PDE2 and PDE10, but not PDE5, inhibition affect basic auditory information processing in rats.

Phosphodiesterase type 2 (PDE2), type 10 (PDE10), and type 5 (PDE5) have been considered as relevant targets for cognition enhancement. Although it is well established that PDE inhibitors (PDE-Is) improve memory functions in animals, the effects on auditory information processing are less clear. The aim of this study was to test the effects of PDE2 (BAY 60-7550), PDE5 (vardenafil) and PDE10 (PQ-10) inhibition on sensory gating in rats. Vehicle or 1mg/kg of a specific PDE-I was given orally 30min before testing. EEG was recorded from the hippocampus, striatum and vertex. Sensory gating was found for the N1 in the vertex and hippocampus, as revealed by diminished amplitudes to S2 compared to S1. Administration of PDE-Is did not affect sensory gating. However, PDE2 inhibition increased the P1 peak after presentation of S1 at the vertex and PQ-10 increased the N1 peak in general compared to vehicle treatment at the hippocampus. PDE2 and PDE10 inhibition affect auditory information processing in general, whereas PDE5 inhibition has no effect. These findings suggest that the positive effects of PDE5 inhibition on cognition previously found in animals are possibly the results of an effect on higher cognitive functioning specifically, whereas the cognition enhancing effects of PDE2 and PDE10 inhibition might also be influenced by effects on earlier stages of information processing.

The effects of the phosphodiesterase type 5 inhibitor vardenafil on cognitive performance in healthy adults: a behavioral-electroencephalography study.

Phosphodiesterase type 5 inhibitors (PDE5-Is) improve cognitive performance of rodents, but the few human studies investigating their effects did not systematically investigate cognitive effects and the results have been quite contradictory. Therefore, we examined whether the PDE5-I vardenafil improves memory and executive functioning and affect electroencephalography (EEG) in healthy young adults. Participants were selected out of a group of volunteers, based on their performance on a memory screening and they were orally treated with vardenafil (10-20 mg or placebo). Memory and executive functioning were tested while EEG activity was recorded. Additionally, a simple reaction time task and questionnaires addressing various complaints were presented. No prominent effects of vardenafil on cognition were found: participants only made more mistakes on a reaction time task after 20 mg vardenafil. During encoding of words, the P300 was generally smaller after vardenafil treatment. Furthermore, the N400 was larger after vardenafil 10 mg than placebo treatment in a spatial memory task at Fz. Finally, headache and feeling weak were reported more after vardenafil treatment. Vardenafil did not affect cognitive performance of healthy adults and showed only some incidental effects on ERPs. These findings in humans do not corroborate the cognition-enhancing effects of PDE5-Is in healthy animals.

The PDE5 inhibitor vardenafil does not affect auditory sensory gating in rats and humans.

RATIONALE: Sensory gating is an adaptive mechanism of the brain to prevent overstimulation. Patients suffering from clinical disorders such as Alzheimer's disease or schizophrenia exhibit a deficit in gating, which indicates not only an impairment in basic information processing that might contribute to the cognitive problems seen in these patients. Phosphodiesterase type 5 inhibitors (PDE5-Is) have been shown to improve cognition in rodents in various behavioural tasks and might consequently be an interesting target for cognition enhancement. However, the effects of PDE5-Is on sensory gating are not known yet. OBJECTIVES: This work aims to study the effects of PDE5 inhibition on auditory sensory gating in rats and humans. METHODS: In the rat study, vehicle or 0.3-3 mg/kg of the PDE5-I vardenafil was given orally 30 min before testing and electrode locations were the vertex, hippocampus and the striatum. The human subjects received placebo, 10-20 mg vardenafil 85 min before testing and sensory gating was measured at the cortex (Fz, Fcz and Cz) electrodes. RESULTS: Significant gating was only found for the N1 component in rats while all three peaks P1, N1 and P2 showed gating in humans, i.e. the response to the second sound click was decreased as compared with the first for these deflections. Administration of vardenafil did neither have an effect on sensory gating in rats nor in humans. CONCLUSIONS: These findings imply that positive effects of PDE5 inhibition on cognition are not mediated by more early phases of information processing.

Two novel 5-HT6 receptor antagonists ameliorate scopolamine-induced memory deficits in the object recognition and object location tasks in Wistar rats.

The 5-hydroxytryptamine(6) (5-HT(6)) receptor has been suggested to play an important role in the regulation of memory and cognition. In the present study, our aim was to investigate whether the novel, selective 5-HT(6) antagonists compound (CMP) X and CMP Y and the reference 5-HT(6) antagonist GSK-742457 could ameliorate impairments in episodic memory in 3-months-old male Wistar rats. The acetylcholinesterase inhibitor (AChEI) donepezil (Aricept®, approved for symptomatic treatment of Alzheimer's disease, AD) was used as a positive reference compound. First, effects of the 5-HT(6) antagonists CMP X, CMP Y and GSK-742457 were investigated on object recognition task (ORT) performance in rats treated with the muscarinic antagonist scopolamine (0.1mg/kg, administered intraperitoneally, i.p., 30 min before trial 1). Second, effects of the combination of suboptimal doses of 5-HT(6) antagonists CMP X and CMP Y with the AChEI donepezil were studied, to determine whether the 5-HT(6) antagonists show additive synergism with donepezil in the ORT. Finally, effects of CMP Y, GSK-742457 and donepezil were investigated on object location task (OLT) performance in rats treated with scopolamine. Donepezil (1mg/kg, oral administration, p.o.), GSK-742457 (3mg/kg, i.p.), CMP X (3mg/kg, i.p.) and CMP Y (30 mg/kg, p.o.), all ameliorated the scopolamine-induced deficits in object recognition. In the ORT, we have found that combined administration of subthreshold doses of CMP X (1mg/kg, i.p.) and CMP Y (10mg/kg, p.o.) with the AChEI donepezil (0.1mg/kg, p.o.), enhanced memory performance in Wistar rats with deficits induced by scopolamine. Donepezil (0.1mg/kg, p.o.) alone had no discernable effects on performance. This suggests additive synergistic effects of the 5-HT(6) antagonists (CMP X and CMP Y) with donepezil on cognitive impairment. Finally, donepezil (1mg/kg, p.o.), GSK-742457 (10mg/kg, p.o.) and CMP Y (30 mg/kg, p.o.) also reduced scopolamine-induced deficits in the OLT. In conclusion, the 5-HT(6) antagonists were found to clearly improve episodic memory deficits induced by scopolamine. In addition, co-administration of the 5-HT(6) receptor antagonists CMP X and CMP Y with the AChEI donepezil to cognitively impaired rats also resulted in potentially additive enhancing effects on cognition. This suggests that these compounds could have potential as monotherapy, but also as adjunctive therapy in patients with AD treated with common treatments such as donepezil.

Automated scoring of novel object recognition in rats.

The object recognition task (ORT) has become increasingly popular as a memory test in neuroscience research. Scoring of ORT performance is still mostly done by hand, which can be liable to subjective scoring. To our knowledge, no suited software is available yet since the direction of the nose of the animal cannot be tracked reliably. We have developed a software paradigm that reliably tracks the nose of the rats and have conducted a series of experiments to evaluate the reliability of this newly developed program. We used Wistar rats, which showed good object memory after 1h interval. Subsequently, we used scopolamine (SCOP) to impair the memory performance of the rats. The object exploration was scored by two observers and the automated system. Both observers and the automated system found an impairing drug effect of scopolamine on ORT performance. When using large objects the correlation between the discrimination index d2 of observers was: 0.60 (SCOP) and 0.79 (SAL). However, the correlation between observers and the automated system was quite low: 0.41 (SCOP) and 0.40 (SAL). Reducing the size of the objects increased the reliability between observers and the automated system substantially (0.82-0.87). We conclude that the use of small objects in combination with our program enables reliable automated scoring in the ORT, thus increasing the objectivity and validity of this task.