PDE2

So far, only a couple of studies have been published that investigated the effects of PDE2 inhibition in behavioral models. To our knowledge, BAY 60-7550 is the only selective PDE2-I which has been tested in animal models of cognition (Boess et al. 2004; Domek-Lopacinska and Strosznajder 2008; Rutten et al. 2007b). It has been shown that BAY 60-7550 improved memory acquisition and consolidation in the object recognition task in both rats and mice and consolidation in the social recognition task in rats (Boess et al. 2004; Domek-Lopacinska and Strosznajder 2008; Rutten et al. 2007b). In addition, this PDE2-I improved acquisition and consolidation in the object recognition task in age-impaired rats (Domek-Lopacinska and Strosznajder 2008).

Furthermore, BAY 60-7550 reversed the MK-801-induced working memory deficit in the T-maze in mice (Boess et al. 2004). A more detailed overview of these studies is provided in Table 3 .

Table 3 Overview of effects of PDE2-Is on cognition Full size table

PDE4

The next section provides a general summary of the available literature on PDE4-Is and cognition. A more detailed overview is provided in Table 4.

Table 4 Overview of effects of PDE4-Is on cognition Full size table

It has been shown in several studies that acute as well as subchronic administration of the PDE4-I rolipram improved memory consolidation in unimpaired rats in the object recognition task (Rutten et al. 2007a, b, 2008c). In addition, memory deficits caused by scopolamine or acute tryptophan depletion were reversed by rolipram in this task (Rutten et al. 2007a, 2006). Several spatial memory tasks (e.g., water escape task and radial arm maze) showed that PDE4-Is did not only improve spatial memory in unimpaired rats and mice (Bach et al. 1999; Huang et al. 2007), but also in rats of which spatial memory was impaired by age or microsphere embolism-induced cerebral ischemia (Nagakura et al. 2002). An impairment of spatial reference memory in the radial arm maze caused by scopolamine, MK-801, or MAPK/ERK kinase (MEK) inhibition was also reversed by various PDE4-Is (Egawa et al. 1997; Zhang et al. 2000, 2004, 2005; Zhang and O’Donnell 2000).

In addition, various studies investigated the effects of PDE4-Is on passive avoidance learning and PDE4-Is reversed impairments caused by scopolamine, MK-801, anisomycin, and MEK inhibition in this task (Egawa et al. 1997; Ghelardini et al. 2002; Imanishi et al. 1997; Randt et al. 1982; Zhang et al. 2005, 2004; Zhang and O’Donnell 2000). Furthermore, it was shown that acute as well as chronic treatment of rolipram improved the performance of unimpaired rats and mice in contextual fear conditioning (Barad et al. 1998; Comery et al. 2005; Monti et al. 2006).

The effects of PDE4-Is on working memory in rats have been studied in various deficit models. It was shown that working memory deficits caused by scopolamine, MK-801, cerebral ischemia, or electroconvulsive shocks (ECS) were reversed by the administration of PDE4-Is in the radial arm maze and the three-panel runway task (Egawa et al. 1997; Imanishi et al. 1997; Zhang et al. 2000, 2005, 2004). Of note, the effects of rolipram on spatial working memory are twofold; on one hand, rolipram tended to improve working memory in young rhesus monkeys in a delayed responding task (Ramos et al. 2003). However, on the other hand, rolipram had a negative effect on working memory in aged monkeys in this task (Ramos et al. 2003, 2006).

The effects of rolipram on information processing have been studied in several behavioral setups in the prepulse inhibition and startle response task. Rolipram did not only facilitate information processing in unimpaired mice and zebrafish, but also reversed deficits caused by d-amphetamine in mice (Best et al. 2008; Kanes et al. 2007). In contrast, PDE4-I RO-20-1724 did not reverse the prepulse inhibition deficit caused by d-amphetamine (Halene and Siegel 2008). In another model of information processing, sensory gating, this PDE-I increased the amplitudes of P20 and N40 in the CA3 area during the first stimulus and reversed the N40 deficit in the first click caused by d-amphetamine (Halene and Siegel 2008). Additionally, executive functioning was improved in an object retrieval task in cynomolgus macaques after the administration of rolipram (Rutten et al. 2008a). In this task, monkeys try to retrieve a food reward from a transparent box with one open side that alternates between trials. This is a prefrontal cortical-mediated task likely to capture attention and response inhibition, and rolipram treatment significantly dose-dependently enhanced performance, as measured by an increased percentage of correct first reaches.

Besides deficit models based on pharmacological or surgical interventions, the use of transgenic animals, i.e., isoform-specific knockout models of PDE4B or PDE4D, have been recently introduced to study the role of PDE4 in the central nervous system (CNS). It was shown that PDE4B knockout (KO) in mice had no effect on spatial memory performance in the water escape task and the passive avoidance task (Siuciak et al. 2008a). Furthermore, these mice showed an impairment in information processing in the prepulse inhibition task (Siuciak et al. 2008a), although they performed similar to wild-type animals on conditioned avoidance responding (Siuciak et al. 2007). A recent study showed more controversial data demonstrating enhanced LTP but impaired fear conditioning in PDE4D knockout mice (Rutten et al. 2008b).

In addition, a variety of transgenic mice models was used in combination with the administration of PDE4-Is. It has been shown that acute as well as chronic treatment of PDE4-Is improved long-term memory (LTM) functioning in a Rubenstein–Taybi syndrome and two Alzheimer’s disease KO mouse models for cognitive impairment in the fear conditioning and object recognition task (Bourtchouladze et al. 2003; Comery et al. 2005; Gong et al. 2004). Also, PDE4-I rolipram improved working memory and spatial memory in a transgenic model of Alzheimer’s disease, i.e., PS1/PDAPP KO mice in the radial arm water maze (Costa et al. 2007; Gong et al. 2004).

To our knowledge, no studies have been published in which the effects of PDE4-Is on cognition in humans are described. However, PDE4-I MK 0952 is now entering phase 2 clinical trials for cognition enhancement (Merck and Co. 2006).

PDE5

Prickaerts et al. (1997) were the first to describe memory-enhancing effects of PDE5 inhibition using the PDE5-I zaprinast. However, zaprinast is not selective for PDE5, as it also inhibits PDE1, 9, 10, and 11 (Bender and Beavo 2006). Recently, more highly selective PDE5 inhibitors have been developed mainly for the treatment of erection disorder, e.g., sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) (Setter et al. 2005). The next section will give a general summary of the available literature on PDE5-Is and cognition; a more detailed overview is provided in Table 5.

Table 5 Overview of effects of PDE5-Is on cognition Full size table

So far, several studies have shown positive effects of selective PDE5-Is on memory performance in the object recognition task in adult rats; zaprinast (Domek-Lopacinska and Strosznajder 2008; Prickaerts et al. 1997), sildenafil (Prickaerts et al. 2005, 2002b), and vardenafil (Prickaerts et al. 2002b; Rutten et al. 2007b) improved memory consolidation. In addition, Rutten et al. (2005) showed that sildenafil also improved memory consolidation in mice in this task. Previous work from our group showed that zaprinast reversed the object memory deficits induced by the NOS inhibitor 7-nitroindazole in rats in the object recognition task (Prickaerts et al. 1997). However, zaprinast was unable to reverse memory deficits in aged rats in this task (Domek-Lopacinska and Strosznajder 2008).

Several studies have shown spatial memory improvement in an adapted version of the elevated plus-maze in rats (Singh and Parle 2003) and mice (Patil et al. 2004a) after treatment with a PDE5-I. Furthermore, sildenafil treatment ameliorated the deficits induced by diabetes or ECS in this task (Patil et al. 2004a, 2006). Previous studies showed no effects of PDE5-Is on spatial tasks in healthy rats, i.e., the water escape task or the Y-maze (Prickaerts et al. 2004). However, since only one dose was tested in this study, further investigation will be needed. Finally, in hyperammonemia and portacaval shunt deficit models for liver failure, both sildenafil and zaprinast reversed spatial recognition deficits of rats in the Y-maze (Erceg et al. 2006, 2005a, b). Recent work adds to this since sildenafil reversed the effects the nitric oxide synthase (NOS) inhibitor L-NAME in a complex maze learning paradigm (Devan et al. 2006, 2007).

Furthermore, various studies investigated the effects of PDE5-Is on active and passive avoidance learning in rats, mice, and neonatal chicks. Although one study failed to show improvement in learning performance after sildenafil treatment in unimpaired and aged rats (Shafiei et al. 2006), others have shown improvements in unimpaired and aged mice and in neonatal chicks (Baratti and Boccia 1999; Campbell and Edwards 2006; Patil et al. 2004a). In contrast, Edwards and Lindley (2007) found that zaprinast could also have a negative effect on learning and memory when given at a high dose. Memory impairments in avoidance learning caused by scopolamine, diabetes, or ECS in rats were reversed by sildenafil treatment (Devan et al. 2004; Patil et al. 2006). In addition, zaprinast as well as sildenafil reversed memory deficits caused by a model for diabetes in mice (Patil et al. 2004a).

Finally, a recent study showed that the PDE5-I sildenafil dose-dependently improved performance in a prefrontal task, i.e., the object retrieval task (see above), in cynomolgus macaques (Rutten et al. 2008a).

Most research regarding the cognition-enhancing effects of PDE5-Is so far has focused on preclinical animal models; there are only two papers in which the effects of the PDE5-I sildenafil on human cognition were investigated. Grass et al. (2001) have shown that 100 mg sildenafil enhanced performance in a simple reaction time test when given 1 h before testing. However, no effects were found on short-term memory (STM), divided attention, and other psychomotor tasks (Grass et al. 2001). In addition, Schultheiss et al. (2001) studied the effects of sildenafil (100 mg, 1 h before testing) on auditory attention and word recognition. Again, no cognition-enhancing effects were found with regard to the behavioral measures

In both studies, STM tasks were performed that are thought to measure memory performance processes comparable to the object recognition task in rats. However, the object recognition task in animals usually measures more aspects of memory, such as that for object and for location, even though only the object memory itself might have been measured. The human tasks, on the other hand, only assess memory for words, pictures, or location, but never the combination of these aspects. Possibly, the fact that spatial information was lacking in the human studies has caused this discrepancy in findings.

Sildenafil changed certain components of event-related potentials (ERPs) in the study of Schultheiss et al. (2001). The Nd component, although it only showed a marginally significant effect, was increased after treatment with sildenafil. This indicates improved focused attention. The P3 component, which measures controlled processes of target selection, was significantly enhanced after the administration of sildenafil (Schultheiss et al. 2001). Again, this is evidence for improvements after treatment with sildenafil. Finally, a reduced negativity between 150 and 250 ms was found in the word recognition experiment after sildenafil treatment; this may also indicate an effect on information processing, although the exact role of this component remains uncertain (Schultheiss et al. 2001).

Several possible explanations for not finding any cognition-enhancing effects after PDE5-I treatment in humans in contrast to the results in animal studies exist. First, only one dose of sildenafil on one specific time point was tested in both studies. Investigating different doses, both higher and lower, at different administration time points might reveal possible cognition-enhancing effects in humans. In addition, a “ceiling effect” might have occurred in the cognitive tasks; this means that healthy subjects in these studies already perform at their maximal level, so their performance cannot be further improved. A final explanation might be that the number of participants was not sufficient, since only six participants were tested by Grass et al. (2001), whereas Schultheiss et al. (2001) examined ten healthy participants.

PDE9

To our knowledge, only one paper has been published in which the effects of PDE9 inhibition on cognition are described (Van der Staay et al. 2008). In this paper, the potent and selective PDE9-I BAY 73-6691 was used (Wunder et al. 2005). It was shown that this PDE9-I improved memory consolidation in unimpaired rats and mice in the object recognition and social recognition task (Van der Staay et al. 2008). Furthermore, this PDE9-I reversed the MK-801- or scopolamine-induced memory deficit in the T-maze and the passive avoidance task, respectively (Van der Staay et al. 2008). More detailed information can be found in Table 6.

Table 6 Overview of effects of PDE9-I on cognition Full size table

PDE10

Only very recently, PDE10-Is have become a target for CNS research, especially concerning the cognitive deficits related to schizophrenia (Schmidt et al. 2008). In the next section, a summary of the available literature on PDE10-Is and cognition will be given; a more detailed overview can be found in Table 7.

Table 7 Overview of effects of PDE10-Is on cognition Full size table

Chronic treatment with the PDE10-I papaverine impaired spatial memory and reversal learning in unimpaired mice in the Morris water maze (Hebb et al. 2008). Administration of TP-10 did not have an effect on information processing in a prepulse inhibition task in unimpaired and MK-801-impaired mice (Schmidt et al. 2008). However, TP-10 reversed the auditory gating deficit caused by d-amphetamine in rats (Schmidt et al. 2008). Papaverine improved attention in the attention shifting task in rats that were impaired by subchronic phenylcyclohexylpiperidine (PCP) treatment, a model of schizophrenia, whereas no effect was found in unimpaired rats (Rodefer et al. 2005).

Several studies also used KO models to study the role of PDE10 in cognition. It was shown that PDE10A knockout in a DBA1LacJ background had no effect on learning and memory in the passive avoidance and water escape task in mice (Siuciak et al. 2006, 2008b). In addition, these mice showed the same conditioned avoidance response as wild-type mice; however, these KO mice required more training to reach the performance of wild-type animals (Siuciak et al. 2006, 2008b). On the other hand, PDE10A KO mice with a C57BL/6N background were unable to reach the performance of the wild-type mice in this task (Siuciak et al. 2008b).

The data discussed in the previous paragraphs showed that PDE10-Is can improve cognition in impaired animals, but can also induce a cognitive impairment in healthy animals. There are several explanations that might account for these contradictory findings. First, the cognitive impairment in healthy animals caused by papaverine was the result of a subchronic treatment, which was not found after acute treatment in impaired animals. Secondly, different aspects of cognition were addressed in these studies. In the healthy animals, learning and memory were studied, whereas in the impaired animals, information processing and attention were investigated. Thirdly, improving cognition of a healthy individual is not the same as restoring impaired cognition; the underlying processes, and thus the effect of a compound, may differ.