Inhibition of hippocampal plasticity in rats performing contrafreeloading for water under repeated administrations of pramipexole
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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.
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.
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.
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.
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.
KeywordsPramipexole Contrafreeloading Obsessive-compulsive disorder Hippocampus D3 receptor
Compliance with ethical standards
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.
- D’Angelo C, Eagle DM, Grant JE, Fineberg NA, Robbins TW, Chamberlain SR (2013) Animal models of obsessive-compulsive spectrum disorders. CNS Spectr 19(1):28–49Google Scholar
- Davidson TL, Jarrard LE (2004) The hippocampus and inhibitory learning: a 'Gray' area? Neurosci Biobehav Rev 28(3):261–271Google Scholar
- Gray JA, McNaughton M (2000) The neuropsychology of anxiet: an enquiry into the functions of the septo-hippocampal system, 2nd edn. Oxford University Press, OxfordGoogle Scholar
- Lisman JE, Grace AA (2005) The hippocampal-VTA loop: controlling the entry of information into long-term memory. Neuron 46(5):703–713Google Scholar
- Radomsky AS, Gilchrist PT, Dussault D (2006) Repeated checking really does cause memory distrust. Behav Res Ther 44(2):305–316Google Scholar
- Raiteri L, Raiteri M (2000) Synaptosomes still viable after 25 years of superfusion. Neurochem Res 25(9–10):1265–1274Google Scholar
- Watson DJ, Loiseau F, Ingallinesi M, Millan MJ, Marsden CA, Fone KC (2012) Selective blockade of dopamine D3 receptors enhances while D2 receptor antagonism impairs social novelty discrimination and novel object recognition in rats: a key role for the prefrontal cortex. Neuropsychopharmacology 37(3):770–786PubMedCentralCrossRefPubMedGoogle Scholar
- Zamanillo D, Sprengel R, Hvalby O, Jensen V, Burnashev N, Rozov A, Kaiser KM, Köster HJ, Borchardt T, Worley P, Lübke J, Frotscher M, Kelly PH, Sommer B, Andersen P, Seeburg PH, Sakmann B (1999) Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning. Science 284(5421):1805–1811CrossRefPubMedGoogle Scholar