Phosphodiesterase Inhibitors Enhance Object Memory Independent of Cerebral Blood Flow and Glucose Utilization in Rats

Abstract

Phosphodiesterase (PDE) inhibitors prevent the breakdown of the second messengers, cyclic AMP (cAMP) and cyclic GMP (cGMP), and are currently studied as possible targets for cognitive enhancement. Earlier studies indicated beneficial effects of PDE inhibitors in object recognition. In this study we tested the effects of three PDE inhibitors on spatial memory as assessed in a place and object recognition task. Furthermore, as both cAMP and cGMP are known vasodilators, the effects of PDE inhibition on cognitive functions could be explained by enhancement of cerebrovascular function. We examined this possibility by measuring the effects of PDE5 and PDE4 inhibitor treatment on local cerebral blood flow and glucose utilization in rats using [ 14 C]-iodoantipyrine and [ 14 C]-2-deoxyglucose quantitative autoradiography, respectively. In the spatial location task, PDE5 inhibition (cGMP) with vardenafil enhanced only early phase consolidation, PDE4 inhibition (cAMP) with rolipram enhanced only late phase consolidation, and PDE2 inhibition (cAMP and cGMP) with Bay 60-7550 enhanced both consolidation processes. Furthermore, PDE5 inhibition had no cerebrovascular effects in hippocampal or rhinal areas. PDE4 inhibition increased rhinal, but not hippocampal blood flow, whereas it decreased glucose utilization in both areas. In general, PDE5 inhibition decreased the ratio between blood flow and glucose utilization, indicative of general oligaemia; whereas PDE4 inhibition increased this ratio, indicative of general hyperemia. Both oligaemic and hyperemic conditions are detrimental for brain function and do not explain memory enhancement. These results underscore the specific effects of cAMP and cGMP on memory consolidation (object and spatial memory) and provide evidence that the underlying mechanisms of PDE inhibition on cognition are independent of cerebrovascular effects.

Object recognition testing: Methodological considerations on exploration and discrimination measures

“…Furthermore the property of one-trial learning makes it suitable for the examination of temporal aspects of memory. Over time, it has become a widely used tool for the assessment of memory functions in combination with pharmacological treatments [6][7][8][9][10] and brain lesions [11][12][13][14]. The ORT is mainly used for rodent experiments, most research is done with rats and mice but the task is also suitable for testing other rodent species [15].…”

Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions

“…I) Cognition. In a study of memory consolidation in animal models, PDE5 inhibitors, like a number of other PDE inhibitors, improve cognitive function (194,309,310,331,386) and exhibit antidepressant effects (208). Vardenafil enhances early phase consolidation independent of its effects on cerebral vasculature (309,310).…”

“…PDE2 is involved in aldosterone production (226), control of cGMP level in certain neurons (143), learning and enhancement of neuronal plasticity (309,331,386), modulation of cardiac L-type calcium current (104), control of specific cGMP pools in cardiomyocytes (58), blunting of anxiety (235), and impacting endothelial cell permeability (338,366). Inhibition of PDE2 in any of these cells could result in elevation of cGMP, cAMP, or both cNs, thereby impacting both cAMP and cGMP signaling.…”

Exploring Standardized Zembrin® Extracts from the South African plant Sceletium tortuosum in Dual Targeting Phosphodiesterase-4 (PDE-4) and Serotonin Reuptake Inhibition as potential treatment in Schizophrenia

“…Rolipram, the PDE4 inhibitor, improved memory consolidation, working memory and information processing in rodent species subject to a variety of cognitive tasks: radial arm maze, passive avoidance, delayed arm water and visual -spatial tasks, working memory and information [25][26][27][28]. In the macaque monkey species, rolipram improved object retrieval performance suggesting positive interaction with executive function [26].…”