Efficacy of selective PDE4D negative allosteric modulators in the object retrieval task in female cynomolgus monkeys (Macaca fascicularis).

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.

The orexin-1 receptor antagonist SB-334867 reduces amphetamine-evoked dopamine outflow in the shell of the nucleus accumbens and decreases the expression of amphetamine sensitization.

Orexin-expressing neurons are present in hypothalamic nuclei and send projections toward mesolimbic regions such as the nucleus accumbens (NAc), a key brain region implicated in the processing of the motivational significance of reinforcers. Recent evidence found that activation of the orexin system can lead to a state of hyperarousal that may facilitate drug craving or contribute to vulnerability to drug relapse. This study aimed at assessing the effects of the orexin-1 receptor antagonist SB-334867 [1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl-urea hydrochloride] on amphetamine-induced dopamine (DA) release in the shell subregion of the NAc by means of in vivo microdialysis in freely moving rats. Since behavioral sensitization is thought to play a role in the maintenance of compulsive drug use, we also tested the effect of SB-334867 on the expression of sensitization to the locomotor activating effects of amphetamine. Acute administration of SB-334867 (30 mg/kg SC) significantly reduced the acute effects of amphetamine (1 mg/kg IP) on extracellular DA levels in the NAc shell. The expression of amphetamine sensitization was also significantly reduced by acute SB-334867 treatment. Altogether our findings show that selective orexin-1 antagonism both reduces the acute effects of amphetamine on DA outflow in the NAc shell and decreases the expression of locomotor sensitization to the repeated, intermittent administration of amphetamine.