The selective 5-HT6 receptor antagonist SLV has putative cognitive- and social interaction enhancing properties in rodent models of cognitive impairment.

In the present study, our aim was to investigate whether the novel highly selective 5-hydroxytryptamine6 (5-HT6) receptor antagonist SLV can ameliorate impairments in cognition and social interaction with potential relevance for both schizophrenia and Alzheimer's disease (AD). SLV sub-chronically - treated Wistar rats reared in isolation showed significantly enhanced prepulse inhibition (PPI) and object recognition performance when compared to vehicle - treated rats. In the isolated rats, also a significant reduction in expression of hippocampal neural cell adhesion molecule polysialylation (NCAM-PSA) was found which was ameliorated following treatment with SLV (30mg/kg). The social engagement deficit in rats exposed in utero (on gestational day 12.5) to valproic acid (VPA) was reversed by treatment with SLV (30mg/kg). SLV (20 and 30mg/kg, p.o.) fully reversed MK-801 - induced deficits in the ORT and also scopolamine - induced deficits in both the Object Recognition Task (ORT) and Object Location Task (OLT) in Wistar rats. In addition, a combination of sub-optimal doses of SLV and donepezil attenuated scopolamine-induced ORT deficits. Furthermore, SLV (10mg/kg, p.o.) reversed spontaneous alternation deficits in the T-maze induced by MK-801 administration in Swiss mice and in aged C57Bl/6J mice. SLV additionally improved T-Maze spatial learning and passive avoidance learning in Sprague-Dawley rats with amyoid-beta (Aß) injections into the hippocampus. In contrast, no benefits were found with SLV or the tested reference compounds (donepezil and RVT-101) on cognitive performance of 12months old Tg2576 mice. Also, in the social recognition task, an absence of cognitive enhancing properties was observed with SLV on "normal forgetting" in Wistar rats. Finally, analysis of spontaneous inhibitory postsynaptic currents (sIPSCs) frequency recorded from pyramidal cells revealed a reduction in the presence of 1µM of SLV. In conclusion, SLV was investigated in several rodent animal models and found to be effective at a least effective dose (LED) of 20mg/kg and 10mg/kg (p.o.) in the rat and the mouse, respectively.

Chronic depression is associated with a pronounced decrease in serum brain-derived neurotrophic factor over time.

One of the leading neurobiological hypotheses on depression states that decreased expression of brain-derived neurotrophic factor (BDNF) contributes to depression. This is supported by consistent findings of low serum BDNF levels in depressed patients compared with non-depressed controls. Whereas it has been generally assumed that this is a state characteristic of depression, strong inferences about state or trait effects require a longitudinal study design. To investigate the longitudinal association between serum BDNF and depression, we measured serum BDNF, (current and past) depression status, use of antidepressants, and all potential covariates at baseline and after 2 years in 1751 individuals, consisting of patients with an incident (n=153), remitted (n=420) and persistent depression (n=310) and non-depressed controls (n=868). We analyzed change/differences in serum BDNF across these four groups with analyses of covariance adjusted for covariates and baseline BDNF value, together with the effects of starting and stopping antidepressant treatment. Our analyses revealed a significant difference for the depression course groups (P=0.007). Compared with non-depressed controls, persistently depressed and remitted patients had a steeper decrease of BDNF levels over time (-1.33 (P=0.001) and -0.97 ng ml(-1) (P=0.011), respectively), whereas BDNF reductions in patients with incident depression were similar to those in healthy controls. Initiation or discontinuation of antidepressants was not associated with BDNF change (P=0.72). These findings suggest that BDNF not only contributes to depression, but that depression in turn may also contribute to low BDNF.

PDE and cognitive processing: beyond the memory domain.

Phosphodiesterase inhibitors (PDE-Is) enhance cAMP and/or cGMP signaling via reducing the degradation of these cyclic nucleotides. Both cAMP and cGMP signaling are essential for a variety of cellular functions and exert their effects both pre- and post-synaptically. Either of these second messengers relays and amplifies incoming signals at receptors on the cell surface making them important elements in signal transduction cascades and essential in cellular signaling in a variety of cell functions including neurotransmitter release and neuroprotection. Consequently, these processes can be influenced by PDE-Is as they increase cAMP and/or cGMP concentrations. PDE-Is have been considered as possible therapeutic agents to treat impaired memory function linked to several brain disorders, including depression, schizophrenia and Alzheimer's disease (AD). This review will, however, focus on the possible role of phosphodiesterases (PDEs) in cognitive decline beyond the memory domain. Here we will discuss the involvement of PDEs on three related domains: attention, information filtering (sensory- and sensorimotor gating) and response inhibition (drug-induced hyperlocomotion). Currently, these are emerging cognitive domains in the field of PDE research. Here we discuss experimental studies and the potential beneficial effects of PDE-I drugs on these cognitive domains, as effects of PDE-Is on these domains could potentially influence effects on memory performance. Overall, PDE4 seems to be the most promising target for all domains discussed in this review.

Mind the gap: delayed manifestation of long-term object memory improvement by phosphodiesterase inhibitors.

We examined the temporal profile of pharmacologically enhanced episodic memory, using the object recognition task. Male Wistar rats were tested at different retention intervals ranging from 1 h to 24 h. The object discrimination performance of all groups (untreated, placebo, drug treatment) gradually decreased up to an interval (8 h). Interestingly, only after this 8 h interval the memory improving effects of vardenafil and rolipram started to emerge. This time-dependent memory performance shows similarities with the Kamin effect. The delayed manifestation of drug-enhanced memory suggests that two separate memory mechanisms are at play, a quick transient form of memory and a more stable memory form that requires several hours to develop. It is important to take this into account when testing treatments intended for long-term memory enhancement.

No effect of acute tryptophan depletion on phosphodiesterase inhibition--related improvements of short-term object memory in male Wistar rats.

OBJECTIVE: To further explore the implication of the serotonin (5-HT) system in the improvement of rat short-term object recognition after administration of the type 2 phosphodiesterase inhibitor (PDE-I) BAY 60-7550 and the type 5 PDE-I vardenafil, the effect of PDE2 and PDE5 inhibition upon central amino acid levels, 5-HT, and related parameters were measured after applying acute tryptophan depletion (ATD). METHOD: Wistar rats were orally administered saline or a protein-carbohydrate mixture with or without tryptophan (TRP). TRP-depleted animals additionally received an oral vehicle injection or the PDE inhibitors BAY 60-7550 or vardenafil at a dose known to improve object memory performance. RESULTS: Although ATD significantly decreased TRP levels in the hippocampus 2 h after administration, 5-HT levels appeared only moderately affected, without any changes observed in the amount of 5-HIAA or 5-HT turnover rate. Moreover, no effects of PDE inhibition upon 5-HT or related parameters were observed. CONCLUSION: Changes in 5-HT neurotransmitter activity might be excluded as a potential underlying mechanism of the previously reported ability of PDE inhibitors to improve short-term object memory in rats. It is suggested that a decrease in cerebral blood flow potentially underlies ATD-induced object memory deficits, most likely due to decrease in NO synthesis.

Mechanism of acute tryptophan depletion: is it only serotonin?

The method of acute tryptophan depletion (ATD), which reduces the availability of the essential amino acid tryptophan (TRP), the dietary serotonin (5-hydroxytryptamine (5-HT)) precursor, has been applied in many experimental studies. ATD application leads to decreased availability of TRP in the brain and its synthesis into 5-HT. It is therefore assumed that a decrease in 5-HT release and subsequent blunted neurotransmission is the underlying mechanism for the behavioural effects of ATD. However, direct evidence that ATD decreases extracellular 5-HT concentrations is lacking. Furthermore, several studies provide support for alternative underlying mechanisms of ATD. This may question the utility of the method as a selective serotonergic challenge tool. As ATD is extensively used for investigating the role of 5-HT in cognitive functions and psychiatric disorders, the potential of alternative mechanisms and possible confounding factors should be taken into account. It is suggested that caution is required when interpreting ATD effects in terms of a selective serotonergic effect.

Serum levels of brain-derived neurotrophic factor in major depressive disorder: state-trait issues, clinical features and pharmacological treatment.

Recent evidence supports 'the neurotrophin hypothesis of depression' in its prediction that brain-derived neurotrophic factor (BDNF) is involved in depression. However, some key questions remain unanswered, including whether abnormalities in BDNF persist beyond the clinical state of depression, whether BDNF levels are related to the clinical features of depression and whether distinct antidepressants affect BDNF levels equally. We addressed these questions and investigated serum BDNF levels in 962 depressed patients, 700 fully remitted persons (≥6 months) and 382 healthy controls. We found serum BDNF levels to be low in antidepressant-free depressed patients relative to controls (P=0.007) and to depressed patients who were treated with an antidepressant (P=0.001). BDNF levels of fully remitted persons (whether unmedicated or treated with an antidepressant) were comparable to those of controls. Analyzing the sample of antidepressant-free depressed patients showed that BDNF levels were unrelated to the core clinical features of depression such as its severity or first versus a recurrent episode. The antidepressant associated upregulation of serum BDNF in depressed patients was confined to selective serotonin reuptake inhibitors (SSRIs) (P=0.003) and St John's wort (P=0.03). Our results suggest that low serum levels of BDNF are a state abnormality that is evident during depression and normalizes during remission. Increases in serum levels of BDNF during antidepressant treatment appear to be confined to some antidepressants and do not parallel clinical characteristics, such as the severity of depressive symptoms.

Recurrent long-lasting tethering reduces BDNF protein levels in the dorsal hippocampus and frontal cortex in pigs.

Brain-derived neurotrophic factor (BDNF) signaling has been implicated in the onset of depression and in antidepressant efficacy, although the exact role of this neurotrophin in the pathophysiology of depression remains to be elucidated. Also, the interaction between chronic stress, which may precede depression, corticosteroids and BDNF is not fully understood. The present study aimed at investigating whether long-lasting, recurrent tethering of sows during a period of 1.5 or 4.5 years leads to enduring effects on measures that may be indicative of chronic stress, compared with animals kept in a group housing system ('loose' sows). Immediately after slaughter, the frontal cortex, dorsal and ventral hippocampus were dissected and protein levels of BDNF and its receptors were analyzed and compared with plasma cortisol levels and adrenal weights. Results indicate that tethering stress reduced BDNF protein levels in the dorsal hippocampus and the frontal cortex, but not in the ventral hippocampus. In addition, levels of TrkB, the high affinity receptor for BDNF, were increased in the dorsal hippocampus. Plasma cortisol levels and adrenal weight were increased after tethering. These stress effects on BDNF levels were more pronounced after 4.5 years of recurrent tethering and negatively correlated in particular in the frontal cortex with cortisol levels and adrenal weight. This suggests that the stress effect of tethered housing on neurotrophin levels may be mediated via cortisol. Taken together, these data indicate that recurrent tethering stress in sows over 4.5 years results in a loss of neurotrophic support by BDNF, mediated by an overactive neuroendocrine system.

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.

SLV330, a cannabinoid CB1 receptor antagonist, ameliorates deficits in the T-maze, object recognition and Social Recognition Tasks in rodents.

Cannabinoid CB(1) receptor (CB(1)R) signaling 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 CB(1)R antagonist SLV330 (doses ranging from 0.3 to 10mg/kg, given orally, p.o.) could ameliorate impairments in distinct aspects of cognition using different disruption models in both mice and rats. Effects of SLV330 were tested on working memory deficits in the T-maze Continuous Alternation Task (T-CAT) in mice; episodic memory deficits in the Object Recognition Task (ORT) and Social Recognition Task (SRT) in rats. The acetylcholinesterase inhibitor (AChEI) donepezil (Aricept, approved for symptomatic treatment of Alzheimer's disease) and nicotine were used as reference compounds. SLV330 markedly improved aging and scopolamine-induced memory deficits in the T-CAT in mice with a lowest effective dose (LED) of 1mg/kg p.o., while reversing the cognitive dysfunction induced by the N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801) only at the middle dose of 3mg/kg. In the ORT, we have found that combined administration of subthreshold doses of SLV330 (1mg/kg, p.o.) and the AChEI donepezil (0.1mg/kg, p.o.), that had no discernable effects on performance when given alone, enhanced memory performance in Wistar rats with deficits induced by the muscarinic antagonist scopolamine, suggestive of additive synergistic effects of SLV330 and donepezil on cognitive impairment. Finally, SLV330 was found to have cognition enhancing properties in a time delay paradigm in the SRT at a LED dose of 3mg/kg (p.o.). In conclusion, the CB(1)R antagonist SLV330 was found to clearly improve memory in several preclinical models for cognitive impairment.

Circulating microRNAs as potential biomarkers for psychiatric and neurodegenerative disorders.

Circulating microRNAs (cimiRNAs) are a class of non-encoding RNAs found in bodily fluids such as blood, cerebrospinal fluid (CSF) and tears. CimiRNAs have been implicated as promising biomarkers for central nervous system (CNS) disorders because they are actively secreted as messengers and are profoundly involved in fine-tuning of developmental and differentiation processes. Furthermore, they are attractive biomarkers because they are extremely stable, tissue enriched and can be determined in a quantitative manner. This review aims to provide a comprehensive assessment on the current progress regarding the potential value of cimiRNAs as CNS biomarkers. Within this framework five CNS disorders are explored which share a common pathological hallmark namely cognitive impairment. The CNS disorders include Major depression disorder (MDD), Bipolar disorder (BD), Schizophrenia (SZ), Alzheimer's disease (AD) and Parkinson disease (PD). The similarities and differences between altered cimiRNAs in the different disorders are described. The miR-29 family, miR-34a-5p and miR-132-3p are discussed as common dysregulated cimiRNAs found in the CNS disorders. Furthermore, it is shown that the type of bodily fluid used for measuring cimiRNAs is important as inconsistencies in cimiRNAs expression directions are found when comparing CSF, blood cell-free and blood cell-bound samples.

The effect of curcumin on cognition in Alzheimer's disease and healthy aging: A systematic review of pre-clinical and clinical studies.

Alzheimer's disease constitutes a growing cause of cognitive impairment in aging population. Given that current treatments do not produce the desired therapeutic effects, the need for finding alternative biological and pharmacological approaches is critical. Accumulating evidence suggests inflammatory and oxidative stress responses as potential causal factors of cognitive impairments in Alzheimer's disease and healthy aging. Curcumin has received increased interest due to its unique molecular structure that targets inflammatory and antioxidant pathways as well as (directly) amyloid aggregation; one of the major hallmarks of Alzheimer's disease. Therefore, this review summarizes preclinical and clinical findings on curcumin as a potential cognitive enhancer in Alzheimer's disease and normal aging. Databases used for literature searches include PubMed, EMBASE and Web of Science; in addition, clinicaltrials.gov was used to search for clinical studies. Overall, animal research has shown very promising results in potentiating cognition, both physiologically and behaviourally. However, human studies are limited and results are less consistent, complicating their interpretation. These inconsistencies may be related to differences in methodology and the included population. Taking into account measurements of important inflammatory and antioxidant biomarkers, optimal dosages of curcumin, food interactions, and duration of treatment would increase our understanding on curcumin's promising effects on cognition. In addition, increasing curcumin's bioavailability could benefit future research.

Sub-chronic rolipram treatment leads to a persistent improvement in long-term object memory in rats.

In the present study the effects of sub-chronic rolipram treatment in an object recognition task in 3-month-old male rats were investigated. Rats remember which object they have explored in a previous trial (T1) when they are tested 1 h later (T2). However, when tested 24 h later, they do not remember which object was presented to them in the first trial. Drug treatments may improve discrimination performance after 24 h, i.e., improve memory for the familiar object. Rats were sub-chronically treated with 0.5 mg/kg rolipram (p.o.) for five consecutive days and tested with a 24 h delay between T1 and T2. Memory performance in the object recognition task was assessed before, during and after sub-chronic treatment. In addition, we investigated whether the timing of the final dose, i.e., 24, 1, or 6 h before training, had an effect on memory performance. During sub-chronic treatment, i.e., after 2-3 days of rolipram treatment, moderate effects on memory performance were observed. Regardless of when the final administration was given, sub-chronic rolipram treatment improved long-term memory performance. Since plasma and brain rolipram levels were undetectable at 24 h before the test, and acute treatment with rolipram 24 h before training had no effects, the observed memory enhancement cannot be attributed to acute rolipram effects. The long-term memory enhancing effects of rolipram might be explained by long-lasting neuronal changes by the chronic treatment due to recurring activation of the cAMP/PKA/CREB pathway leading to CREB phosphorylation.

Selective PDE inhibitors rolipram and sildenafil improve object retrieval performance in adult cynomolgus macaques.

RATIONALE: Selective phosphodiesterase (PDE) inhibitors improve the formation of hippocampus-dependent memories in several rodent models of cognition. However, studies evaluating the effects of PDE inhibition on prefrontal cortex-dependent cognition and in monkeys are rare. OBJECTIVES: The present study investigates the effect of the PDE4 inhibitor rolipram and the PDE5 inhibitor sildenafil on object retrieval performance. Object retrieval is a prefrontal cortical-mediated task, which is likely to capture attention and response inhibition. MATERIALS AND METHODS: The ability to retrieve a food reward from a clear box with an open side positioned in various orientations was assessed in adult male cynomolgus monkeys (Macaca fascicularis). RESULTS: Rolipram (0.003-0.03 mg/kg, intramuscular [i.m.]) and sildenafil (0.3-3 mg/kg, i.m.) dose-dependently increased correct first reaches during difficult trials, reaching significance at 0.01 and 1 mg/kg, respectively. For both drugs, correct reaches were increased approximately 20%; that is, performance was improved from approximately 50 to approximately 70% correct. CONCLUSIONS: Both rolipram and sildenafil improved object retrieval performance, thus demonstrating the cognition-enhancing effects of PDE inhibition on a prefrontal task of executive function in monkeys.

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.

Phosphodiesterase 4 inhibition affects both the direct and indirect pathway: an electrophysiological study examining the tri-phasic response in the substantia nigra pars reticulata.

Fronto-striatal circuits constitute the neurobiological basis of many neuropsychiatric disorders. Part of the intracellular signaling within these circuits, including its dopaminergic modulation, is regulated by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling cascade. Based on the overall expression in human fronto-striatal circuitry, we tested the effects of a cAMP selective phosphodiesterase 4 (PDE4) inhibitor on the tri-phasic response in the dorsomedial substantia nigra pars reticulata (SNr) upon stimulation of the infralimbic cortex in rats. Our results show for the first time that stimulation of the cognitive infralimbic cortex leads to a tri-phasic response in SNr neurons. In addition and in line with previous biochemical and behavioral studies, PDE4 inhibition by roflumilast affects the direct pathway as well as the indirect pathway of which the latter appears more sensitive than the former.

Phosphodiesterase inhibition and modulation of corticostriatal and hippocampal circuits: Clinical overview and translational considerations.

The corticostriatal and hippocampal circuits contribute to the neurobiological underpinnings of several neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease and schizophrenia. Based on biological function, these circuits can be clustered into motor circuits, associative/cognitive circuits and limbic circuits. Together, dysfunctions in these circuits produce the wide range of symptoms observed in related neuropsychiatric disorders. Intracellular signaling in these circuits is largely mediated through the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway with an additional role for the cyclic guanosine monophosphate (cGMP)/ protein kinase G (PKG) pathway, both of which can be regulated by phosphodiesterase inhibitors (PDE inhibitors). Through their effects on cAMP response element-binding protein (CREB) and Dopamine- and cAMP-Regulated PhosphoProtein MR 32 kDa (DARPP-32), cyclic nucleotide pathways are involved in synaptic transmission, neuron excitability, neuroplasticity and neuroprotection. In this clinical review, we provide an overview of the current clinical status, discuss the general mechanism of action of PDE inhibitors in relation to the corticostriatal and hippocampal circuits and consider several translational challenges.

The mediating role of phosphodiesterase type 4 in the dopaminergic modulation of motor impulsivity.

The current study investigated the mediating role of phosphodiesterase type 4 (PDE4) regulated cAMP in the dopaminergic modulation of premature responding (action restraint) in rats. Response inhibition, which includes action restraint, finds its neurobiological origin in cortico-striatal-thalamic circuitry and can be modulated by dopamine. Intracellularly, the effect of dopamine is largely mediated through the cAMP/PKA signaling cascade. Areas in the prefrontal cortex are very sensitive to their neurochemical environment, including catecholamine levels. As a result, we investigated the effects of intracellular modulation of the dopamine cascade by means of PDE4 inhibition by roflumilast on premature responding in a hypo, normal and hyper dopaminergic state of the brain. As a hypo dopaminergic model we induced a 6-OHDA lesion in the (rat) prefrontal cortex, more specifically the infralimbic cortex. For the hyper dopaminergic state we also turned to a well-established model of impaired action restraint, namely the systemic administration of d-amphetamine. In line with the notion of a U-shaped relation between dopamine and impulsive responding, we found that both increasing and decreasing dopamine levels resulted in an increase in premature responding in the choice serial reaction time task (CSRTT). The PDE4 inhibitor roflumilast increased premature responses in combination with d-amphetamine, whereas a decrease in premature responding after roflumilast treatment was found in the 6-OHDA lesioned animals. As a result, it would be interesting to test the effects of PDE4 inhibition in disorders affected by disrupted impulse control related to cortico-striatal-thalamic hypodopaminergia including attention deficit hyperactivity disorder (ADHD).

Acute administration of roflumilast enhances immediate recall of verbal word memory in healthy young adults.

The need for new and effective treatments for dementia remains indisputably high. Phosphodiesterase inhibitors (PDE-Is) have proven efficacy as cognitive enhancers based on their positive effects in numerous preclinical studies. Especially the PDE4 subfamily is of interest due to its expression in the hippocampus, the key structure for memory formation. The current study investigates the memory enhancing effects of the clinically approved PDE4-I roflumilast in a test battery including the Verbal Learning Task (VLT) combined with electroencephalography (EEG) recording. This acute study was conducted according to a double-blind, randomized, placebo-controlled, 4-way crossover design. Three capsulated dosages of roflumilast HCl (Daxas) and a placebo were administered in four study periods. Administration occurred 1 h before testing to reach maximal plasma concentrations. Memory performance was assessed using a 30 word Verbal Learning Task. The number of words recalled both immediately and after 45 min and 24 h were included as outcome measures. EEG was recorded during the cognitive tasks on the first day. Different event-related potentials (ERPs) were considered with special emphasis on P600, as this peak has been related to word learning. Memory performance was significantly improved after acute administration of 100 µg roflumilast. Specifically, immediate recall performance on the VLT increased 2-3 words, accompanied by an enhanced P600 peak during word presentation at the third learning trial. No side effects typical for PDE4-Is were reported for the lowest and effective dose of 100 µg roflumilast. The current proof-of-concept study shows for the first time the potential of low-dose roflumilast administration as a memory enhancer in humans.

Improving memory: a role for phosphodiesterases.

During the last decennia, our understanding of the neurobiological processes underlying learning and memory has continuously improved, leading to the identification of targets for the development of memory-enhancing drugs. Here we review a class of drugs which has more recently been identified: the phosphodiesterase (PDE) inhibitors. An overview is given of the different PDEs that are known and we focus on three PDEs which have been identified as possible relevant targets for memory improvement: PDE2, PDE4 and PDE5. PDEs differ in the substrate, i.e. cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP), being hydrolyzed. Since these cyclic nucleotides have been suggested to play distinct roles in processes of memory, selective PDE inhibitors preventing the breakdown of cAMP and/or cGMP could improve memory. The present data suggest that PDE4 (cAMP) is involved in acquisition processes, although a possible role in late consolidation processes cannot be excluded. PDE5 (cGMP) is involved in early consolidation processes. Since PDE2 inhibition affects both cAMP and cGMP, PDE2 inhibitors may improve both memory processes. The field of PDEs is highly dynamic and new isoforms of PDEs are still being described. This may lead to the discovery and development of new memory enhancing drugs that selectively inhibit such isoforms. Such drugs may exert their effects only in specific brain areas and hence possess an improved side effect profile.