Michel Boulouard

Background/Objectives: Cognitive deficits and negative symptoms associated with schizophrenia are poorly managed by current antipsychotics. In order to develop effective treatments, refining animal models of neurodevelopmental disorders is essential. Methods: To address their multifactorial etiology, we developed a new three-hit mouse model based on the hypoglutamatergic hypothesis of the pathology combined with early stress, offering strong construct validity. Thus, a genetic susceptibility (serine racemase deletion) was associated with an early environmental stress (24 h maternal separation at 9 days of age) and a further pharmacological treatment with phencyclidine (PCP, a glutamate receptor antagonist treatment, 10 mg/kg/day, from 8 to 10 weeks of age). The face validity of this model was assessed in female mice 1 and 6 weeks after the end of PCP treatment by a set of behavioral experiments investigating positive- and negative-like symptoms and cognitive deficits. Results: Our results showed that the three-hit mice displayed persistent hyperlocomotion (positive-like symptoms) and social behavior impairment deficits (negative-like symptoms) but non-persistent spatial working memory deficits (cognitive symptoms). Conclusions: Our work confirms the usefulness of a three-hit combination to model, particularly for negative-like symptoms associated with schizophrenia and other psychiatric disorders. The model therefore gathers powerful construct and face validities and supports an involvement of glutamate dysfunction in behavioral symptoms.

Anxiety appears among the most frequent psychiatric disorders. During recent years, a growing incidence of anxiety disorders can be attributed, at least in part, to the modification of our eating habits. To treat anxiety disorders, clinicians use benzodiazepines, which unfortunately display many side effects. Herein, the anxiolytic-like properties of two natural products (αS1–casein hydrolysate and Gabolysat^®) were investigated in rats and compared to the efficacy of benzodiazepine (diazepam). Thus, the conditioned defensive burying test was performed after a unique oral dose of 15 mg/kg, at two time-points (60 min and then 30 min post oral gavage) to show potential fast-onset of anxiolytic effect. Both natural products proved to be as efficient as diazepam to reduce the time rats spent burying the probe (anxiety level). Additionally, when investigated as early as 30 min post oral gavage, Gabolysat^® also revealed a fast-anxiolytic activity. To date, identification of bioactive peptide, as well as how they interact with the gut–brain axis to sustain such anxiolytic effect, still remains poorly understood. Regardless, this observational investigation argues for the consideration of natural compounds in care pathway.

For a better translation from treatment designs of schizophrenia to clinical efficiency, there is a crucial need to refine preclinical animal models. In order to consider the multifactorial nature of the disorder, a new mouse model associating three factors (genetic susceptibility—partial deletion of the MAP6 gene, early-life stress—maternal separation, and pharmacological treatment—chronic Δ-9-tetrahydrocannabinol during adolescence) has recently been described. While this model depicts a schizophrenia-like phenotype, the neurobiological correlates remain unknown. Synaptic transmission and functional plasticity of the CA1 hippocampal region of male and female 3-hit mice were therefore investigated using electrophysiological recordings on the hippocampus slice. While basal excitatory transmission remained unaffected, NMDA receptor (NMDAr)-mediated long-term potentiation (LTP) triggered by theta-burst (TBS) but not by high-frequency (HFS) stimulation was impaired in 3-hit mice. Isolated NMDAr activation was not affected or even increased in female 3-hit mice, revealing a sexual dimorphism. Considering that the regulation of LTP is more prone to inhibitory tone if triggered by TBS than by HFS, the weaker potentiation in 3-hit mice suggests a deficiency of intrinsic GABA regulatory mechanisms. Indeed, NMDAr activation was increased by GABA_A receptor blockade in wild-type but not in 3-hit mice. This electrophysiological study highlights dysregulations of functional properties and plasticity in hippocampal networks of 3-hit mice, one of the mechanisms suspected to contribute to the pathophysiology of schizophrenia. It also shows differences between males and females, supporting the sexual dimorphism observed in the disorder. Combined with the previously reported study, the present data reinforce the face validity of the 3-hit model that will help to consider new therapeutic strategies for psychosis.

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease which is still poorly understood. The drugs currently used against AD, mainly acetylcholinesterase inhibitors (AChEI), are considered clinically insufficient and are responsible for deleterious side effects. AChE is, however, currently receiving renewed interest through the discovery of a chaperone role played in the pathogenesis of AD. But AChE could also serve as an activating protein for pleiotropic prodrugs. Indeed, inhibiting central AChE with brain-penetrating designed carbamates which are able to covalently bind to the enzyme and to concomitantly liberate active metabolites in the brain could constitute a clinically more efficient approach which, additionally, is less likely to cause peripheral side effects. We aim in this article to pave the road of this new avenue with an in vitro and in vivo study of pleiotropic prodrugs targeting both the 5-HT₄ receptor and AChE, in order to display a neuroprotective activity associated with a sustained restoration of the cholinergic neurotransmission and without the usual peripheral side effects associated with classic AChEI. This plural activity could bring to AD patients effective, relatively safe, symptomatic and disease-modifying therapeutic benefits.

Gambling disorder is associated to an increased impulsivity, a high level of novelty‐seeking and a dysregulation of the forebrain neurotransmission systems. However, the neurobiological mechanisms of this addictive disorder are not fully understood and no valid pharmacological approach has yet been approved. The present study aimed to investigate the effect of 5‐HT7 receptor (5‐HT₇R) stimulation with a brain penetrant and selective agonist, LP‐211 (0.25 and 0.50 mg kg⁻¹ i.p.) during post‐experience consolidation, (i) acutely in a novelty‐preference test (Exp. 1) or (ii) sub‐chronically in the Probabilistic‐Delivery Task (rPDT, commonly used to measure individual differences in risk proneness of rats; Exp. 2). Results of Exp. 1 showed that 5‐HT₇R activation improves consolidation of chamber‐shape memory in the novelty‐preference test, leading to significant novelty‐induced hyperactivity and recognition, in conditions where controls displayed a null‐preference. These results suggest that 5‐HT₇Rs may be involved in the consolidation of information inherent to spatial environments, facilitating the recognition of novelty. Furthermore, in the operant rPDT (Exp. 2), 5‐HT₇R activation shifts the choice towards a larger yet unlikely reward and turns the propensity of rats towards risk‐prone behavior. Thus, 5‐HT₇Rs stimulation apparently strengthens the consideration of future, bigger rewards, also enhancing the seeking of it by operant pokes. These effects may well be explained by LP‐211 actions on hippocampal versus prefrontal cortex‐mediated regulations, leading to improved (though suboptimal) strategy formation. However, further experiments are necessary to determine more in depth the serotonergic pathways involved.

It is widely assumed that the upcoming therapeutics for Alzheimer’s disease will require to act on more than one target to be effective. We investigated here whether a combination of the nicotinic receptor allosteric modulator/cholinesterase inhibitor galantamine can act synergistically with the type 4 serotonin receptor (5-HT4R) partial agonist, RS-67333, to counterbalance deficits in short- and long-term memory. To select sub-efficacious doses of both drugs, dose-response studies were first performed on the scopolamine-induced deficits of spontaneous alternation in the Y-maze task and of acquisition and retrieval processes in a passive avoidance task.