Effects of the selective 5-HT(7) receptor antagonist SB-269970 in animal models of psychosis and cognition.

The 5-hydroxytryptamine7 (5-HT7) receptor is a G-protein coupled receptor for serotonin that has been implicated in the pathophysiology of psychiatric and neurological disorders including anxiety, depression and schizophrenia. A number of studies have attempted to evaluate the potential role of the 5-HT7 receptor in schizophrenia by utilising genetic or pharmacological tools but to date these have provided conflicting results. Here we investigate the effect of a selective 5-HT7 receptor antagonist, SB-269970, in in vivo psychosis and cognition models and relate efficacy to brain exposures of the compound. SB-269970 significantly attenuated amphetamine-induced rearing and circling in rats. A similar effect was observed in an N-methyl d-aspartic acid (NMDA) receptor antagonist driven psychosis model, where SB-269970 significantly reversed phencyclidine-induced hyperlocomotion, rearing and circling; although the effect was not as robust as with the 5-HT2a receptor antagonist positive control, MDL100,907. SB-269970 also attenuated a temporal deficit in novel object recognition (NOR), indicative of an improvement in recognition memory. Pharmacokinetic analysis of plasma and brain samples taken after behavioural testing confirmed that efficacy was achieved at doses and pre-treatment times where receptor occupancy was substantial. These findings highlight the anti-psychotic and pro-cognitive potential of 5-HT7 receptor antagonists and warrant further studies to explore their therapeutic potential in schizophrenia.

Selective dopamine D4 receptor agonist (A-412997) improves cognitive performance and stimulates motor activity without influencing reward-related behaviour in rat.

Current therapies for attention deficit hyperactivity disorder comprise psychostimulants, which block the dopamine transporter and/or stimulate the release of dopamine, leading to a global elevation in extrasynaptic dopamine. These drugs are, however, associated with a series of unwanted side effects such as insomnia, anorexia, headache, stomach problems and potential drug abuse. Recent evidence suggests that the dopamine D4 receptor may represent a selective dopamine target that could mediate cognitive as well as striatal motor processes. In this study we compare the effects of a selective D4 receptor agonist, A-412997, with methylphenidate or amphetamine in preclinical models of efficacy versus abuse liability. Both methylphenidate and A-412997 improved a temporally induced deficit in the rat novel object recognition task at doses 10-fold lower than those stimulating activity. In both cases, procognitive doses were associated with elevated extracellular levels of dopamine and acetylcholine in the medial prefrontal cortex. In contrast to amphetamine, A-412997 did not mediate reward-related behaviour in the conditioned place preference paradigm, a preclinical rodent test used to assess potential abuse liability. Collectively, these data suggest that selective activation of the D4 receptor may represent a target for the treatment of attention deficit hyperactivity disorder without the potential drug abuse liability associated with current psychostimulant therapies.

Behavioral and neurochemical alterations in mice deficient in anaplastic lymphoma kinase suggest therapeutic potential for psychiatric indications.

The receptor tyrosine kinase product of the anaplastic lymphoma kinase (ALK) gene has been implicated in oncogenesis as a product of several chromosomal translocations, although its endogeneous role in the hematopoietic and neural systems has remained poorly understood. We describe that the generation of animals homozygous for a deletion of the ALK tyrosine kinase domain leads to alterations in adult brain function. Evaluation of adult ALK homozygotes (HOs) revealed an age-dependent increase in basal hippocampal progenitor proliferation and alterations in behavioral tests consistent with a role for this receptor in the adult brain. ALK HO animals displayed an increased struggle time in the tail suspension test and the Porsolt swim test and enhanced performance in a novel object-recognition test. Neurochemical analysis demonstrates an increase in basal dopaminergic signalling selectively within the frontal cortex. Altogether, these results suggest that ALK functions in the adult brain to regulate the function of the frontal cortex and hippocampus and identifies ALK as a new target for psychiatric indications, such as schizophrenia and depression, with an underlying deregulated monoaminergic signalling.

Assessment of modafinil on attentional processes in a five-choice serial reaction time test in the rat.

It is well known that modafinil is an effective wake-promoting agent, but there is growing evidence to suggest that modafinil may also enhance some aspects of cognition. In man, modafinil has been shown to enhance vigilance in sleep-deprived and/or narcoleptic subjects and also to improve executive-type functioning (predominantly inhibitory response control processes) across a variety of human patient population groups. Preclinically, a delay-dependent improvement has been reported with modafinil in a mouse T-maze test of working memory. To investigate further the role of modafinil as a potential cognition enhancer, the effects of modafinil on attentional processes were assessed in the rat. The aim of the present study was to evaluate the potential of modafinil to enhance five-choice serial reaction time test (5-CSRT) performance. Lister Hooded rats received 32-128 mg/kg modafinil and 5-CSRT performance was assessed under standard and test parametric conditions in which the attentional load was increased, and also under conditions of scopolamine pre-treatment. Modafinil failed to significantly enhance 5-CSRT performance under standard conditions. Similarly, modafinil was unable to reverse the deficits in accuracy and/or increased omission errors induced by either parametric or pharmacological manipulations. Indeed, at higher doses, modafinil caused an increase in premature responding under certain test conditions, suggestive of increased impulsivity. The present findings suggest that, although modafinil may enhance vigilance in sleep-deprived human subjects, attentional processes in normal awake rats remain unaffected. No evidence was found to support a modafinil-induced improvement in response control; rather, under conditions of increased attentional load, modafinil appeared to facilitate impulsive responding. Finally, the failure of modafinil to improve a scopolamine-induced performance deficit suggests that modafinil does not act on the cholinergic system directly.