124/jpet.105.086140.
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ABBREVIATIONS: NAcc, nucleus accumbens; LTP, long-term potentiation; MAPK, mitogen-activated protein kinase; PKC, protein kinase C; FSSLT, food search spatial learning task; GF109203X, bisindolylmaleimide or [1-(3-dimethylaminopropyl)-indol-3-yl]-3-(indol-3-yl) maleimide; DMSO, dimethyl sulfoxide; U0126, 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophynyltio)butadiene; MAPKK, mitogen-activated protein kinase kinase; PBS, phosphate-buffered saline; P-MAPK, phosphorylated mitogen-activated protein kinase; T-MAPK, total mitogen-activated protein kinase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; OD, optical density; ANOVA, analysis of variance; RM ANOVA, repeated measures analysis of variance.
- Received March 10, 2005.
- Accepted May 10, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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