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Background: Electronic clinical decision support (CDS) is increasingly establishing its role in evidence-based clinical practice. Considerable evidence supports its enhancement of efficiency in e-Prescribing, but some controversy remains. This study evaluated the practicality and identified the perceived benefits of, and barriers to, its future adoption in the West of Ireland. Methods: This cross sectional study was carried out by means of a 27-part questionnaire sent to 262 registered general practitioners in Counties Galway, Mayo and Roscommon. The survey domains encompassed general information of individual's practice, current use of CDS and the practitioner's attitudes towards adoption of CDS-eP. Descriptive and inferential analyses were performed to analyse the data collected. Results: The overall response rate was 37%. Nearly 92% of respondents employed electronic medical records in their practice. The majority acknowledged the value of electronic CDS in improving prescribing quality (71%) and reducing prescribing errors (84%). Despite a high degree of unfamiliarity (73%), the practitioners were open to the use of CDS-eP (94%) and willing to invest greater resources for its implementation (62%). Lack of a strategic implementation plan (78%) is the main perceived barrier to the incorporation of CDS-eP into clinical practice, followed by i) lack of financial incentives (70%), ii) lack of standardized product software (61%), iii) high sensitivity of drug-drug interaction or medication allergy markers (46%), iv) concern about overriding physicians' prescribing decisions(44%) and v) lack of convincing evidence on the systems' effectiveness (22%). Conclusions: Despite favourable attitudes towards the adoption of CDS-eP, multiple perceived barriers impede its incorporation into clinical practice. These merit further exploration, taking into consideration the structure of the Irish primary health care system, before CDS-eP can be recommended for routine clinical use in the West of Ireland. [ABSTRACT FROM AUTHOR]

Abstract: Behavior maintained under a differential-reinforcement-of-low-rate (DRL) 72-s operant schedule, which reinforces responses with interresponse times greater than 72s, exhibits a rather unique sensitivity to antidepressant drugs. Antidepressants from a number of pharmacological classes, including tricyclic antidepressants, selective serotonin or norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, as well as a number of atypical antidepressants and putative antidepressants, reduce response rate and increase reinforcement rate of rats under this schedule. These effects are observed acutely but persist or are augmented with repeated treatment. By contrast, drugs from a number of other psychotherapeutic classes do not, in general, produce similar effects. This includes anxiolytic, sedative, stimulant, opioid, antihistaminic, and anticholinergic drugs, which can produce false positive results in some preclinical tests for antidepressant efficacy. There are conflicting data regarding the utility of DRL behavior for discriminating the effects of antidepressant and antipsychotic drugs. This results in part from methodological differences among studies, but likely also reflects the overlap between the neuropharmacological and clinical effects of some antipsychotic and antidepressant drugs. DRL behavior also has proven useful for identifying neurochemical and neuroanatomical mediators of antidepressant effects on behavior. Consistent with clinical data, it appears that activation of noradrenergic or serotonergic systems provides for parallel means of producing antidepressant-like effects on DRL behavior. Finally, the results of studies using DRL behavior highlight important roles for central beta-1 adrenergic receptors, as well as 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT2C receptors, in the mediation of antidepressant-like behavioral effects. [Copyright &y& Elsevier]

Despite initial promise, the development of type 4 phosphodiesterase (PDE4) inhibitors as antidepressants has not advanced significantly. This is due to an incomplete understanding of the functional importance of PDE4 subtypes and high-affinity and low-affinity inhibitor-binding conformers. However, recent developments have rekindled interest in the therapeutic potential of PDE4 inhibitors. First, PDE4 has been shown to be involved in cAMP signaling pathways that are affected by antidepressants. Second, data obtained using mouse knockout lines indicate that PDE4D and PDE4B mediate antidepressant effects. Third, it appears that the interaction of inhibitors with the high-affinity binding conformer of PDE4 is particularly important for antidepressant efficacy. These developments highlight the difficulties of dissociating the actions of PDE4 inhibitors and provide a guide for future research. [Copyright &y& Elsevier]

We describe the use of a commercially available telemetry and data acquisition system to record heart rate, body temperature and activity of freely behaving rats with transmitters that operate without batteries (transponders). The system uses PDT 4000HR E-Mitters (Mini Mitter, OR, USA) to acquire animal temperature, heart rate and motor activity data. E-Mitters obtain power from a radiofrequency field produced by an ER-4000 energizer/receiver so that transponders can collect data on heart rate, body temperature and gross motor activity. ER-4000 energizers/receivers are designed to be placed below the animals'' cage. Data output from receivers is managed by a Windows PC-based data acquisition system, VitalView™. In this study, we report that a good correlation exists between VitalView™ and Powerlab for the determination of heart rate and between intra-abdominal (telemetric) and colonic body temperature (rectal digital thermometer) in rats. Assessment of this system by using agents that have well-documented effects on heart rate, body temperature and locomotor activity have also been determined. An additional feature of VitalView™ is the incorporation of behavioural inputs (feeding monitors to monitor duration and frequency of feeding and a lickometer to monitor drinking bouts) into the data acquisition system designed primarily to acquire data from the implanted transponders. Circadian rhythms for all parameters were established in rats with E-Mitters implanted. VitalView™ may be used for the determination of multiple parameters in freely behaving animals using transponders, which operate without batteries. This capability is unique in its field and represents a recent advance in biotelemetric monitoring of laboratory animals. [Copyright &y& Elsevier]

Abstract Rationale: Rolipram, a selective inhibitor of cyclic AMP-specific phosphodiesterase (PDE4), has been shown to enhance scopolamine-induced impairment of working memory. However, its effect on reference memory, which appears to be related to the level of cyclic AMP (cAMP), has not been investigated yet; in addition, the mechanism involved in its effects on memory remains to be elucidated. Objectives: To investigate the effects of rolipram on working and reference memories impaired by scopolamine and the involvement of cAMP. Methods: By administration (IP) of rolipram and forskolin, an activator of adenylyl cyclase (AC), the effects of both drugs on the number of correct choices and errors in experiment 1 and, the frequency of both working memory errors and reference memory errors in experiment 2 were observed in two eight-arm radial maze tasks in rats. Results: In experiment 1, rolipram (0.01-1.0 mg/kg) attenuated the scopolamine-induced (0.5 mg/kg) increase in the total number of errors in dose- and time-dependent manners. The minimum effective dose of rolipram was 0.05 mg/kg and the effects lasted nearly 60 min. By contrast, forskolin (1.010.0 mg/kg) failed significantly to affect any of the above indices altered by scopolamine. In experiment 2, rolipram (0.05 and 0.1 mg/kg) decreased the frequencies of both working and reference memory errors that were elevated by scopolamine. Forskolin did not alter either type of error at a dose that increased the exploration time. Conclusion: Rolipram may exert its effects of reversing both working and reference memory impairments via increased cyclic AMP concentrations in certain signal transduction pathways, rather than by a generalized increase in cAMP. [ABSTRACT FROM AUTHOR]

Abstract: Phosphodiesterase-10A (PDE10A), -1B (PDE1B), -4B (PDE4B), and -4A (PDE4A) are important regulators of signal transduction in striatum due to their catalysis of cyclic AMP and cyclic GMP. The typical antipsychotic drug haloperidol and the atypical antipsychotic drug clozapine are thought to regulate cyclic nucleotide signaling in striatum. Since this brain region is essential in mediation of both therapeutic and extrapyramidal side effects, it was of interest to determine whether chronic treatment for 21days with haloperidol (1mg/kg) or clozapine (20mg/kg) affected PDE expression in rat striatum. This was accomplished using SDS-PAGE/immunoblotting and real-time RT-PCR. Both antipsychotic drugs increased PDE10A and did not change PDE4A. By contrast, PDE1B was increased by haloperidol treatment, but not clozapine treatment, while PDE4B was increased by clozapine, but not haloperidol. In all cases, changes in protein expression were accompanied by corresponding changes in mRNA, and only were observed with chronic treatment. Up-regulation of PDEs may represent compensatory responses to haloperidol and clozapine treatments, due to altered cyclic nucleotide signaling, and that different patterns of effects produced by these drugs may be associated with their mechanisms of action. [Copyright &y& Elsevier]

Abstract: Cyclic nucleotide phosphodiesterase-4 (PDE4) is a component of signaling pathways involved in the mediation of antidepressant activity. Of the four PDE4 subtypes, PDE4D appears to be of particular importance, given the finding that PDE4D-deficient mice exhibit an antidepressant-like behavioral phenotype. In mouse hippocampus and cerebral cortex, the effects of repeated treatment with the antidepressants desipramine and fluoxetine or the PDE4 inhibitor rolipram on the expression of PDE4D was compared to that of PDE4A and PDE4B, the other two subtypes expressed in the brain. Expression of PDE4D was increased by all drugs tested, with the exception of desipramine in hippocampus. By contrast, these treatments affected PDE4A and PDE4B expression differentially. In hippocampus, antidepressants increased PDE4A and decreased PDE4B, whereas ROL decreased PDE4A and did not change PDE4B. In cerebral cortex, antidepressants increased PDE4A and did not change PDE4B, whereas ROL did not change PDE4A and increased PDE4B. 3H-Rolipram binding was increased in cytosolic, but not in membrane, fractions of cerebral cortex by all drugs tested; there were no changes observed in hippocampus. Overall, the present results suggest some species-dependence of the regulation of PDE4 subtypes, based on data obtained previously using rats. They also suggest that the PDE4D subtype may be of particular importance as an antidepressant target in that it is regulated by repeated treatment with both norepinephrine and serotonin reuptake inhibitors as well as by the PDE4 inhibitor rolipram, drugs that produce antidepressant effects via different neuropharmacological mechanisms. [Copyright &y& Elsevier]

Background: N6-methyladenosine (m6A) modification of RNA influences fundamental aspects of RNA metabolism and m6A dysregulation is implicated in various human diseases. In this study, we explored the potential role of RNA m6A modification in the pathogenesis of Alzheimer disease (AD). Methods: We investigated the m6A modification and the expression of m6A regulators in the brain tissues of AD patients and determined the impact and underlying mechanism of manipulated expression of m6A levels on AD-related deficits both in vitro and in vivo. Results: We found decreased neuronal m6A levels along with significantly reduced expression of m6A methyltransferase like 3 (METTL3) in AD brains. Interestingly, reduced neuronal m6A modification in the hippocampus caused by METTL3 knockdown led to significant memory deficits, accompanied by extensive synaptic loss and neuronal death along with multiple AD-related cellular alterations including oxidative stress and aberrant cell cycle events in vivo. Inhibition of oxidative stress or cell cycle alleviated shMettl3-induced apoptotic activation and neuronal damage in primary neurons. Restored m6A modification by inhibiting its demethylation in vitro rescued abnormal cell cycle events, neuronal deficits and death induced by METTL3 knockdown. Soluble Aβ oligomers caused reduced METTL3 expression and METTL3 knockdown exacerbated while METTL3 overexpression rescued Aβ-induced synaptic PSD95 loss in vitro. Importantly, METTL3 overexpression rescued Aβ-induced synaptic damage and cognitive impairment in vivo. Conclusions: Collectively, these data suggested that METTL3 reduction-mediated m6A dysregulation likely contributes to neurodegeneration in AD which may be a therapeutic target for AD. [ABSTRACT FROM AUTHOR]

Rationale. Stimulation of central β[sub 2] adrenergic receptors produces antidepressant-like effects on behavior. At present, it is not known what brain sites are involved in mediating such effects, although some recent evidence suggests the importance of the dorsal hippocampus. Objective. Experiments were carried out to determine whether central administration of β-adrenergic antagonists blocks antidepressant-like effects produced by peripheral administration of the β[sub 2]-adrenergic agonist clenbuterol. Methods. The following were determined: 1) the ability of ICV or intrahippocampal administration of the non-selective β adrenergic antagonists propranolol and CGP-12177, which are lipophilic and hydrophilic, respectively, to antagonize the effects of peripherally administered clenbuterol on differential-reinforcement-of-low-rate (DRL) behavior; 2) the effects of clenbuterol, administered bilaterally into the dorsal hippocampus, on DRL behavior. Results. The antidepressant-like effects of clenbuterol, i.e. reduced response rate and increased reinforcement rate under the DRL schedule, were antagonized by either ICV or bilateral intrahippocampal infusions of propranolol or CGP-12177; CGP-12177 was approximately 8-fold more potent than propranolol. Direct infusion of clenbuterol into the bilateral dorsal hippocampus also produced antidepressant-like effects. Conclusions. Central β-adrenergic receptors, in particular those in the dorsal hippocampus, are involved in the mediation of the antidepressant-like effect of clenbuterol. Probably resulting from its enhanced access to the sites of action, the hydrophilic antagonist CGP-12177 was more potent than the lipophilic antagonist propranolol, even though they exhibit similar potency in vitro. [ABSTRACT FROM AUTHOR]

Rationale: Rolipram, an inhibitor of cyclic AMP phosphodiesterase (PDE4) produces discriminative stimulus effects in rats. These effects may be related to a wide range of central nervous system effects described previously. Objective: The purposes of the present study were to: (i) assess the specificity of the discriminative stimulus effects of rolipram; (ii) examine the role of beta adrenergic receptors; (iii) assess the effects of imipramine and nisoxetine; and (iv) determine whether SKF 38393, a compound which also increases cAMP levels, substitutes for rolipram. Methods: Rats were trained to discriminate 0.1 mg/kg rolipram from its vehicle in a two-lever task. Following discrimination training, substitution and antagonism tests were carried out. Results: In generalization tests, the PDE4 inhibitors ICI 63,197 and Ro 20-1724 substituted for rolipram in a dose-dependent manner (substitution at 0.3 mg/kg and 3 mg/kg, respectively). The selective inhibitors of PDE1, PDE2, and PDE5/6 did not substitute for rolipram; however, a dose of 10 mg/kg of the PDE3 inhibitor milrinone did substitute. The beta adrenergic agonists clenbuterol and dobutamine at least partially substituted for rolipram (0.1 mg/kg and 18 mg/kg, respectively). By contrast, the D1 dopaminergic agonist SKF 38393 and the monoamine uptake inhibitors imipramine and nisoxetine were ineffective (at doses up to 3, 10, and 10 mg/kg, respectively). Conclusions: The present results indicate that the discriminative stimulus effects of rolipram are related to the inhibition of the hydrolytic activity of PDE4. Generalized increases in cyclic nucleotides do not appear to be sufficient for producing rolipram-like effects. It appears that a mechanism involving beta adrenergic receptors may contribute to the effects of rolipram, consistent with previous neuropharmacological data. Finally, the discriminative stimulus effects of rolipram appear to be unrelated to its antidepressant-like effect, but may provid... [ABSTRACT FROM AUTHOR]

Abstract Rationale: Centrally active beta-1 and beta-2 agonists produce antidepressant-like effects in several behavioral tests, suggesting that these receptors may be involved in the mediation of the effects of antidepressant drugs. Objectives: This study aimed to evaluate the ability of intra-cerebral ventricular (ICV) isoproterenol to produce discriminative stimulus effects mediated by beta adrenergic receptors, establishing a reliable model of in vivo activation of central beta adrenergic receptors. Methods: Rats were trained to discriminate the non-selective beta adrenergic agonist isoproterenol (10 mu g ICV) from artificial cerebral spinal fluid (aCSF) using a water-reinforced two-lever operant task [fixed ratio-10 schedule of reinforcement (FR10)]. For substitution and antagonism tests, drugs were administered IP. Results: Following acquisition of the discrimination, ICV isoproterenol produced dose-related increases in drug-appropriate responding (ED[sub 50]=1.14 mu g). The beta-1 selective adrenergic agonist dobutamine fully substituted for isoproterenol at a dose of 0.3 mg/kg (ED[sub 50]=0.15 mg/kg). By contrast, the beta-2 selective adrenergic agonist clenbuterol produced 20% isoproterenol-appropriate responding when administered at doses up to 0.1 mg/kg. The beta adrenergic antagonist propranolol fully antagonized the isoproterenol cue at a... [ABSTRACT FROM AUTHOR]

Rationale: Currently available PDE2 inhibitors have poor brain penetration that limits their therapeutic utility in the treatment of depression. Hcyb1 is a novel selective PDE2 inhibitor that was introduced more lipophilic groups with polar functionality to the scaffold pyrazolopyrimidinone to improve the blood-brain barrier (BBB) penetration. Our previous study suggested that Hcyb1 increased the neuronal cell viability and exhibited antidepressant-like effects, which were parallel to the currently available PDE2 inhibitor Bay 60-7550. Objectives: The present study investigated whether Hcyb1 protected HT-22 cells against corticosterone-induced neurotoxicity and produced antidepressant-like effects in behavioral tests in stressed mice. Methods: The neuroprotective effects of Hcyb1 against corticosterone-induced cell lesion were examined by cell viability (MTS) assay. The enzyme-linked immunosorbent assay (ELISA) and immunoblot analysis were used to determine the levels of cAMP or cGMP and expression of pCREB or BDNF, respectively, in the corticosterone-treated HT-22 cells. The antidepressant-like effects of Hcyb1 were determined in the tail suspension and novelty suppressed feeding tests in stressed mice. Results: In the cell-based assay, Hcyb1 significantly increased cell viability of HT-22 cells against corticosterone-induced neurotoxicity in a time- and dose-dependent manner. Hcyb1 also rescued corticosterone-induced decreases in both cGMP and cAMP levels, pCREB/CREB and BDNF expression. These protective effects of Hcyb1 were prevented by pretreatment with either the PKA inhibitor H89 or the PKG inhibitor KT5823. Moreover, Hcyb1 reversed acute stress–induced increases in immobility time and the latency to feed in the tail suspension and novelty suppressed feeding tests, respectively, which were prevented by pretreatment with H89 or KT5823. Conclusion: These findings provide evidence that the neuroprotective effects of Hcyb1 are mediated by PDE2-dependent cAMP/cGMP signaling. [ABSTRACT FROM AUTHOR]

Single‐housed stress elicits a range of social isolation‐related behavioral and neurobiological abnormalities. To investigate single housing‐induced behavioral changes and sex differences on stress outcomes, we examined single‐housed stress‐induced learning and memory impairment, depression‐like behaviors, neuroplasticity abnormalities and underlying mechanism. The results showed that male and female mice socially isolated for 8 weeks had significantly decreased memory acquisition, as demonstrated in the learning curve of the Morris water maze task. Memory consolidation and retrieval were also decreased in both the single‐housed male and female mice. These findings were corroborated further by the two classical animal models, Y‐maze and novel object recognition tests, as demonstrated by reduced spontaneous alternation and recognition index in both sexes of single‐housed mice. Subsequent studies suggested that single‐housed male mice exhibited increased immobility time in both the forced swim and tail suspension tests, while the female mice only exhibited increased immobility time in the tail suspension test. Moreover, single‐housed stress significantly decreased the apical and basal branch points, dendritic length, and spine density in the CA1 of hippocampal neurons in both male and female mice. These effects were consistent with decreased neuroplasticity and neuroprotective‐related molecules such as synaptophysin, PSD95, PKA, pCREB and BDNF expression. These findings suggest that loss of neuronal remodeling and neuroprotective mechanisms due to single housing are involved in behavioral changes in both male and female mice. The results provide further evidence that neuroplasticity‐related signaling plays a crucial role in isolation‐induced effects on neuropsychiatric behavioral deficits in both sexes. [ABSTRACT FROM AUTHOR]

Resveratrol is a natural non-flavonoid polyphenol found in red wine, which has numerous pharmacological properties including anti-stress and antidepressant-like abilities. However, whether the antidepressant- and anxiolytic-like effects of resveratrol are related to the inhibition of phosphodiesterase 4 (PDE4) and its subtypes remains unknown. The same holds true for the subsequent cAMP-dependent pathway. The first set of studies investigated whether resveratrol exhibited neuroprotective effects against corticosterone-induced cell lesion as well as its underlying mechanism. We found that 100 μM corticosterone induced PDE2A, PDE3B, PDE4A, PDE4D, PDE10 and PDE11 expression in HT-22 cells, which results in significant cell lesion. However, treatment with resveratrol increased cell viability in a dose- and time-dependent manner. These effects seem related to the inhibition of PDE4D, as evidenced by resveratrol dose-dependently decreasing PDE4D expression. In addition, the PKA inhibitor H89 reversed resveratrol's effects on cell viability. Resveratrol prevented corticosterone-induced reduction in cAMP, pVASP(s157), pCREB, and BDNF levels, indicating that cAMP signaling is involved in resveratrol-induced neuroprotective effects. Not to mention, PDE4D knockdown by PDE4D siRNA potentiated the effect of low dose of resveratrol on cAMP, pVASP, pCREB, and BDNF expression, while PDE4D overexpression reversed the effect of high dose of resveratrol on the expression of the above proteins. Finally, the subsequent in vivo data supports the in vitro findings, suggesting that resveratrol-induced antidepressant- and anxiolytic-like effects are mediated by PDE4D. Overall, these findings support the hypothesis that PDE4D-mediated cAMP signaling plays an important role in resveratrol's protective effects on stress-induced depression- and anxiety-like behavior. • The neuroprotective effects of resveratrol in vitro or in vivo were investigated. • The increases of PDE4D in the hippocampus led to depression- and anxiety-like behavior. • PDE4D-mediated cAMP signaling may play an important role in resveratrol's protective effects in stressed mice. [ABSTRACT FROM AUTHOR]

Background: Phosphodiesterase-2 (PDE2) is a cyclic nucleotide phosphodiesterase and is highly expressed in the amygdala, which suggests its important role in anxiety-like behavior.Aims: The present study examined whether reduced PDE2A expression in the central nucleus of the amygdala (CeA) produces anxiolytic-like effects in mice.Methods: PDE2A knockdown in amygdaloid (AR5) cells or the CeA was established using a lentiviral vector-based siRNA system. The anxiety-like behaviors were detected by the elevated plus maze (EPM) and hole-board tests in mice. The related proteins involved in cAMP/cGMP-dependent signaling, such as specific marker VASPser239, CREBser133 and BDNF were detected by immunoblot analysis.Results: PDE2A inhibition in AR-5 cells resulted in increases in cAMP/cGMP-related pVASPser239 and pCREBser133. Behavioral tests showed that PDE2A knockdown in the CeA induced anxiolytic-like effects as evidenced by the increases in percentages of open-arm entries and time spent in the open arms in the EPM test, and the increases in head dips and time spent in head dipping in the hole-board test. However, these anxiolytic-like effects were antagonized by pre-treatment of soluble guanylyl cyclase inhibitor ODQ or adenylate cyclase inhibitor SQ. Furthermore, PDE2A knockdown significantly increased pVASPSer239, pCREBSer133 and decreased BDNF expression in the amygdala. Pre-intra-CeA of ODQ or SQ reversed or partially prevented the effects of PDE2A knockdown on these proteins.Conclusions: The results suggest that PDE2A plays a crucial role in the regulation of anxiety by the cGMP/cAMP-dependent pVASP-pCREB-BDNF signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract Phosphodiesterase 2 (PDE2) plays an important role in treatment of stress-related depression through regulation of antioxidant defense and neuroprotective mechanisms. However, the causal relationship between PDE2 and the prevalence of depression and anxiety upon exposure to oxidative stress has not been investigated. The present study examined whether the effects of PDE2 inhibition on oxidative stress were directly involved in reduced ROS by regulating NADPH subunits gp91phox oxidase. The results suggested that the PDE2 inhibitor Bay 60-7550 reversed oxidative stress-induced behavioral signature, i.e. depression and anxiety. Pretreatment with the oxidizing agent DTNB completely blocked, while the reducing agent DTT and the NADPH oxidase inhibitor apocynin potentiated the effects of Bay 60-7550 on behavioral abnormalities, demonstrating the relationship between PDE2 and oxidative stress. Consistently, an in vitro test revealed the positive correlation between ROS and PDE2 levels. Moreover, Bay 60-7550 decreased corticosterone-induced gp91phox expression, which is the source of ROS. The subsequent study suggested that Bay 60-7550 induced decrease in ROS and increase in cAMP/cGMP, pVASP, pCREB, and the neurotrophic factor BDNF levels, which were completely blocked by CRISPR/Cas9-mediated gp91phox overexpression and potentiated by gp91phox siRNA-based antioxidant strategies. The in vivo test in stressed mice further suggested that gp91phox overexpression completely blocked the antidepressant- and anxiolytic-like effects of Bay 60-7550, while gp91phox knockdown enhanced such effects. These results provide solid evidence that the antidepressant- and anxiolytic-like effects of Bay 60-7550 against stress are causally related to down-regulation of gp91phox and activation of the cAMP/cGMP-pVASP-CREB-BDNF signaling pathway. [ABSTRACT FROM AUTHOR]

Summary: Background: Major depressive disorder (MDD) is a mental disease characterized by depressed mood, lifetime anxiety, and deficits of learning and memory. Inhibition of phosphodiesterase 9 (PDE9) has been reported to improve rodent cognitive and memory function. However, the role of PDE9 in MDD, in particular its manifestations of depression and anxiety, has not been investigated. Methods: We examined the protective effects of WYQ‐C36D (C36D), a novel PDE9 inhibitor, against corticosterone‐induced cytotoxicity, pCREB/CREB and BDNF expression by cell viability, and immunoblot assays in HT‐22 cells. The potential effects of C36D at doses of 0.1, 0.5, and 1 mg/kg on stress‐induced depression‐ and anxiety‐like behaviors and memory deficits were also examined in mice. Results: C36D significantly protected HT‐22 cells against corticosterone‐induced cytotoxicity and rescued corticosterone‐induced decreases in cGMP, CREB phosphorylation, and BDNF expression. All these effects were otherwise blocked by the PKG inhibitor Rp‐8‐Br‐PET‐cGMPS (Rp8). In addition, when tested in vivo in stressed mice, C36D produced antidepressant‐like effects on behavior, as shown by decreased immobility time both in the forced swimming and tail suspension tests. C36D also showed anxiolytic‐like and memory‐enhancing effects in the elevated plus‐maze and novel object recognition tests. Conclusion: Our results show that inhibition of PDE9 by C36D produces antidepressant‐ and anxiolytic‐like behavioral effects and memory enhancement by activating cGMP/PKG signaling pathway. PDE9 inhibitors may have the potential as a novel class of drug to treat MDD. [ABSTRACT FROM AUTHOR]

Rationale: Alcohol use disorder (AUD) is a chronically relapsing condition, which affects nearly 11% of population worldwide. Currently, there are only three FDA-approved medications for treatment of AUD, and normally, satisfactory effects are hard to be achieved. Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling has been implicated in regulation of ethanol intake. Phosphodiesterase 2 (PDE), a dual substrate PDE that hydrolyzes both cAMP and cGMP, may play a crucial role in regulating ethanol consumption.Methods: The present study determined whether PDE2 was involved in the regulation of ethanol intake and preference. The two-bottle choice procedure was used to examine the effects of the selective PDE2 inhibitor Bay 60-7550 on ethanol intake. The sucrose and quinine intake (taste preference) and locomotor activity (sedative effects) were also measured to exclude the false positive effects of Bay 60-7550.Results: Treatment with Bay 60-7550 (1 and 3 mg/kg, i.p.) decreased ethanol intake and preference, without changing total fluid intake. In addition, Bay 60-7550 at doses that reduced ethanol intake did not affect sucrose and quinine intake and preference, which excluded the potential influence of taste preference and sedative effects on ethanol drinking behavior. Moreover, Bay 60-7550 at 3 mg/kg did not alter locomotor activity or ethanol metabolism, further supporting the specific effect of Bay 60-7550 on ethanol drinking behavior.Conclusions: The results suggest that PDE2 plays a role in the regulation of ethanol consumption and that PDE2 inhibitors may be a novel class of drugs for treatment of alcoholism. [ABSTRACT FROM AUTHOR]

Summary: Aims: Depression is currently the most common mood disorder. Regulation of intracellular cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP) signaling by phosphodiesterase (PDE) inhibition has been paid much attention for treatment of depression. This study aimed to investigate the neuroprotective effects of Hcyb1, a novel PDE2 inhibitor, in HT‐22 cells and antidepressant‐like effects in mouse models of depression. Methods: Hcyb1 was synthesized and its selectivity upon PDE2 was tested. Moreover, HT‐22 hippocampal cells were used to determine the effects of Hcyb1 on cell viability, cyclic nucleotide levels, and the downstream molecules related to cAMP/cGMP signaling by neurochemical, enzyme‐linked immunosorbent, and immunoblot assays in vitro. The antidepressant‐like effects of Hcyb1 were also determined in the forced swimming and tail suspension tests in mice. Results: Hcyb1 had a highly selective inhibition of PDE2A (IC50 = 0.57 ± 0.03 μmol/L) and over 250‐fold selectivity against other recombinant PDE family members. Hcyb1 at concentrations of 10−10 and 10−9 mol/L significantly increased cell viability after treatment for 24 hours. At concentrations of 10−9~10−7 mol/L, Hcyb1 also increased cGMP levels by 1.7~2.3 folds after 10‐minute treatment. Furthermore, Hcyb1 at the concentrations of 10−9 mol/L increased both cGMP and cAMP levels 24 hours after treatment. The levels of phosphorylation of CREB and BDNF were also increased by Hcyb1 treatment in HT‐22 cells for 24 hours. Finally, in the in vivo tests, Hcyb1 (0.5, 1, and 2 mg/kg, i.g.) decreased the immobility time in both forced swimming and tail suspension tests, without altering locomotor activity. Conclusion: These results suggest that the novel PDE2 inhibitor Hcyb1 produced neuroprotective and antidepressant‐like effects most likely mediated by cAMP/cGMP‐CREB‐BDNF signaling. [ABSTRACT FROM AUTHOR]

Our previous study suggested that inhibition of Phosphodiesterase 2 ameliorates memory loss upon exposure to oxidative stress. While whether memory enhancing effects of PDE2 inhibition on Alzheimer's disease mouse model are involved in antioxidant defense and neuronal remodeling, are largely unexplored. The present study addressed whether and how PDE2 inhibitor Bay 60–7550 rescued Aβ oligomers (Aβo)-induced neuronal damage and memory impairment. The results suggested that exposure of primary cortical neurons to Aβo induced neuronal cells damage and increased PDE2 expression, which were paralleled to an increase in the oxidative parameter malondialdehyde (MDA) level and cellular apoptosis. However, this Aβo-induced oxidative damage was blocked by pre-treatment with protein kinase A or G (PKA or PKG) inhibitor, suggesting the involvement of cAMP/cGMP signaling. Moreover, microinjection of Aβo into the prefrontal cortex of mice increased the MDA level; while Bay 60–7550 reversed this effect and increased antioxidant and anti-apoptotic factors, i.e. increased trolox-equivalent-antioxidant capacity and Bcl-2/Bax ratio. Bay 60–7550 also rescued Aβo-induced synaptic atrophy and memory deficits, as evidenced by the increased synaptic proteins' levels and spine density in the prefrontal cortex, and improved cognitive behaviors by decreased working memory errors in the eight-arm maze and increased discrimination index in the novel object recognition test. These findings suggest that inhibition of PDE2 contributes to antioxidant defense and neuronal remodeling by regulation of cAMP/cGMP signaling, which provide a theoretical basis for the future use of PDE2 inhibitors as the anti-AD drugs. • Bay 60–7550 exerts antioxidant and antiapoptotic effects on Aβ-induced neurotoxicity in primary cortical neurons. • Bay 60–7550 improves neuronal remodeling and decreases oxidative damage in Aβ-treated mice. • Bay 60–7550 enhances memory in Aβ-treated mice. [ABSTRACT FROM AUTHOR]

R765 --> 537.3 --> Disorders affecting memory and cognition including Alzheimer's disease (AD) affect millions of Americans. Although dozens of compounds have been reported for the treatment of mild cognitive deficits (MCI) in Alzheimer's disease (AD), these drugs have not proven beneficial in ameliorating cognitive impairment in clinic. Phosphodiesterase 4B (PDE4B) plays a crucial role in the mediation of memory due to its primary role in hydrolyzing cyclic adenosine monophosphate (cAMP). However, the development of PDE4B inhibitors is challengeable due to the high conservation of the catalytic site of PDE4, across subtypes, to which classical inhibitors bind. The present study suggested that the newly synthesized allosteric inhibitor of PDE4, T2409, exhibits at least 150‐fold PDE4B selectivity. It exhibited low potency in a mouse surrogate model of emesis and nausea, suggesting its low side effects. Chronic treatment of T2409 for 14 days reversed cognitive and memory deficits in the novel object recognition and Morris water maze tests as evidenced by increased discrimination index and reduced the mean latency to platform via decreasing beta amyloid plaques both in the cortex and hippocampus in 8‐month‐old APP/PS1 mouse model of AD. Further study showed that these effects were related to decreased inflammatory factors, such as IL‐6, IL‐1β and TNF‐α, in the brain, and increased cAMP signaling dependent markers of neuroprotection associated with memory, such as p‐CREB and BDNF. These results accelerate the development of highly selective PDE4B inhibitors as novel treatments for illnesses that affect memory and cognitive function, such as AD. [ABSTRACT FROM AUTHOR]

Chronic stress and neuronal vulnerability have recently been recognized as factors contributing to cognitive disorders. One way to modify neuronal vulnerability is through mediation of phosphodiesterase 2 (PDE2), an enzyme that exerts its action on cognitive processes via the control of intracellular second messengers, cGMP and, to a lesser extent, cAMP. This study explored the effects of a PDE2 inhibitor, Bay 60-7550, on stress-induced learning and memory dysfunction in terms of its ramification on behavioral, morphologic, and molecular changes. Bay 60-7550 reversed stress-induced cognitive impairment in the Morris water maze, novel object recognition, and location tasks (object recognition test and/or object location test), effects prevented by treatment with 7-NI, a selective inhibitor of neuronal nitric oxide synthase; MK801, a glutamate receptor (NMDAR) inhibitor; myr-AIP, a CaMKII inhibitor; and KT5823, a protein kinase G inhibitor. Bay 60-7550 also ameliorated stress-induced structural remodeling in the CA1 of the hippocampus, leading to increases in dendritic branching, length, and spine density. However, the neuroplasticity initiated by Bay 60-7550 was not seen in the presence of 7-NI, MK801, myr-AIP, or KT5823. PDE2 inhibition reduced stress-induced extracellular-regulated protein kinase activation and attenuated stress-induced decreases in transcription factors (e.g., Elk-1, TORC1, and CREB phosphorylation) and plasticity-related proteins (e.g., Egr-1 and brain-derived neurotrophic factor). Pretreatment with inhibitors of NMDA, CaMKII, neuronal nitric oxide synthase, and protein kinase G (or protein kinase A) blocked the effects of Bay 60-7550 on cGMP or cAMP signaling. These findings indicate that the effect of PDE2 inhibition on stress-induced memory impairment is potentially mediated via modulation of neuroplasticity-related NMDAR-CaMKII-cGMP/cAMP signaling. [ABSTRACT FROM AUTHOR]

Highlights: [•] Bay 60-7550 exhibits antidepressant- and anxiolytic-like effects in mouse behaviors. [•] Increased cGMP signaling may contribute to the protective effects of Bay 60-7550. [•] Bay 60-7550 is able to antagonize the oxidative damage produced by chronic stress. [•] Another possible mechanism of Bay 60-7550's function is its anti-apoptotic effects. [ABSTRACT FROM AUTHOR]

Objective Through its location on nociceptors, acid-sensing ion channel 3 (ASIC-3) is activated by decreases in pH and plays a significant role in musculoskeletal pain. We recently showed that decreases in pH activate ASIC-3 located on fibroblast-like synoviocytes (FLS), which are key cells in the inflammatory process. The purpose of this study was to test whether ASIC-3-deficient mice with arthritis have altered inflammation and pain relative to controls. Methods Collagen antibody-induced arthritis (CAIA) was generated by injection of an anti-type II collagen antibody cocktail. Inflammation and pain parameters in ASIC-3−/− and ASIC-3+/+ mice were assessed. Disease severity was assessed by determining clinical arthritis scores, measuring joint diameters, analyzing joint histology, and assessing synovial gene expression by quantitative polymerase chain reaction analysis. Cell death was assessed with a Live/Dead assay of FLS in response to decreases in pH. Pain behaviors in the mice were measured by examining withdrawal thresholds in the joints and paws and by measuring their physical activity levels. Results Surprisingly, ASIC-3−/− mice with CAIA demonstrated significantly increased joint inflammation, joint destruction, and expression of interleukin-6 (IL-6), matrix metalloproteinase 3 (MMP-3), and MMP-13 in joint tissue as compared to ASIC-3+/+ mice. ASIC-3+/+ FLS showed enhanced cell death when exposed to pH 6.0 in the presence of IL-1β, which was abolished in ASIC-3−/− FLS. Despite enhanced disease severity, ASIC-3−/− mice did not develop mechanical hypersensitivity of the paw and showed greater levels of physical activity. Conclusion Our findings are consistent with the hypothesis that ASIC-3 plays a protective role in the inflammatory arthritides by limiting inflammation through enhanced synoviocyte cell death, which reduces disease severity, and through the production of pain, which reduces joint use. [ABSTRACT FROM AUTHOR]

Abstract: Trans-resveratrol is a phenolic compound enriched in polygonum cuspidatum and has diverse biological activities. There is only limited information about the antidepressant-like effect of trans-resveratrol. The present study investigated whether trans-resveratrol has antidepressant-like activity in rats exposed to chronic stress by using two behavioral tasks, shuttle box and sucrose preference tests. The monoamines (5-HT, noradrenaline and dopamine) and their metabolites as well as monoamine oxidase (MAO) enzyme activities in different brain regions were also measured. Compared to unstressed rats, those exposed to chronic stress paradigm showed performance deficits in the shuttle box, reduced sucrose preference, less weight gain and the increase in the ratio of adrenal gland to body weight, which were reversed by chronic treatment with trans-resveratrol (40 and 80 mg/kg, i.g.). The neurochemical assay showed that higher dose of trans-resveratrol (80 mg/kg) produced a marked increase of 5-HT levels in three brain regions, the frontal cortex, hippocampus and hypothalamus. Noradrenaline and dopamine levels were also increased both in the frontal cortex and striatum. Furthermore, chronic treatment with trans-resveratrol was found to inhibit monoamine oxidase-A (MAO-A) activity in all the four brain regions, particularly in the frontal cortex and hippocampus; while MAO-B activity was not affected. These findings indicate that the antidepressant-like effect of trans-resveratrol involves the regulation of the central serotonin and noradrenaline levels and the related MAO-A activities. [Copyright &y& Elsevier]

Background and Purpose Phosphodiesterase 4 ( PDE4) inhibitors produce potent antidepressant-like and cognition-enhancing effects. However, their clinical utility is limited by the major side effect of emesis, which appears to be PDE4 isoform-specific. Although PDE4D subtype plays the pivotal role in these therapeutic profiles, it is also the primary subtype responsible for emesis. Therefore, the aim of present research was to investigate whether long-form PDE4D variants mediate antidepressant-like and cognition-enhancing effects, but are irrespective with emesis. Experimental Approach In mice microinfused with lentiviral vectors that contained shRNA-mir hairpin structure targeting long-form PDE4Ds into bilateral prefrontal cortices, the tail-suspension and forced-swim tests were used to measure antidepressant-like effects; novel object recognition and Morris water-maze tasks were used to determine cognition-enhancing effects. The emetic potential was assessed by alpha2 adrenergic receptor-mediated anaesthesia, a surrogate measure of emesis. Intracellular cAMP signalling was analysed by time-resolved FRET immunoassay and Western-blot. Dendritic complexity was assessed by Golgi staining. Key Results Microinfusions of lentiviral PDE4D-shRNA down-regulated PDE4D4 and PDE4D5, and imitated the antidepressant-like and cognition-enhancing effects of the prototypical PDE4 inhibitor rolipram. The behavioural effects were related to dendritic complexity and mediated by the increased cAMP signalling. In addition, these effects were not enhanced in the presence of rolipram. Finally, while rolipram shortened the duration of combined anaesthesia, RNA interference-mediated PDE4D knock-down in the prefrontal cortex did not. Conclusion and Implications These data suggest that long-form PDE4Ds, at least PDE4D4 and PDE4D5, may be the promising targets for the development of PDE4 variant-selective inhibitors as the new pharmacotherapies for depressive disorders and neurodegenerative diseases involving memory deficits. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2011) 118, 784-795. Abstract Curcumin, a major active component of Curcuma longa, possesses antioxidant and neuroprotective activities. The present study explores the mechanisms underlying the neuroprotective effect of curcumin against corticosterone and its relation to 5-hydroxy tryptamine (5-HT) receptors. Exposure of cortical neurons to corticosterone results in decreased mRNA levels for three 5-HT receptor subtypes, 5-HT1A, 5-HT2A and 5-HT4, but 5-HT1B, 5-HT2B, 5-HT2C, 5-HT6 and 5-HT7 receptors remain unchanged. Pre-treatment with curcumin reversed this effect on mRNA for the 5-HT1A and 5-HT4 receptors, but not for the 5-HT2A receptor. Moreover, curcumin exerted a neuroprotective effect against corticosterone-induced neuronal death. This observed effect of curcumin was partially blocked by either 5-HT1A receptor antagonist p-MPPI or 5-HT4 receptor antagonist RS 39604 alone; whereas, the simultaneous application of both antagonists completely reversed the effect. Curcumin was also found to regulate corticosterone-induced morphological changes such as increases in soma size, dendritic branching and dendritic spine density, as well as elevate synaptophysin expression in cortical neurons. p-MPPI and RS 39604 reversed the effect of curcumin-induced change in neuronal morphology and synaptophysin expression of corticosterone-treated neurons. In addition, an increase in cyclic adenosine monophosphate (cAMP) level was observed after curcumin treatment, which was further prevented by RS 39604, but not by p-MPPI. However, curcumin-induced elevation in protein kinase A activity and phosphorylation of cAMP response element-binding protein levels were inhibited by both p-MPPI and RS 39604. These findings suggest that the neuroprotection and modulation of neuroplasticity exhibited by curcumin might be mediated, at least in part, via the 5-HT receptor-cAMP-PKA-CREB signal pathway. [ABSTRACT FROM AUTHOR]

Phosphodiesterase-4 (PDE4) plays an important role in mediating memory via the control of intracellular cAMP signaling; inhibition of PDE4 enhances memory. However, development of PDE4 inhibitors as memory enhancers has been hampered by their major side effect of emesis. PDE4 has four subtypes (PDE4A-D) consisting of 25 splice variants. Mice deficient in PDE4D displayed memory enhancement in radial arm maze, water maze, and object recognition tests. These effects were mimicked by repeated treatment with rolipram in wild-type mice. In addition, similarly as rolipram-treated wild-type mice, PDE4D-deficient mice also displayed increased hippocampal neurogenesis and phosphorylated cAMP response element-binding protein (pCREB). Furthermore, microinfusion of lentiviral vectors that contained microRNAs (miRNAs) targeting long-form PDE4D isoforms into bilateral dentate gyri of the mouse hippocampus downregulated PDE4D4 and PDE4D5, enhanced memory, and increased hippocampal neurogenesis and pCREB. Finally, while rolipram and PDE4D deficiency shortened α2 adrenergic receptor-mediated anesthesia, a surrogate measure of emesis, miRNA-mediated PDE4D knock-down in the hippocampus did not. The present results suggest that PDE4D, in particular long-form PDE4D, plays a critical role in the mediation of memory and hippocampal neurogenesis, which are mediated by cAMP/CREB signaling; reduced expression of PDE4D, or at least PDE4D4 and PDE4D5, in the hippocampus enhances memory but appears not to cause emesis. These novel findings will aid in the development of PDE4 subtype- or variant-selective inhibitors for treatment of disorders involving impaired cognition, including Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Inhibition of phosphodiesterase-4 (PDE4), an enzyme that catalyzes the hydrolysis of cyclic AMP (cAMP), increases phosphorylation of the cAMP response element binding protein (pCREB) and hippocampal neurogenesis, and produces antidepressant-like effects on behavior; however, causal links among these actions have not been established. In this study, chronic administration of rolipram (0.31–1.25 mg/kg, 16–23 days) produced antidepressant- and anxiolytic-like effects on behavior in mice. It also increased cAMP and pCREB levels in the hippocampus and prefrontal cortex, but increased Sox2, a marker for mitotic progenitor cells, only in the hippocampus. Chronic rolipram treatment also increased hippocampal neurogenesis, as evidenced by increased bromodeoxyuridine (BrdU)-positive cells in the hippocampal dentate gyrus. Methylazoxymethanol (MAM), which is toxic to proliferating cells, reversed rolipram-induced increases in BrdU-positive cells and pCREB in the hippocampus and partially blocked its behavioral effects. Approximately 84% of BrdU-positive cells became newborn neurons, 93% of which co-expressed pCREB; these proportions were not altered by rolipram or MAM, either alone or in combination. Finally, 3 weeks after the end of the MAM treatment, when neurogenesis was no longer inhibited, rolipram again increased hippocampal pCREB and its antidepressant- and anxiolytic-like effects were restored. Overall, these results suggest that rolipram produces its effects on behavior in a manner that at least partially depends on its neurogenic action in the hippocampus, targeting mitotic progenitor cells rather than newborn or mature neurons; cAMP/CREB signaling in hippocampal newborn neurons is critical for neurogenesis and contributes to the behavioral effects of rolipram. [ABSTRACT FROM AUTHOR]

Previous work has shown that repeated desipramine treatment causes downregulation of the norepinephrine transporter (NET) and persistent antidepressant-like effects on behavior, ie effects observed 2 days after discontinuation of drug treatment when acute effects are minimized. The present study examined whether this mechanism generalizes to other antidepressants and also is evident for the serotonin transporter (SERT). Treatment of rats for 14 days with 20 mg/kg per day protriptyline or 7.5 mg/kg per day sertraline reduced NET and SERT expression, respectively, in cerebral cortex and hippocampus; these treatments also induced a persistent antidepressant-like effect on forced-swim behavior. Increased serotonergic neurotransmission likely mediated the behavioral effect of sertraline, as it was blocked by inhibition of serotonin synthesis with p-chlorophenylalanine; a parallel effect was observed previously for desipramine and noradrenergic neurotransmission. Treatment with 20 mg/kg per day reboxetine for 42, but not 14, days reduced NET expression; antidepressant-like effects on behavior were observed for both treatment durations. Treatment for 14 days with 70 mg/kg per day venlafaxine, which inhibits both the NET and SERT, or 10 mg/kg per day phenelzine, a monoamine oxidase inhibitor, produced antidepressant-like effects on behavior without altering NET or SERT expression. For all drugs tested, reductions of NET and SERT protein were not accompanied by reduced NET or SERT mRNA in locus coeruleus or dorsal raphe nucleus, respectively. Overall, the present results suggest an important, though not universal, role for NET and SERT regulation in the long-term behavioral effects of antidepressants. Understanding the mechanisms underlying transporter regulation in vivo may suggest novel targets for the development of antidepressant drugs.Neuropsychopharmacology (2009) 34, 1467–1481; doi:10.1038/npp.2008.183; published online 15 October 2008 [ABSTRACT FROM AUTHOR]

The relationship between the ability of repeated desipramine treatment to cause downregulation of the norepinephrine transporter (NET) and produce antidepressant-like effects on behavior was determined. Treatment of rats with 15 mg/kg per day desipramine reduced NET expression, measured by 3H-nisoxetine binding and SDS–PAGE/immunoblotting, in cerebral cortex and hippocampus and reduced the time of immobility in the forced-swim test. The antidepressant-like effect on forced-swim behavior was evident 2 days following discontinuation of desipramine treatment when plasma and brain levels of desipramine and its major metabolite desmethyldesipramine were not detectable. Reduced NET expression resulted in reduced norepinephrine uptake, measured in vitro, and increased noradrenergic neurotransmission, measured in vivo using microdialysis. Overall, the dose–response and time-of-recovery relationships for altered NET expression matched those for production of antidepressant-like effects on behavior. The importance of increased noradrenergic neurotransmission in the persistent antidepressant-like effect on behavior was confirmed by demonstrating that it was blocked by inhibition of catecholamine synthesis with α-methyl-p-tyrosine. The present results suggest an important role for NET regulation in the long-term behavioral effects of desipramine and are consistent with clinical data suggesting that enhanced noradrenergic neurotransmission is necessary, but not sufficient, for its antidepressant actions. Understanding the mechanisms underlying NET regulation in vivo may suggest novel targets for therapeutic intervention in the treatment of depression.Neuropsychopharmacology (2008) 33, 3190–3200; doi:10.1038/npp.2008.45; published online 16 April 2008 [ABSTRACT FROM AUTHOR]

Phosphodiesterase-4 (PDE4), an enzyme that catalyzes the hydrolysis of cyclic AMP and plays a critical role in controlling its intracellular concentration, has been implicated in depression- and anxiety-like behaviors. However, the functions of the four PDE4 subfamilies (PDE4A, PDE4B, PDE4C, and PDE4D) remain largely unknown. In animal tests sensitive to anxiolytics, antidepressants, memory enhancers, or analgesics, we examined the behavioral phenotype of mice deficient in PDE4B (PDE4B−/−). Immunoblot analysis revealed loss of PDE4B expression in the cerebral cortex and amygdala of PDE4B−/− mice. The reduction of PDE4B expression was accompanied by decreases in PDE4 activity in the brain regions of PDE4B−/− mice. Compared to PDE4B+/+ littermates, PDE4B−/− mice displayed anxiogenic-like behavior, as evidenced by decreased head-dips and time spent in head-dipping in the holeboard test, reduced transitions and time on the light side in the light–dark transition test, and decreased initial exploration and rears in the open-field test. Consistent with anxiogenic-like behavior, PDE4B−/− mice displayed increased levels of plasma corticosterone. In addition, these mice also showed a modest increase in the proliferation of neuronal cells in the hippocampal dentate gyrus. In the forced-swim test, PDE4B−/− mice exhibited decreased immobility; however, this was not supported by the results from the tail-suspension test. PDE4B−/− mice did not display changes in memory, locomotor activity, or nociceptive responses. Taken together, these results suggest that the PDE4B subfamily is involved in signaling pathways that contribute to anxiogenic-like effects on behavior.Neuropsychopharmacology (2008) 33, 1611–1623; doi:10.1038/sj.npp.1301537; published online 15 August 2007 [ABSTRACT FROM AUTHOR]

Abstract: NMDA receptor-induced cAMP and cGMP are selectively hydrolyzed by PDE4 and PDE2, respectively, in rat primary cerebral cortical and hippocampal cultures. Because cAMP levels regulate the expression of PDE4 in rat primary cortical cultures, we examined the manner in which NMDA receptor activity regulates the age-dependent increase in the expression of PDE4A observed in vivo and in vitro. Inhibiting the activity of NR2B subunit with ifenprodil blocked NMDA receptor-induced cGMP synthesis and increased NMDA receptor-induced cAMP levels in a manner that reduced PDE4 activity. Therefore, NR1/NR2B receptor-induced cGMP signaling is involved in an acute cross-talk regulation of NR1/NR2A receptor-induced cAMP levels, mediated by PDE4. Chronic inhibition of NMDA receptor activity with MK-801 reduced PDE4A1 and PDE4A5 expression and activity in a time-dependent manner; this effect was reversed by adding the PKA activator dbr-cAMP. Inhibiting GABA receptors with bicuculline increased NMDA receptor-induced cAMP synthesis and PDE4A expression in cultures treated between DIV 16 and DIV 21 but not in cultures treated between DIV 8 and DIV 13. This effect was due to a high tone of NMDA receptor-induced cGMP in younger cultures, which negatively regulated the expression of PDE4A by a PKG-mediated process. The present results are consistent with behavioral data showing that both PDE4 and PDE2 are involved in NMDA receptor-mediated memory processes. [Copyright &y& Elsevier]

Phosphodiesterase-4 (PDE4) has two conformation states based on rolipram binding, the high-affinity rolipram binding state (HARBS) and the low-affinity rolipram binding state (LARBS); their functions remain to be fully explained. Objective: Experiments were carried out to determine the roles of the HARBS and LARBS in the mediation of antidepressant-like effects on behavior. Materials and methods: Two animal models sensitive to antidepressant drugs, the forced-swim test (FST), and the differential-reinforcement-of-low-rate (DRL) 72-s operant schedule, were used to examine the antidepressant-like effects of rolipram, CDP840, and piclamilast, PDE4 inhibitors that interact differentially with the HARBS and LARBS, and MEM1018 and MEM1091, two novel PDE4 inhibitors. Drug discrimination vs rolipram and rolipram competition binding assays also were carried out. Results: In the FST, rolipram and piclamilast, both at 0.1 mg/kg, produced an antidepressant- like effect, i.e., reduced immobility and increased swimming, whereas, 1 mg/kg of CDP840 or 0.5 mg/kg of MEM1018 or MEM1091 was required to produce a similar effect. Consistent with this, only rolipram and piclamilast produced antidepressant-like effects in rats under the DRL schedule of reinforcement, as evidenced by decreased response rates and increased reinforcement rates. In addition, in rats trained to discriminate rolipram from its vehicle, only rolipram and piclamilast substituted. Finally, [³H]rolipram and [³H]piclamilast binding analysis revealed that CDP840 and the two novel PDE4 inhibitors MEM1018 and MEM1091 exhibited a lower affinity for the HARBS than did rolipram. Conclusion: These results suggest that the HARBS of PDE4 is the primary conformation important for antidepressant-like effects on behavior. [ABSTRACT FROM AUTHOR]

Rationale: Inhibition of cyclic AMP (cAMP)-specific phosphodiesterase (PDE4) enhances memory in rodents. MEM1018 and MEM1091 are newly developed PDE4 inhibitors that had not been evaluated as yet for their effects on working and reference memory. Objective: Experiments were carried out to determine whether these two drugs alter memory and if these effects are associated with changes in intracellular cAMP in the brain. Methods: The effects of MEM1018 and MEM1091 on memory deficits induced by the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 were determined in the eight-arm radial maze and step-through inhibitory avoidance tasks in rats. Their effects on cAMP concentrations in primary cultures of rat cerebral cortical neurons and their potency for inhibiting recombinant PDE4 subtypes were examined. Results: In the radial-arm maze, MEM1018 and MEM1091 (0.1-2.5 mg/kg, IP) enhanced working and reference memory impaired by MK-801 (0.1 mg/kg). In addition, both drugs antagonized the amnesic effect of MK-801 on passive avoidance behavior. Overall, the behavioral effects of MEM1018 and MEM1091 were similar to the prototypic PDE4 inhibitor rolipram (0.1 mg/kg). Consistent with this, and similar to the effects of rolipram, both MEM1018 (10-30 µ M) and MEM1091 (10 µ M) enhanced the ability of NMDA (30 µ M) to increase cAMP concentrations in rat cerebral cortical neurons, in vitro. MEM1018 and MEM1091 showed greater relative selectivity for PDE4D than rolipram, although the general profiles of the three compounds were similar. Conclusions: The novel PDE4 inhibitors MEM1018 and MEM1091 enhance memory in a manner generally similar to rolipram. PDE4D may be the primary target for the PDE4 inhibitors in the mediation of memory. [ABSTRACT FROM AUTHOR]

Cyclic AMP-specific phosphodiesterase 4 (PDE4), which is an integral component of NMDA receptor-mediated cAMP signaling, is involved in the mediation of memory processes. Given that NMDA receptors also mediate MEK/mitogen-activated protein kinase (MAPK, ERK) signaling, which is involved in synaptic plasticity, and that some PDE4 subtypes are phosphorylated and regulated by ERK, it was of interest to determine if PDE4 is involved in MEK/ERK signaling-mediated memory. It was found that rolipram, a PDE4-selective inhibitor, reversed the amnesic effect in the radial-arm maze test of the MEK inhibitor U0126 administered into the CAI subregion of the rat hippocampus. Consistent with this, rolipram, either by peripheral administration or direct intra-CAI infusion, enhanced the retrieval of long-term memory impaired by intra-CAI infusion of U0120 using the step-through inhibitory avoidance test. The same dose of rolipram did not affect U0126-induced reduction of phospho-EPK½ levels in the CAI subregion. However, in primary cultures of rat cerebral cortical neurons, pretreatment with U0126 increased PDE4 activity; this was correlated with the U0126-induced reduction of phosphoERK½ levels. These results suggest that MEK/ERK signaling plays an inhibitory role in regulating PDE4 activity in the brain; this may be a novel mechanism by which MEK/ERK signaling mediates memory. PDE4 is likely to be an important link between the cAMP/PKA and MEK/ERK signaling pathways in the mediation of memory. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate dose- and time-dependent effects of NiCl2 on T-lymphocyte and macrophage-derived cytokine production in rats. Moreover we have determined the concentrations of nickel in the plasma that are required to elicit alterations in T-lymphocyte and macrophage function. NiCl2 suppressed T-lymphocyte proliferation and Th1 (IFN-γ) and Th2 (IL-10) cytokine production in a dose- and time-dependent fashion. In addition, NiCl2 inhibited production of the pro-inflammatory cytokine TNF-α and increased production of the anti-inflammatory cytokine IL-10 from lipopolysaccharide (LPS) stimulated cultures. We have determined that the minimal plasma concentrations of nickel required to provoke immunosuppression are in the range 209–585 ng/mL. In the time-course study NiCl2 (3.3 mg/kg) provoked immunological changes that were maximal 1 h following administration, and some of these changes persisted for up to 24 h post administration. Overall these data clearly demonstrate that NiCl2 suppresses T-cell function and promotes an immunosuppressive macrophage phenotype in rats. This study also indicates that measuring T-cell proliferation is as sensitive a marker of NiCl2-induced immunotoxicity as measuring T-cell or macrophage cytokine production. Co-measurement of circulating nickel concentrations and immune parameters yields valuable information with regard to the potency of nickel to alter immune function in vivo. These data also suggest that quite a large quantity of nickel needs to reach the systemic circulation before any adverse effects on immune function are observed. [ABSTRACT FROM AUTHOR]

Pharmacological inhibition of type 4 cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase (PDE4) produces antidepressant-like effects in animals; however, it is not known which of the four PDE4 subtypes mediates these actions. In the present study, immunoblot analysis showed loss of phosphodiesterase 4D (PDE4D) expression in the cerebral cortex and hippocampus of PDE4D knockout (PDE4D−/−) mice, but unchanged PDE4A and PDE4B expression, relative to the wild type (PDE4D+/+) and heterozygous knockout (PDE4D+/−) mice. This reduced expression was accompanied by a reduction in PDE4 activity, while non-PDE4 activity was unchanged. PDE4D−/− mice exhibited decreased immobility in tail-suspension and forced-swim tests, which is indicative of an antidepressant-like effect on behavior. Desipramine and fluoxetine produced similar antidepressant-like effects in all three genotypes, even though their behavioral baselines differed markedly. By contrast, the PDE4 inhibitor rolipram only produced antidepressant-like effects in PDE4D+/+ mice. Consistent with this, rolipram potentiated isoproterenol-induced cyclic AMP formation only in the PDE4D+/+ mice. These results suggest that PDE4D is an essential mediator of the antidepressant-like effects of rolipram, and that PDE4D-regulated cyclic adenosine monophosphate signaling may play a role in the pathophysiology and pharmacotherapy of depression. [Copyright &y& Elsevier]

Rationale: Central administration of isoproterenol, a non-selective beta adrenergic agonist, produces behavioral changes in animal models sensitive to antidepressants. However, it is not clear which brain regions mediate these effects. Objectives: To investigate the antidepressant-like effects of site-specific administration of isoproterenol and the involvement of beta adrenergic receptor subtypes. Methods: The effects of isoproterenol, which was administered into the lateral ventricle, hippocampus, frontal cortex, or amygdala, were determined in rats under a differential-reinforcement-of-low-rate (DRL) 72-s schedule. The effects of beta adrenergic antagonists on the actions of isoproterenol also were determined. Results: When injected bilaterally into the hippocampus, isoproterenol (1–30 µg/side) decreased response rate and increased reinforcement rate in a dose-dependent manner. The minimum dose of isoproterenol required for changing DRL behavior was 6 µg (i.e., 3 µg bilaterally), compared to 10 µg for intracerebroventricular and 60 µg (30 µg bilaterally) for administration into the frontal cortex or amygdala. These effects of isoproterenol were blocked by the beta adrenergic antagonist propranolol. In addition, the effects of isoproterenol injected intrahippocampally also were antagonized dose-dependently by the beta-1 selective antagonist betaxolol and the beta-2 selective antagonist ICI 118,551. The relative potency of these antagonists for blocking the effects of isoproterenol suggested predominant mediation by beta-1 adrenergic receptors. Conclusions: The hippocampus is an important site involved in mediating the antidepressant-like effect of isoproterenol. This suggests a key, although not exclusive, role for this site in the pathophysiology of depression and its pharmacotherapy. [ABSTRACT FROM AUTHOR]

Abstract Rationale: Inhibition of glutamatergic N-methyl-D-aspartate (NMDA) receptors following the administration of NMDA receptor antagonists results in psychotic-like behaviour. Whereas it is known that pharmacological manipulation of dopaminergic and serotonergic pathways affect this drug-induced psychosis, a role for noradrenaline has not yet been clearly defined. Objectives: Thus, in the present study, we assessed a possible role for noradrenaline in the behavioural response to the non-competitive NMDA receptor anatgonist, MK-801, in male CD-I mice. Results: MK-801 (0.02-1.28 mg/kg; ED[sub 50] 0.2 mg/kg; S.C.) induced a dose-dependent increase in locomotor, stereotypic and ataxic behaviours. Pre-treatment with the noradrenaline re-uptake inhibitors, desipramine (10 mg/kg; i.p.) and reboxetine (20 mg/kg; i.p.), attenuated the locomotor, stereotypic and ataxic response to MK-801 (0.2 mg/kg; S.C.). The noradrenergic system was lesioned with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4, 50 mg/kg; i.p., 7 and 4 days prior to challenge) to reduce noradrenaline concentrations in the cortex by 70%-80%. Whereas DSP-4 lesioning had little effect on the response to MK-801, it completely reversed the attenuating effects of reboxetine. Pre-treatment with the alpha[sub 2] adrenoceptor agonist, clonidine (0.2 mg/kg; i.p.), and the antagonist, yohimbine (2 mg/kg; i.p.), attenuated and potentiated the response to MK-801, respectively. Pre-treatment with the alpha[sub 1] adrenoceptor antagonist, prazosin (2 mg/kg; i.p.), reduced the MK-801-induced response. Conclusions: It therefore appears that presynaptic noradrenergic alpha[sub 2] and postsynaptic alpha[sub 1] adrenoceptor stimulation exert opposing effects on the behavioural expression of MK-801 in mice. [ABSTRACT FROM AUTHOR]

Inhibition of cyclic AMP (cAMP)-specific phosphodiesterase 4 (PDE4) has been proposed as a potential treatment for a series of neuropsychological conditions such as depression, anxiety and memory loss. However, the specific involvement of each of the PDE4 subtypes (PDE4A, 4B and 4C) in different categories of behavior has yet to be elucidated. In the present study, we compared the possible pharmacological effects of PDE4B and PDE4D selective inhibitors, A-33 and D159687, in mediating neurological function in mice. Both compounds were equally potent in stimulating cAMP signaling in the mouse hippocampal cell line HT-22 leading to an increase in CREB phosphorylation. In contrast, A-33 and D159687 displayed distinct neuropharmacological effects in mouse behavioral tests. A-33 has an antidepressant-like profile as indicated by reduced immobility time in the forced swim and tail suspension tasks, as well as reduced latency to feed in the novelty suppressed feeding test. D159687, on the other hand, had a procognitive profile as it improved memory in the novel object recognition test but had no antidepressant or anxiolytic benefit. The present data suggests that inhibitors targeting specific subtypes of PDE4 may exhibit differential pharmacological effects and aid a more efficient pharmacotherapy towards neuropsychological conditions. [ABSTRACT FROM AUTHOR]

The antidepressant desipramine inhibits the reuptake of norepinephrine (NE), leading to activation of both pre- and postsynaptic adrenergic receptors, including α-1, α-2, β-1, and β-2 subtypes. However, it is not clear which adrenergic receptors are involved in mediating its antidepressant effects. Treatment of mice with desipramine (20 mg/kg, i.p.) produced an antidepressant-like effect, as evidenced by decreased immobility in the forced-swim test; this was antagonized by pretreatment with the α-2 adrenergic antagonist idazoxan (0.1–2.5 mg/kg, i.p.). Similarly, idazoxan, administered peripherally (0.5–2.5 mg/kg, i.p.) or centrally (1–10 μg, i.c.v.), antagonized the antidepressant-like effect of desipramine in rats responding under a differential-reinforcement-of-low-rate (DRL) 72-s schedule, ie, decreased response rate and increased reinforcement rate. By contrast, pretreatment with the β-adrenergic antagonists propranolol and CGP-12177 or the α-1 adrenergic antagonist prazosin did not alter the antidepressant-like effect of desipramine on DRL behavior. The lack of involvement of β-adrenergic receptors in mediating the behavioral effects of desipramine was confirmed using knockout lines. In the forced-swim test, the desipramine-induced decrease in immobility was not altered in mice deficient in β-1, β-2, or both β-1 and β-2 adrenergic receptors. In addition, desipramine (3–30 mg/kg) produced an antidepressant-like effect on behavior under a DRL 36-s schedule in mice deficient in both β-1 and β-2 adrenergic receptors. As antagonism of presynaptic α-2 adrenergic receptors facilitates NE release, which potentiates the effects of desipramine, the present results suggest that postsynaptic α-2 adrenergic receptors play an important role in its antidepressant effects.Neuropsychopharmacology (2009) 34, 1067–1077; doi:10.1038/npp.2008.184; published online 15 October 2008 [ABSTRACT FROM AUTHOR]

Phosphodiesterase 4 (PDE4) has four isoforms (PDE4A-D) with at least 25 splice variants. PDE4 subtype nonselective inhibitors produce potent antidepressant-like and cognition-enhancing effects via increased intracellular cyclic AMP (cAMP) signaling in the brain. Our previous data have demonstrated that long-form PDE4Ds appear to be involved in these pharmacological properties of PDE4 inhibitors in the normal animals. However, it is not clear whether long-form PDE4Ds are critical for the behaviors and related cellular signaling/neuronal plasticity/neuroendocrine alterations in the depressed animals. In the present study, animals exposed to the chronic unpredictable stress (CUS), a rodent model of depression, exhibited elevated corticosterone, depressive-like behavior, memory deficits, accompanied with decreased cAMP-PKA-CREB and cAMP-ERK1/2-CREB signaling and neuroplasticity. These alterations induced by CUS were reversed by RNA interference (RNAi)-mediated prefrontal cortex long-form PDE4Ds (especially PDE4D4 and PDE4D5) knock-down, similar to the effects of the PDE4 subtype nonselective inhibitor rolipram. Furthermore, these effects of RNAi were not enhanced by rolipram. These data indicate a predominant role of long-form PDE4Ds in the pharmacotherapies of PDE4 inhibitors for depression and concomitant memory deficits. Long-form PDE4Ds, especially PDE4D4 and PDE4D5, appear to be the promising targets for the development of antidepressants with high therapeutic indices. [ABSTRACT FROM AUTHOR]