title: Inhibition of hippocampal plasticity in rats performing contrafreeloading for water under repeated administrations of pramipexole.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University, Piazzale Aldo Moro 5, 00185, Rome, Italy. chiara.schepisi@gmail.com.
authors.forename: Chiara
authors.initials: C
authors.lastname: Schepisi
authors.affiliation: IRCCS Santa Lucia, Rome, Italy.
authors.forename: Annabella
authors.initials: A
authors.lastname: Pignataro
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University, Piazzale Aldo Moro 5, 00185, Rome, Italy.
authors.forename: Salvatore Simone
authors.initials: SS
authors.lastname: Doronzio
authors.affiliation: European Brain Research Institute, Rome, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Piccinin
authors.affiliation: European Brain Research Institute, Rome, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Ferraina
authors.affiliation: Department of Pharmacy, Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Di Prisco
authors.affiliation: European Brain Research Institute, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Feligioni
authors.affiliation: Department of Pharmacy, Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Pittaluga
authors.affiliation: IRCCS Santa Lucia, Rome, Italy.
authors.forename: Nicola Biagio
authors.initials: NB
authors.lastname: Mercuri
authors.affiliation: IRCCS Santa Lucia, Rome, Italy.|Institute of Cell Biology and Neurobiology, National Research Council, Rome, Italy.
authors.forename: Martine
authors.initials: M
authors.lastname: Ammassari-Teule
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University, Piazzale Aldo Moro 5, 00185, Rome, Italy.|European Brain Research Institute, Rome, Italy.
authors.forename: Robert
authors.initials: R
authors.lastname: Nisticò
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University, Piazzale Aldo Moro 5, 00185, Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Nencini
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000008:administration & dosage*; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism; D018491:Dopamine Agonists / Q000008:administration & dosage*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D000077487:Pramipexole; D017966:Pyramidal Cells / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014867:Water / Q000008:administration & dosage*
chemical_list: D052160:Benzothiazoles; D018491:Dopamine Agonists; D014867:Water; D000077487:Pramipexole
keywords: Contrafreeloading; D3 receptor; Hippocampus; Obsessive-compulsive disorder; Pramipexole