Abstract
Inhibition of phosphodiesterase type 4 (PDE4) by rolipram (4-(3-(cyclopentyloxy)-4-methoxyphenyl)-pyrrolidin-2-one) has been the focus of many behavioral and molecular studies in the recent years. Rolipram exhibits memory-enhancing effects in rodents. In vitro studies have shown that long-term potentiation (LTP), which may comprise a cellular substrate for learning, is also enhanced by rolipram. However, effects have not been assessed in vivo. Rolipram has antipsychotic properties. Psychosis affects cognition and in animal models of psychosis LTP is impaired. In this study, we investigated if PDE4 inhibition improves LTP in healthy animals in vivo and if PDE4 inhibition rescues impaired LTP and prevents object recognition memory deficits in an animal model of psychosis. Recordings were made from the hippocampus of adult, freely behaving Wistar rats. Thirty minutes after treatment with rolipram or vehicle, a tetanus was applied to the medial perforant path to elicit short-term potentiation (STP) in the dentate gyrus. At this time-point, radioimmunoassay revealed that rolipram significantly elevated cyclic adenosine monophosphate levels in the dorsal hippocampus, in line with reports by others that rolipram mediates decreased PDE4 activity. In healthy animals, both intracerebroventricular and subcutaneous treatment with rolipram facilitated STP into LTP, suggesting that PDE4 inhibition may have a permissive role in plasticity mechanisms that are relevant for learning and memory. One week after a single systemic treatment with the irreversible N-methyl--aspartate antagonist, MK801, LTP and object recognition memory were significantly impaired, but could be rescued by PDE4 inhibition. These data suggest that the relief of cognitive disturbances in psychosis models by rolipram may be mediated in part by a rescue of hippocampal LTP.
Highlights
Inhibition of the phosphodiesterase type 4 (PDE4) by rolipram (4–3–Cyclopentyloxy)-4–methoxyphenyl)-pyrrolidin-2–one) enhances cognition in animals
Basal synaptic transmission was unaffected by rolipram, as no significant changes were found between vehicle-treated control animals (n 1⁄4 6) and animals treated with rolipram (5.5 mg, n 1⁄4 6) in a baseline experiment (PS: F [1,228] 1⁄4 0.780, not significant (NS), Figure 1a; field excitatory postsynaptic potential (fEPSP): F [1,229] 1⁄4 1.311, NS, Figure 1b)
The present study demonstrates that PDE4 inhibition facilitates hippocampal long-term potentiation (LTP) in freely behaving healthy animals after intracerebroventricular (i.c.v.) as well as after systemic (s.c.) administration, and that it rescues long-term impairments in LTP and in object recognition memory that occur in an animal model of psychosis
Summary
Inhibition of the phosphodiesterase type 4 (PDE4) by rolipram (4–3–Cyclopentyloxy)-4–methoxyphenyl)-pyrrolidin-2–one) enhances cognition in animals. Several studies have demonstrated that rolipram improves animals’ performance in memory-dependent behavioral tests, such as the object recognition task (ORT) and freezing-to-context task.. Several studies have demonstrated that rolipram improves animals’ performance in memory-dependent behavioral tests, such as the object recognition task (ORT) and freezing-to-context task.2 It selectively inhibits PDE4, which comprises a family of four enzymes (PDE4A-D) that control the hydrolysis of cyclic adenosine monophosphate (cAMP). The cAMP/PKA/CREB pathway has been shown to be critically involved in learning and memory.. In vitro studies in CA1 region have further demonstrated that rolipram facilitates long-term potentiation (LTP) in hippocampal slice preparations.. Besides being involved in learning and memory, the cAMP/ PKA/CREB pathway is crucial for LTP and transcription of LTP-related genes.. The question as to whether rolipram facilitates LTP in intact brains of healthy freely moving animals has not yet been answered
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