Cyclic adenosine monophosphate (cAMP) signalling plays an important role in synaptic plasticity and information processing in the hippocampal and basal ganglia systems. The augmentation of cAMP signalling through the selective inhibition of phosphodiesterases represents a viable strategy to treat disorders associated with dysfunction of these circuits. The phosphodiesterase (PDE) type 4 inhibitor rolipram has shown significant pro-cognitive effects in neurological disease models, both in rodents and primates. However, competitive non-isoform selective PDE4 inhibitors have a low therapeutic index which has stalled their clinical development. Here, we demonstrate the pro-cognitive effects of selective negative allosteric modulators (NAMs) of PDE4D, D159687 and D159797 in female Cynomolgous macaques, in the object retrieval detour task. The efficacy displayed by these NAMs in a primate cognitive task which engages the corticostriatal circuitry, together with their suitable pharmacokinetic properties and safety profiles, suggests that clinical development of these allosteric modulators should be considered for the treatment of a variety of brain disorders associated with cognitive decline.
Interest in the influence of sex hormones within the central nervous system is a rapidly expanding area of research. A considerable amount of evidence has recently been obtained to support an important role of the gonadal steroids in cognitive processing. Not only are distinct and complementary behavioural phenotypes evident for each gender, in the case of the female but they are also reliant upon hormonal status. Gender influences and hormonal status are thus paramount and should encourage the development of more hypothesis-driven research strategies to understand gender differences in both normal behaviour and where this is altered in neuropsychiatric disorders.
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