Comunicación

RETRIEVAL OF THE AVERSIVE MEMORY TO EMOTIONAL WITHDRAWAL-SYNDROME TO OPIATES INCREASES THE EXPRESSION OF ARC PROTEIN IN THE BASOLATERAL AMYGDALA AND DENTATE GYRUS.

Autores:

Aurelio Franco García1, Victoria Gómez Murcia1, FRANCISCO JOSÉ FERNÁNDEZ GÓMEZ1, Juana María Hidalgo Céspedes1, M. VICTORIA MILANÉS MAQUILÓN1, María Cristina Núñez Parra1

Afiliaciones:

(1) FARMACOLOGÍA CELULAR Y MOLECULAR, IMIB-Arrixaca, España

Comunicación:

Antecedentes:

Opioid epidemic is a serious problem in the western world. Avoiding relapse is a major challenge in the treatment of addiction, which is characterized by alterations in learning processes in which the environment is associated with the drugs’ positive (reward) and negative (withdrawal) effects. The emotional aversive state to the environment is a major challenge to tackle and contributes, in part, to addicts’ relapse. One of the most common therapeutical approaches is extinction therapy, in which addicts are exposed to the environmental cues previously associated to the drug effects to develop a better responsive outcome by means of a new associative learning. Memory formation relies on new protein synthesis in the nuclei involved in this process, such as the basolateral amygdala (BLA) and the dentate gyrus (DG). This synthesis is partially facilitated by mTORC1 modulation, which regulates the expression levels of several immediate early genes, such as Arc, Grin1 and Homer1. A number of studies have proposed that these genes take part in the generation and retrieval of aversive memories related to opiate physical and emotional withdrawal. However, their role during the emotional aversive state, without physical symptoms, or during the extinction memory formation has not been elucidated yet.

Métodos:

Morphine dependence was induced to Wistar male rats through s.c. pellet implantation. Withdrawal syndrome was precipitated with a low dose of naloxone (15 ug/kg) to reduce physical symptoms of withdrawal. Animals were subjected to a conditioned place aversion paradigm (CPA) to morphine withdrawal and later to a CPA extinction protocol. After CPA and extinction tests rats were perfused intracardially and brains were processed for immunofluorescence analysis. Data are expressed as the mean ± S.E.M and analyzed through two-way ANOVA followed by Bonferroni’s post-hoc test or Student’s t test. P values < 0.05 were considered significant.

Resultados:

Morphine dependent animals spent significantly less time in the opiate withdrawal-associated compartment during the CPA test when compared with control animals. However, morphine-treated rats stayed significantly more time in this chamber in the extinction test than that during the CPA test. We found a significant increase in Arc-immunoreactivity (IR) levels in BLA and DG after the retrieval of aversive memories to withdrawal syndrome. Nonetheless, no changes were observed after the extinction test. We also found a statistically significant increase in Grin1-IR in DG after CPA test, but not after the extinction test.

Conclusiones:

Our results show that morphine treated rats extinguished morphine withdrawal-induced CPA following repeated exposures to the naloxone-paired compartment, which agree with previous evidences showing a decrease in CPA. The increase in Arc in DG and BLA observed after CPA, together with with recent findings revealing enhanced Arc levels in BLA after several morphine withdrawal conditioning sessions, point out an important role of synaptic protein synthesis in aversive memory processing, mostly through BDNF and mTORC1 signaling pathways, in nuclei related to emotional and declarative memory. On the other hand, the increase in Grin1 in DG but not in BLA after the aversive memory retrieval suggest a main role of glutamate signaling in this process particularly in this nucleus. Funding: FSÉneca (20847/PI/18; 21133/SF/19); MINECO (SAF2017-85679-R; PID2020-113557RB-I00); MICINN (FPU/01722).


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Campus de Ciencias de la Salud
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Murcia, España

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