Subchronic Rolipram Delivery Activates Hippocampal CREB and Arc, Enhances Retention and Slows Down Extinction of Conditioned Fear

Abstract

Rolipram, a type IV-specific phosphodiesterase inhibitor, is known to improve memory under various learning tasks. Moreover, Rolipram treatments have been shown to increase expression and phosphorylation of a key factor for hippocampal memory consolidation, the cAMP-dependent response element-binding protein, CREB. However, the exact correlation between hippocampal CREB phosphorylation and memory improvement induced by Rolipram has not yet been determined in a CREB-dependent type of hippocampal-related learning in normogenic, intact rodents. Here, we report that subchronic Rolipram delivery by using osmotic minipumps increased the basal rat hippocampal expression and phosphorylation of CREB, as well as the expression of the cAMPdependent, memory-related protein, Arc. In parallel, the same treatment improved memory consolidation of conditioned fear. Furthermore, the increase of CREB phosphorylation and Arc expression consequent to the learning experience was enhanced in Rolipram-treated rats, compared to controls. By evaluating the time course of memory extinction over 10 days after the initial learning test, we also observed significant slowing down of the memory extinction rate in Rolipram-treated rats. This effect could be attributed to CREB phosphorylation and memory having been initially higher, as osmotic minipumps stopped to release Rolipram the first day after the initial learning test. Our data define the conditions through which the pharmacological manipulation of hippocampal CREB expression and activation result in memory amelioration in normogenic, intact animals. These results are relevant for the study of molecular correlates of memory, and may also be important in view of the efforts to design new pharmacological treatments, targeting the CREB pathway and leading to enhancement of learning and memory, even in the absence of patent neuropathology.

Transgenic Inhibition of Neuronal Protein Kinase A Activity Facilitates Fear Extinction

“…Moreover, subchronic delivery of rolipram in rats has been shown to slow extinction of conditioned fear (Monti et al, 2006). Similarly, McNally et al (2005) found that administration of the cAMP analog 8-Br-cAMP impaired extinction, although PKA activation by Sp-cAMPs had no effect.…”

Mechanisms of fear extinction

“…Similarly, Monti et al 282 reported that rolipram, a phosphodiesterase inhibitor that increases cAMP concentrations in the brain, facilitates acquisition of fear and delays extinction. In these experiments, rats were implanted with osmotic minipumps that released rolipram or vehicle steadily for 7 days.…”

Advanced Research on Dopamine Signaling to Develop Drugs for the Treatment of Mental Disorders: Biochemical and Behavioral Profiles of Phosphodiesterase Inhibition in Dopaminergic Neurotransmission

“…Subsequent work supported a role for PDE4 in learning and memory processes (59), including activation of cAMP/PKA/CREB signaling and facilitation of longterm potentiation (LTP) in the hippocampus (60,61). Furthermore, rolipram reverses MK801-induced cognitive deficits in radial arm maze (62) and passive avoidance tests (63).…”