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

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, goalcentered behaviors. We suggest that the hippocampus is a promising target in the pharmacotherapy of compulsive disorders.

[18F]-FDG PET neuroimaging in rats with quinpirole-induced checking behavior as a model for obsessive compulsive disorder

“…More recently, preclinical results have revealed that lesions in the hippocampal regions can cause a perseveration of certain behaviors (Kosaki and Watanabe, 2012;Chudasama et al 2012). Also in another model for compulsive behavior, characterized by the contrafreeloading of water that is induced by pramipexole (D3-agonist), a significant decrease in hippocampal long-term potentiation (LTP) was found (Schepisi et al 2015) Additionally, lower ratios of N-acetyl-l-aspartate/choline (NAA/CHO) were found in OCD patients when compared to healthy controls (Atmaca et al 2009) in the hippocampus.…”

Pigeons consistently prefer easy over harder access to food: No reversal after direct dopaminergic stimulation.

“…However, some information can reasonably be deduced from current data. In rodents, PPX results in an increase in foraging activity on the harder food option (e.g., Johnson et al, 2011, 2012; Schepisi et al, 2013, 2016). Effort facilitation is compatible with the view that dopamine agonists enhance incentive motivational processes (Salamone & Correa, 2002).…”

“…Neurobiological investigations show that striatal dopamine is involved in suboptimal choices. In rats, contrafreeloading is enhanced after repeated injection of pramipexole (PPX)—a dopamine D2/3 receptor agonist (Schepisi, De Carolis, & Nencini, 2013; Schepisi et al, 2016). Also, rats given a choice between a variable ratio and a fixed ratio of responses to levers have a natural preference for variability, and this preference is increased after receiving an acute injection of PPX (Johnson et al, 2011, 2012).…”

Domestic pet dogs (Canis lupus familiaris) do not show a preference to contrafreeload, but are willing

“…Contrafreeloading is the behavior of working for a resource that requires effort to obtain when also provided with a similar resource that is freely available 1 – 3 . Historically, this resource has been food, although contrafreeloading for water and other resources has also been studied [e.g., 4 ]. The presence of contrafreeloading behavior is particularly interesting given that it seems to oppose a basic tenet of animal learning and evolutionary theory, as well as optimal foraging theory 1 —that animals should maximize rewards and minimize costs 5 , 6 .…”