INTERLEUKIN-1b (IL-1b) IMPAIRS MEMORY RECONSOLIDATION AND a-MELANOCYTE-STIMULATING HORMONE (a-MSH) INHIBITS THIS EFFECT
Machado Ia, Patricia Gonzáleza, Mercedes Lasagab ; Teresa Nieves Scimonellia#.
a IFEC CONICET Departamento Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba.Ciudad Universitaria, Córdoba, Argentina. b Centro de Investigaciones en Reproducción. Facultad de Medicina. UBA. Buenos Aires, Argentina,
Introduction
The effects of cytokines on cognitive processes have been extensively studied. Particularly, IL-1b significantly influences consolidation and persistence of memories that depend on hippocampus (1). However, the impact of IL-1b on memory reconsolidation, an important memory process, has not been yet established.
A variety of effects of central IL-1b administration are blocked by the melanocortin a-MSH. Five subtypes of melanocortin receptors (MC1R-MC5R) have been identified, being the MC3R and MC4R predominant in the central nervous system (2).
Therefore, in the present work we studied the effect of IL-1b on the reconsolidation of a contextual fear memory. We also examined the influence of a-MSH and the role of MC4 receptors on the IL-1b effects on memory reconsolidation.
Materials and methods
Adult male Wistar rats, maintained on controlled conditions, were implanted bilaterally in hippocampus under ketamine -xylazine anesthesia.
Each experiment consisted of three phases: conditioning, reactivation session and testing sessions. Training consisted in placing the rat in a chamber with a grid floor attached to a scrambled shocker to provide footshock. Rats were allowed a 3 min acclimation period. After this period, rats received three unsignaled footshocks (0.3mA; 2.5 s). Animals remained in the chamber for additional 2 min and immediately after they were placed in their home cages. Reactivation session: 24hs after training, rats were reexposed to the training context without shocks during 2 min. Test session: Contextual fear conditioning was assessed 24 h after training, by placing the rats in the training environment for a period of 5 min. Memory was assessed and expressed as the percentage of time that rats spent freezing. Different treatments (vehicle, rrIL-1b (R&D Systems), a-MSH (Peninsula Laboratories ) and HS024 (selective MC4-R antagonist (NeoMPS) were administered after reactivation.
Results
We demonstrated that the injection of IL-1b (5ng/0,25ul) in dorsal hippocampus after reexposition to the context decreases freezing during the contextual fear test .
The treatment with a-MSH (0,05ug/0,25ul) blocked this effect. Administration of the MC4 receptor antagonist HS014 (0.5ug/0,25ul) reverses the effect of a-MSH. The injection of a-MSH administered alone did not produce any significant effect on the reconsolidation of the fear memory.
Conclusions
We determined that IL-1b has a detrimental effect on the reconsolidation of contextual memory, and also that a-MSH, through the activation of MC4-R, could reverse the effect of IL-1b on the reconsolidation of fear memory.
Our results are in agreement with the fact that melanocortins have potent neuroprotective effects. Besides, it is important to determine the specific melanocortin receptors that are involved in the effects of a-MSH. The importance of this is exposed by the fact that the pharmaceutical industry is investing great efforts in the search for agonists and antagonist of these receptors.
Acknowledgments
This work was supported by grants from FONCYT, CONICET and SeCYT
References.
(1) Gonzalez PV, Schiöth HB, Lasaga M, Scimonelli TN. Memory impairment induced by IL-1beta is reversed by a-MSH through central melanocortin-4 receptors. Brain Behav Immun. 2009; 23(6):817-22.
(2) Bertolini A, Tacchi R, Vergoni A. Brain effects of melanocortins. Pharmacol. Res. 2009,59:13-47
