In vitro and in vivo characterisation of Lu AF64280, a novel, brain penetrant phosphodiesterase (PDE) 2A inhibitor: potential relevance to cognitive deficits in schizophrenia

In this paper we describe a new memory test in rats, based on the differential exploration of familiar and new objects. In a first trial (T1), rats are exposed to one or to two identical objects (samples) and in a second trial, to two dissimilar objects, a familiar (the sample) and a new one. For short intertrial intervals (approximately 1 min), most rats discriminate between the two objects in T2: they spend more time in exploring the new object than the familiar one. This test has several interesting characteristics: (1) it is similar to visual recognition tests widely used in subhuman primates, this allows interspecies comparisons; (2) it is entirely based on the spontaneous behavior of rats and can be considered as a 'pure' working-memory test completely free of reference memory component; (3) it does not involve primary reinforcement such as food or electric shocks, this makes it comparable to memory tests currently used in man.

If rodents do not display the behavioral complexity that is subserved in primates by prefrontal cortex, then evolution of prefrontal cortex in the rat should be doubted. Primate prefrontal cortex has been shown to mediate shifts in attention between perceptual dimensions of complex stimuli. This study examined the possibility that medial frontal cortex of the rat is involved in the shifting of perceptual attentional set. We trained rats to perform an attentional set-shifting task that is formally the same as a task used in monkeys and humans. Rats were trained to dig in bowls for a food reward. The bowls were presented in pairs, only one of which was baited. The rat had to select the bowl in which to dig by its odor, the medium that filled the bowl, or the texture that covered its surface. In a single session, rats performed a series of discriminations, including reversals, an intradimensional shift, and an extradimensional shift. Bilateral lesions by injection of ibotenic acid in medial frontal cortex resulted in impairment in neither initial acquisition nor reversal learning. We report here the same selective impairment in shifting of attentional set in the rat as seen in primates with lesions of prefrontal cortex. We conclude that medial frontal cortex of the rat has functional similarity to primate lateral prefrontal cortex.

It is generally accepted that cognitive deficits in schizophrenia are related to functional outcome. However, support for longitudinal relationships between cognition and functional outcome has not been as well documented. The current paper presents a review of 18 recently published longitudinal studies (minimum 6-month follow up) of the relationships between cognition and community outcome in schizophrenia. Results from these studies reveal considerable support for longitudinal associations between cognition and community outcome in schizophrenia. These studies demonstrate that cognitive assessment predict later functional outcome and provide a rationale for psychopharmacological interventions for cognitive deficits in schizophrenia. Although the relationships between cognition and community outcome are well-supported, it is clear that community functioning is also affected by a host of factors apart from cognition that are usually not considered in clinical trial studies (e.g., psychosocial rehabilitation and educational/vocational opportunities). In the second part of the paper, we consider intervening steps between cognitive performance measures and community outcome. These steps are apt to have important implications for clinical trials of cognition-enhancing agents in schizophrenia.