Amphetamine sensitization alters hippocampal neuronal morphology and memory and learning behaviors


It is known that continuous abuse of amphetamine (AMPH) results in alterations in neuronal structure and cognitive behaviors related to the reward system. However, the impact of AMPH abuse on the hippocampus remains unknown. The aim of this study was to determine the damage caused by AMPH in the hippocampus in an addiction model. We reproduced the AMPH sensitization model proposed by Robinson et al. in 1997 and performed the novel object recognition test (NORt) to evaluate learning and memory behaviors. After the NORt, we performed Golgi–Cox staining, a stereological cell count, immunohistochemistry to determine the presence of GFAP, CASP3, and MT-III, and evaluated oxidative stress in the hippocampus. We found that AMPH treatment generates impairment in short- and long-term memories and a decrease in neuronal density in the CA1 region of the hippocampus. The morphological test showed an increase in the total dendritic length, but a decrease in the number of mature spines in the CA1 region. GFAP labeling increased in the CA1 region and MT-III increased in the CA1 and CA3 regions. Finally, we found a decrease in Zn concentration in the hippocampus after AMPH treatment. An increase in the dopaminergic tone caused by AMPH sensitization generates oxidative stress, neuronal death, and morphological changes in the hippocampus that affect cognitive behaviors like short- and long-term memories.

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Fig. 1: Experimental design and NORt.
Fig. 2: Neuronal density after 35 days of chronic amphetamine (AMPH) administration.
Fig. 3: Amphetamine (AMPH) sensitization reorganizes the dendritic arbor as well as the dendritic spine dynamics in the pyramidal neurons of the hippocampus.
Fig. 4: Oxidative response in the hippocampus because of the amphetamine (AMPH) sensitization.
Fig. 5: Inflammatory response after amphetamine (AMPH) sensitization.


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LEA-G and HT-B acknowledge CONACYT for the fellowship. EB, PA-A, AD, RAV-R, FDLC, EM, and GF acknowledge the “Sistema Nacional de Investigadores” of Mexico for memberships. Thanks to Miguel Tapia-Rodríguez (Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México) for stereological procedures assistance and to Professor Robert Simpson for editing the English language text.


Funding for this study was provided by grants from the PRODEP (CA-BUAP-120) and the CONACYT grant (No. 252808) to GF and MINECO/FEDER (BFU2012-38208) and the Junta de Andalucía (P11-CVI-7290) to AR-M. None of the funding institutions had any further role in the study design, the collection or interpretation of data, analyses, the writing of the report or the decision to submit the paper for publication.

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LEA-G, HT-B, AR-M, RAV-R, FDLC, and GF designed the study and wrote the protocol. LEA-G, HT-B, EEJT, AD, PA-A, EB, and EM performed the experiments. LEA-G, AR-M, and GF performed the literature searches and analysis and LEA-G and GF undertook the statistical analysis. LEA-G, AR-M, and GF wrote the first draft of the manuscript. All contributing authors have approved the final manuscript.

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Correspondence to Gonzalo Flores.

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Arroyo-García, L.E., Tendilla-Beltrán, H., Vázquez-Roque, R.A. et al. Amphetamine sensitization alters hippocampal neuronal morphology and memory and learning behaviors. Mol Psychiatry (2020).

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