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Inhibition of hippocampal plasticity in rats performing contrafreeloading for water under repeated administrations of pramipexole

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Abstract

Rationale

Compulsive symptoms develop in patients exposed to pramipexole (PPX), a dopaminergic agonist with high selectivity for the D3 receptor. Consistently, we demonstrated that PPX produces an exaggerated increase in contrafreeloading (CFL) for water, a repetitive and highly inflexible behavior that models core aspects of compulsive disorders.

Objectives

Given the role of the hippocampus in behavioral flexibility, motivational control, and visuospatial working memory, we investigated the role of hippocampus in the expression of PPX-induced CFL. To this aim, rats were subjected to CFL under chronic PPX, and then examined for the electrophysiological, structural, and molecular properties of their hippocampus.

Methods

We measured long-term potentiation (LTP) at CA1 Schaffer collaterals, dendritic spine density in CA1 pyramidal neurons, and then glutamate release and expression of pre and postsynaptic proteins in hippocampal synaptosomes. The effects of PPX on hippocampal-dependent working memory were assessed through the novel object recognition (NOR) test.

Results

We found that PPX-treated rats showing CFL exhibited a significant decrease in hippocampal LTP and failed to exhibit the expected increase in hippocampal spine density. Glutamate release and PSD-95 expression were decreased, while pSYN expression was increased in hippocampal synaptosomes of PPX-treated rats showing CFL. Despite a general impairment of hippocampal synaptic function, working memory was unaffected by PPX treatment.

Conclusions

Our findings demonstrate that chronic PPX affects synaptic function in the hippocampus, an area that is critically involved in the expression of flexible, goal-centered behaviors. We suggest that the hippocampus is a promising target in the pharmacotherapy of compulsive disorders.

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, Sapienza University, Piazzale Aldo Moro 5, 00185, Rome, Italy

    Chiara Schepisi, Salvatore Simone Doronzio, Robert Nisticò & Paolo Nencini

  2. IRCCS Santa Lucia, Rome, Italy

    Annabella Pignataro, Nicola Biagio Mercuri & Martine Ammassari-Teule

  3. European Brain Research Institute, Rome, Italy

    Sonia Piccinin, Caterina Ferraina, Marco Feligioni & Robert Nisticò

  4. Department of Pharmacy, Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy

    Silvia Di Prisco & Anna Pittaluga

  5. Institute of Cell Biology and Neurobiology, National Research Council, Rome, Italy

    Martine Ammassari-Teule

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  1. Chiara Schepisi
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  2. Annabella Pignataro
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Correspondence to Chiara Schepisi.

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Funding and disclosures

This study was funded by intramural grants from Sapienza University. The authors report no biomedical financial interests or potential conflicts of interest.

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Supplementary Materials and Methods

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Figure S1

Chronic systemic treatment with PPX decreases the fraction of water consumed over water gained during the session. Bars represent the average of the: (a) Operant phase . b) Choice phase. Data are expressed as mean ± SEM. *=p<.05 PPX vs VEH. (DOC 165 kb)

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Schepisi, C., Pignataro, A., Doronzio, S.S. et al. Inhibition of hippocampal plasticity in rats performing contrafreeloading for water under repeated administrations of pramipexole. Psychopharmacology 233, 727–737 (2016). https://doi.org/10.1007/s00213-015-4150-4

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  • DOI: https://doi.org/10.1007/s00213-015-4150-4

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