Phosphodiesterase Inhibition and Regulation of Dopaminergic Frontal and Striatal Functioning:Clinical Implications

BACKGROUND: The fronto-striatal circuits are the common neurobiological basis for neuropsychiatric disorders, including schizophrenia, Parkinson’s disease, Huntington’s disease, attention deficit hyperactivity disorder, obsessive-compulsive disorder, and Tourette’s syndrome. Fronto-striatal circuits consist of motor circuits, associative circuits, and limbic circuits. All circuits share 2 common features. First, all fronto-striatal circuits consist of hyper direct, direct, and indirect pathways. Second, all fronto-striatal circuits are modulated by dopamine. Intracellularly, the effect of dopamine is largely mediated through the cyclic adenosine monophosphate/protein kinase A signaling cascade with an additional role for the cyclic guanosine monophosphate/protein kinase G pathway, both of which can be regulated by phosphodiesterases. Phosphodiesterases are thus a potential target for pharmacological intervention in neuropsychiatric disorders related to dopaminergic regulation of fronto-striatal circuits. METHODS: Clinical studies of the effects of different phosphodiesterase inhibitors on cognition, affect, and motor function in relation to the fronto-striatal circuits are reviewed. RESULTS: Several selective phosphodiesterase inhibitors have positive effects on cognition, affect, and motor function in relation to the fronto-striatal circuits. CONCLUSION: Increased understanding of the subcellular localization and unraveling of the signalosome concept of phosphodiesterases including its function and dysfunction in the fronto-striatal circuits will contribute to the design of new specific inhibitors and enhance the potential of phosphodiesterase inhibitors as therapeutics in fronto-striatal circuits

Acute treatment with the PDE4 inhibitor roflumilast improves verbal word memory in healthy old individuals: a double-blind placebo-controlled study

There is ample evidence that phosphodiesterase 4 (PDE4) inhibition can improve memory performance in animal studies. In the present study, we examined the acute effects of the PDE4 inhibitor roflumilast on memory performance in healthy individuals (60-80 years of age). We tested the effects of acute roflumilast administration (100, 250, 1000 μg) in a double-blind, placebo-controlled, 4-way crossover design. Participants were first screened for their verbal word memory performance to ensure normal memory performance (within 0.5 standard deviation from norm score; n = 20) Drug effects on memory performance were tested in a verbal memory test and a spatial memory test. Reported side effects of drug treatment were registered. Roflumilast (100 μg) improved the delayed recall performance of the participants (Cohen's d, 0.69). No effects were observed in the spatial memory task. Roflumilast was well tolerated at this low dose. Although no clear adverse side effects were reported at the low dose, mild adverse events (including headache, dizziness, insomnia, and diarrhea) were reported after the 1000 μg dose. The present study provides first evidence that the PDE4 inhibitor roflumilast improves verbal memory performance in old participants. The current data encourage further development of PDE4 inhibitors for improving memory

Effects of experimental panic on neuroimmunological functioning

Objective: Psychoimmunological research in panic disorder (PD) so far focussed on single time point evaluation in resting conditions. No robust evidence for changes in the immune system was found using this method. However, PD is characterized by the occurrence of unexpected panic attacks (PAs). The current research focuses on cytokine and acute phase protein (APP) levels and mitogen-induced cytokine secretion following 35% CO2 inhalation-induced panic. Methods: Eighteen PD patients and 18 matched healthy control subjects underwent both a placebo and a 35% CO2 inhalation on separate days. Blood samples for cytokine and APP determination were taken before and after the inhalation. In addition to serum determination, whole blood samples were cultured and stimulated with mitogens for assessment of the functional capacity of the immune system. Results: The 35% CO2 inhalation induced significantly higher levels of anxiety in PD patients as compared to the control subjects, but no differences in immune parameters were found, either in basal conditions or after experimental panic induction. Conclusion: In our sample we do not find any changes in serum levels or functional capacity of several immunological parameters in the experimentally provoked PAs. Similar results have been found in social phobia, whereas in other affective disorders such as depression and posttraumatic stress disorder, immune changes are evident. Changes seem to coincide with alterations in hypothalamic-pituitary-adrenal (HPA) axis function. Therefore, the bidirectional communication pathway between the immune system and the HPA axis might play a role in some affective disorders, but it does not specifically seem to be involved in the etiology of PD. (C) 2008 Elsevier Inc. All rights reserved