Altered dopaminergic firing pattern and novelty response underlie ADHD-like behavior of SorCS2-deficient mice.

Attention deficit hyperactivity disorder (ADHD) is the most frequently diagnosed neurodevelopmental disorder worldwide. Affected individuals present with hyperactivity, inattention, and cognitive deficits and display a characteristic paradoxical response to drugs affecting the dopaminergic system. However, the underlying pathophysiology of ADHD and how this relates to dopaminergic transmission remains to be fully understood.

Correction to: Co-treatment with rivastigmine and idalopirdine reduces the propensity for falls in a rat model of falls in Parkinson's disease.

After publication of this paper, the authors determined that the "Acknowledgments" section was omitted. Below is the "Acknowledgments" statement.

Co-treatment with rivastigmine and idalopirdine reduces the propensity for falls in a rat model of falls in Parkinson's disease.

Rationale: Falls in patients with Parkinson's disease (PD) are associated with cognitive, specifically attentional impairments and with losses in cholinergic projection systems. We previously established an animal model of the combined basal forebrain cholinergic-striatal dopaminergic losses of PD fallers (Dual Lesioned, DL, rats) and demonstrated that treating DL rats with an acetylcholinesterase inhibitor (AChEI), donepezil, together with a 5HT receptor antagonist, idalopirdine, reduced fall frequency and improved associated aspects of the performance of DL rats traversing rotating rods.

Objectives: Here, we employed a longer and more taxing rotating beam apparatus to determine the potential therapeutic efficacy of idalopirdine when combined with the pseudo-irreversible, and thus relatively long-acting, AChE- and butyrylcholinesterase- (BuChE) inhibitor rivastigmine.

Impaired Kv7 channel function in cerebral arteries of a tauopathy mouse model (rTg4510).

In tauopathies, such as Alzheimer's disease with or without concomitant amyloid β plaques, cerebral arteries display pathological remodeling, leading to reduced brain tissue oxygenation and cognitive impairment. The precise mechanisms that underlie this vascular dysfunction remain unclear. Kv7 voltage-dependent K channels contribute to the development of myogenic tone in rat cerebral arteries.

Antagonism of the 5-HT receptor - Preclinical rationale for the treatment of Alzheimer's disease.

Antagonism of the 5-HT receptor is a promising approach for the symptomatic treatment of Alzheimer's disease (AD). There is compelling preclinical evidence for the procognitive potential of 5-HT receptor antagonists and several compounds are in clinical development, as adjunct therapy to acetylcholinesterase inhibitors (AChEIs). This manuscript summarizes the scientific rationale for the use of 5-HT receptor antagonists as AD treatment, with some focus on the selective and high-affinity 5-HT receptor antagonist idalopirdine (Lu AE58054).

The Serotonin Receptor 6 Antagonist Idalopirdine and Acetylcholinesterase Inhibitor Donepezil Have Synergistic Effects on Brain Activity-A Functional MRI Study in the Awake Rat.

The 5-HT receptor is a promising target for cognitive disorders, in particular for Alzheimer's disease (AD) and other CNS disorders. The high-affinity and selective 5-HT receptor antagonist idalopirdine (Lu AE58054) is currently in development for mild-moderate AD as adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We studied the effects of idalopirdine alone and in combination with the AChEI donepezil on brain activity using BOLD (Blood Oxygen Level Dependent) functional magnetic resonance imaging (fMRI) in the awake rat.

Effects of the 5-HT receptor antagonist idalopirdine on extracellular levels of monoamines, glutamate and acetylcholine in the rat medial prefrontal cortex.

Idalopirdine (Lu AE58054) is a high affinity and selective antagonist for the human serotonin 5-HT receptor (K 0.83nM) in phase III development for mild-to-moderate Alzheimer's disease as an adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We have studied the effects of idalopirdine on extracellular levels of monoamines, glutamate and acetylcholine in the medial prefrontal cortex (mPFC) of freely-moving rats using microdialysis.

The 5-HT receptor antagonist idalopirdine potentiates the effects of donepezil on gamma oscillations in the frontal cortex of anesthetized and awake rats without affecting sleep-wake architecture.

The 5-HT receptor is a promising target for cognitive disorders, in particular for Alzheimer's disease (AD). The high affinity and selective 5-HT receptor antagonist idalopirdine (Lu AE58054) is currently in development for mild-moderate AD as adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We studied the effects of idalopirdine alone and in combination with the AChEI donepezil on cortical function using two in vivo electrophysiological methods.

Reducing falls in Parkinson's disease: interactions between donepezil and the 5-HT receptor antagonist idalopirdine on falls in a rat model of impaired cognitive control of complex movements.

Falls are a leading cause of death in the elderly and, in a majority of patients with Parkinson's disease (PD), the leading levodopa-insensitive cause of hospitalization and long-term care. Falling in PD has been attributed to degeneration of forebrain cholinergic neurons that, in interaction with striatal dopamine losses, impairs the cognitive control of balance, gait, and movement. We previously established an animal model of these dual cholinergic-dopaminergic losses ("DL rats") and a behavioral test system (Michigan Complex Motor Control Task, MCMCT) to measure falls associated with traversing dynamic surfaces and distractors.

The 5-HT6 receptor antagonist idalopirdine potentiates the effects of acetylcholinesterase inhibition on neuronal network oscillations and extracellular acetylcholine levels in the rat dorsal hippocampus.

The 5-HT6 receptor has emerged as a promising target for cognitive disorders and combining a 5-HT6 receptor antagonist with an acetylcholinesterase inhibitor (AChEI) represents a novel approach for the symptomatic treatment of Alzheimer's disease (AD). A recent phase 2 trial showed that the selective 5-HT6 receptor antagonist idalopirdine (Lu AE58054) improved cognition in patients with moderate AD on stable treatment with the AChEI donepezil. Here we investigated the effects of idalopirdine in combination with donepezil on hippocampal function using in vivo electrophysiology and microdialysis.

Hyperactivity with Agitative-Like Behavior in a Mouse Tauopathy Model.

Tauopathies, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), are characterized by formation of neurofibrillary tangles consisting of hyperphosphorylated tau. In addition to memory loss, patients experience behavioral symptoms such as agitation, aggression, depression, and insomnia. We explored the behavioral phenotype of a mouse model (rTg4510) carrying the human tau P301L mutation found in a familial form of FTD.

Identification of the first small-molecule ligand of the neuronal receptor sortilin and structure determination of the receptor-ligand complex.

Sortilin is a type I membrane glycoprotein belonging to the vacuolar protein sorting 10 protein (Vps10p) family of sorting receptors and is most abundantly expressed in the central nervous system. Sortilin has emerged as a key player in the regulation of neuronal viability and has been implicated as a possible therapeutic target in a range of disorders. Here, the identification of AF40431, the first reported small-molecule ligand of sortilin, is reported.

The identification of AF38469: an orally bioavailable inhibitor of the VPS10P family sorting receptor Sortilin.

The identification of the novel, selective, orally bioavailable Sortilin inhibitor AF38469 is described. Structure-activity relationships and syntheses are reported, along with an X-ray crystal structure of the sortilin-AF38469 protein-inhibitor complex.

Negative modulation of GABAA α5 receptors by RO4938581 attenuates discrete sub-chronic and early postnatal phencyclidine (PCP)-induced cognitive deficits in rats.

Rationale: A growing body of evidence suggests that negative modulation of γ-aminobutyric acid (GABA) GABA(A) α5 receptors may be a promising strategy for the treatment of certain facets of cognitive impairment; however, selective modulators of GABA(A) α5 receptors have not yet been tested in "schizophrenia-relevant" cognitive assay/model systems in animals.

Objectives: The objectives of this study were to investigate the potential of RO4938581, a negative modulator of GABA(A) α5 receptors, and to attenuate cognitive impairments induced following sub-chronic (sub-PCP) and early postnatal PCP (neo-PCP) administration in the novel object recognition (NOR) and intra-extradimensional shift (ID/ED) paradigms in rats. Complementary in vitro, ex vivo and in vivo studies were performed to confirm negative modulatory activity of RO4938581 and to investigate animal model validity, concept validity and potential side effect issues, respectively.

Hippocampal CA1 region shows differential regulation of gene expression in mice displaying extremes in behavioral sensitization to amphetamine: relevance for psychosis susceptibility?

Rationale: Psychosis susceptibility is mediated in part by the dopaminergic neurotransmitter system. In humans, individual differences in vulnerability for psychosis are reflected in differential sensitivity for psychostimulants such as amphetamine. We hypothesize that the same genes and pathways underlying behavioral sensitization in mice are also involved in the vulnerability to psychosis.

Behavioral sensitization to cocaine: cooperation between glucocorticoids and epinephrine.

Rationale: Stressful life experiences facilitate responsiveness to psychostimulant drugs. While there is ample evidence that adrenal glucocorticoids mediate these effects of stress, the role of the sympatho-adrenal system in the effects of psychostimulants is poorly understood.

Objectives: The present study investigated the role of the two adrenal stress hormones, corticosterone and epinephrine, in sensitization to the locomotor stimulant effects of cocaine.

Critical time-window for the actions of adrenal glucocorticoids in behavioural sensitisation to cocaine.

Glucocorticoids, secreted by the adrenals in response to stress, have profound effects on behavioural responsiveness to psychostimulant drugs. We have studied the critical time-window for the influence of corticosterone on behavioural sensitisation to cocaine in relation to i) the stage of behavioural sensitisation, and ii) the time of drug exposure. Previously, we have identified a mouse strain (DBA/2) in which surgical removal of the adrenals (adrenalectomy) fully prevented locomotor sensitisation to cocaine.

Neuropharmacology of glucocorticoids: focus on emotion, cognition and cocaine.

Hormone pharmacology has been quite interesting in The Netherlands the past century and this contribution is dedicated to the glucocorticoid hormones underlying adaptation to stress. The story starts in 1936 with Tadeus Reichstein and Ernst Laqueur who discovered corticosterone at the time Hans Selye formulated the stress concept. Today highly sophisticated technologies help to unravel the action mechanism of the glucocorticoids from gene to behaviour.

Adrenalectomy prevents behavioural sensitisation of mice to cocaine in a genotype-dependent manner.

The objective of the present study was to investigate the contribution of adrenal stress hormones to strain differences in cocaine sensitivity. For this purpose, we have studied sensitisation to the locomotor stimulant effect of cocaine and, in parallel, cocaine-induced corticosterone secretion in two inbred mouse strains: C57BL/6 and DBA/2. Adrenalectomy ('ADX': surgical removal of the adrenal glands) was performed in a subset of animals to investigate the contribution of the adrenals.

SCH 23390 in the prefrontal cortex enhances the effect of apomorphine on prepulse inhibition of rats.

The aim of this study was to investigate the role of dopaminergic activity in the prefrontal cortex in the regulation of prepulse inhibition (PPI) of acoustic startle. Rats were instrumented with permanent indwelling cannulas into the prefrontal cortex region and tested at least one week after surgery using a randomized sequence, repeated-measures protocol. Doses of apomorphine (0.

Glucocorticoids and vulnerability to psychostimulant drugs: toward substrate and mechanism.

Glucocorticoid hormones can modulate the propensity of individuals to develop addictive behavior and, by doing so, contribute to the existence of individual differences in vulnerability to drugs. This article summarizes recent findings that increase our knowledge about drug-induced neuronal adaptations in the brain reward system and the role glucocorticoids may play in this process. Evidence exists that drugs and stress can induce similar changes in excitatory synaptic strength within the mesolimbic dopamine system, suggesting a coordinate mechanism for drugs of abuse and glucocorticoids.

Very low levels of the glucocorticoid receptor beta isoform in the human hippocampus as shown by Taqman RT-PCR and immunocytochemistry.

The hippocampus is an important target for glucocorticoid hormones. Glucocorticoid receptor (GR) mediated feedback in this area is important for control of behavioural adaptation. An alternative splice variant, the GRbeta (GRbeta) isoform, does not bind ligand and has been proposed to inhibit classic GRalpha-mediated transactivation of target genes.