Han-Ting Zhang

Antidepressant-like profile and reduced sensitivity to rolipram in mice deficient in the PDE4D phosphodiesterase enzyme.

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.

Inhibition of cyclic AMP phosphodiesterase (PDE4) reverses memory deficits associated with NMDA receptor antagonism

Rolipram, a selective inhibitor of type 4 cyclic AMP phosphodiesterase (PDE4), completely reversed the amnesic effects of MK-801 on working and reference memory (F[4,64] = 11.10; p < .0001 and F[4,64] = 2.53; p < .05, respectively) at doses of 0.01–0.1 mg/kg in the radial-arm maze task. Similar antagonism by rolipram of the effects of MK-801 was observed on inhibitory avoidance behavior (F[3,35] = 190.8; p < .0001). In vitro evidence suggests that an increase in cAMP concentrations may mediate the observed behavioral effects of rolipram. In the absence of PDE4 inhibition, NMDA did not increase cAMP concentrations in primary cultures of rat cerebral cortical neurons. However, when PDE4 was inhibited with rolipram, NMDA markedly elevated cAMP. These observations suggest that PDE4 is an integral component of the NMDA receptor-mediated signal transduction pathway involved in memory processes. Inhibitors of PDE4 may act on this pathway to produce their effects on memory and may represent a new class of cognitive enhancers.

PDE4 as a target for cognition enhancement

Introduction: The second messengers cAMP and cGMP mediate fundamental aspects of brain function relevant to memory, learning, and cognitive functions. Consequently, cyclic nucleotide phosphodiesterases (PDEs), the enzymes that inactivate the cyclic nucleotides, are promising targets for the development of cognition-enhancing drugs. Areas covered: PDE4 is the largest of the 11 mammalian PDE families. This review covers the properties and functions of the PDE4 family, highlighting procognitive and memory-enhancing effects associated with their inactivation. Expert opinion: PAN-selective PDE4 inhibitors exert a number of memory- and cognition-enhancing effects and have neuroprotective and neuroregenerative properties in preclinical models. The major hurdle for their clinical application is to target inhibitors to specific PDE4 isoforms relevant to particular cognitive disorders to realize the therapeutic potential while avoiding side effects, in particular emesis and nausea. The PDE4 family comprises four genes, PDE4A-D, each expressed as multiple variants. Progress to date stems from characterization of rodent models with selective ablation of individual PDE4 subtypes, revealing that individual subtypes exert unique and non-redundant functions in the brain. Thus, targeting specific PDE4 subtypes, as well as splicing variants or conformational states, represents a promising strategy to separate the therapeutic benefits from the side effects of PAN-PDE4 inhibitors.

Antagonism of the antidepressant-like effects of clenbuterol by central administration of β-adrenergic antagonists in rats

RationaleStimulation of central β2 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.ObjectiveExperiments were carried out to determine whether central administration of β-adrenergic antagonists blocks antidepressant-like effects produced by peripheral administration of the β2-adrenergic agonist clenbuterol.MethodsThe 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.ResultsThe 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.ConclusionsCentral 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.