BACKGROUND AND PURPOSEStrategies designed to enhance cerebral cAMP have been proposed as symptomatic treatments to counteract cognitive deficits. However, pharmacological therapies aimed at reducing PDE4, the main class of cAMP catabolizing enzymes in the brain, produce severe emetic side effects. We have recently synthesized a 3-cyclopentyloxy-4-methoxybenzaldehyde derivative, structurally related to rolipram, and endowed with selective PDE4D inhibitory activity. The aim of the present study was to investigate the effect of the new drug, namely GEBR-7b, on memory performance, nausea, hippocampal cAMP and amyloid-b (Ab) levels. EXPERIMENTAL APPROACHTo measure memory performance, we performed object recognition tests on rats and mice treated with GEBR-7b or rolipram. The emetic potential of the drug, again compared with rolipram, was evaluated in rats using the taste reactivity test and in mice using the xylazine/ketamine anaesthesia test. Extracellular hippocampal cAMP was evaluated by intracerebral microdialysis in freely moving rats. Levels of soluble Ab peptides were measured in hippocampal tissues and cultured N2a cells by ELISA. KEY RESULTSGEBR-7b increased hippocampal cAMP, did not influence Ab levels and improved spatial, as well as object memory performance in the object recognition tests. The effect of GEBR-7b on memory was 3 to 10 times more potent than that of rolipram, and its effective doses had no effect on surrogate measures of emesis in rodents. CONCLUSION AND IMPLICATIONSOur results demonstrate that GEBR-7b enhances memory functions at doses that do not cause emesis-like behaviour in rodents, thus offering a promising pharmacological perspective for the treatment of memory impairment.

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Nociceptin/orphanin FQ (N/OFQ) and nocistatin (NST) are two recently identified neuropeptides with opposing effects on several CNS functions, including spinal nociception. The cellular mechanisms that underlie this antagonism are not known. Here, we have investigated the effects of both peptides on synaptic transmission mediated by the three fast neurotransmitters l-glutamate, glycine, and GABA in the superficial layers of the rat spinal cord horn, which constitute the first important site of integration of nociceptive information in the pain pathway. NST selectively reduced transmitter release from inhibitory interneurons via a presynaptic Bordetella pertussis toxin-sensitive mechanism but left excitatory glutamatergic transmission unaffected. In contrast, N/OFQ only inhibited excitatory transmission. In the rat formalin test, an animal model of tonic pain in which N/OFQ exerts antinociceptive activity, NST induced profound hyperalgesia after intrathecal application. Similar to glycine and GABA(A) receptor antagonists, NST had no significant effects in the rat tail-flick test, a model of acute thermal pain. Our results provide a cellular basis for the antagonism of N/OFQ and NST and suggest the existence of a so far unidentified membrane receptor for NST. In addition, they support a role of NST as an endogenous inhibitor of glycinergic and GABAergic neurotransmission in the sensory part of the spinal cord and as a mediator of spinal hyperalgesia.

The aims of this study were to investigate the dose-dependent effects of spinally delivered nociceptin (0.3, 1, 3.3 and 10 nmol) on flinching behaviour in the rat formalin test and whether these effects were influenced by the concomitant systemic administration of naloxone (3 mg/kg, i.p.). The effect of the highest nociceptin dose differed statistically from vehicle, 0.3 and 1 nmol nociceptin. Following the administration of 1, 3.3 or 10 nmol nociceptin mean total flinches decreased dose-dependently. The effects of 10 nmol nociceptin were not reversed by a high dose of naloxone. We observed a decrease in flinching behaviour with intrathecally to the lumbar enlargement delivered nociceptin and conclude that nociceptin has antinociceptive effects in the rat formalin test.