The 3-hit animal models of schizophrenia: Improving strategy to decipher and treat the disease?

Schizophrenia is a complex disease related to combination and interactions between genetic and environmental factors, with an epigenetic influence. After the development of the first mono-factorial animal models of schizophrenia (1-hit), that reproduced patterns of either positive, negative and/or cognitive symptoms, more complex models combining two factors (2-hit) have been developed to better fit with the multifactorial etiology of the disease. In the two past decades, a new way to design animal models of schizophrenia have emerged by adding a third hit (3-hit). This review aims to discuss the relevance of the risk factors chosen for the tuning of the 3-hit animal models, as well as the validities measurements and their contribution to schizophrenia understanding. We intended to establish a comprehensive overview to help in the choice of factors for the design of multiple-hit animal models of schizophrenia.

Micropipette-guided Drug Administration (MDA) as a non-invasive chronic oral administration method in male rats.

BACKGROUND: In preclinical studies resorting to rodents, the effects of prolonged oral intake of active substances are difficult to evaluate. Indeed, to get closer to clinical reality, oral gavage (OG) is frequently used but the repetition of administrations induces risks of lesions of the digestive tract, and stress for animals which can compromise the quality of the results. NEW METHOD: This study describes the development of a non-invasive oral administration method in male Sprague Dawley rats, as a safe alternative of OG, more faithful to clinical reality and limiting biases in pharmacokinetics and/or pharmacodynamics interpretation. Micropipette-guided Drug Administration (MDA) is based on the administration by micropipette of a sufficiently palatable vehicle for the animals to voluntarily take its contents. RESULTS: MDA was not demonstrated as less stressful than OG. A pharmacokinetics equivalence between MDA and OG was demonstrated for pregabalin administration but not for aripiprazole. Despite the use of a sweet vehicle, the MDA method does not result in weight gain or significant elevation of blood glucose and fructosamines level. Regarding the time needed to administrate the solution, the MDA method is significantly faster than OG. COMPARISON WITH EXISTING METHOD(S): Contrastingly to procedures using food or water, this method allows for a rigorous control of the time and dose administered and is delivered in discrete administration windows which is therefore closer to the clinical reality. This method appears particularly suitable for pharmacological evaluation of hydrophilic compounds. CONCLUSIONS: The MDA procedure represents a respectful and adapted pharmacological administration method to study the effects of chronic oral administration in rats.

5-HT6 Receptors Sex-Dependently Modulate Hippocampal Synaptic Activity through GABA Inhibition.

The subtype 6 of the serotoninergic receptors (5-HT6Rs) is highly expressed in the hippocampus, and evidence indicates the beneficial effects of 5-HT6Rs blockade on short- and long-term memory in rodents. Nevertheless, the underlying functional mechanisms still need to be established. To this end, we performed electrophysiological extracellular recordings to assess the effects of the 5-HT6Rs antagonist SB-271046 on the synaptic activity and functional plasticity at the CA3/CA1 hippocampal connections of male and female mice slices. We found that basal excitatory synaptic transmission and isolated N-methyl-D-aspartate receptors (NMDARs) activation were significantly increased by SB-271046. The NMDARs-related improvement was prevented by the GABAAR antagonist bicuculline in male but not in female mice. Regarding synaptic plasticity, neither paired-pulse facilitation (PPF) nor NMDARs-dependent long-term potentiation (LTP) (induced either by high-frequency or theta-burst stimulation) was affected by the 5-HT6Rs blockade. Taken together, our results indicate a sex-dependent 5-HT6Rs effect on synaptic activity at the CA3/CA1 hippocampal connections through changes in the excitation/inhibition balance.

Frontoparietal anodal tDCS reduces ketamine-induced oscillopathies.

During the prodromal phase of schizophrenia with its complex and insidious clinical picture, electroencephalographic recordings detect widespread oscillation disturbances (or oscillopathies) during the wake-sleep cycle. Neural oscillations are electrobiomarkers of the connectivity state within systems. A single-systemic administration of ketamine, a non-competitive NMDA glutamate receptor antagonist, transiently reproduces the oscillopathies with a clinical picture reminiscent of the psychosis prodrome. This acute pharmacological model may help the research and development of innovative treatments against psychotic transition. Transcranial electrical stimulation is recognized as an appropriate non-invasive therapeutic modality since it can increase cognitive performance and modulate neural oscillations with little or no side effects. Therefore, our objective was to set up, in the sedated adult rat, a stimulation method that is able to normalize ketamine-induced increase in gamma-frequency (30-80 Hz) oscillations and decrease in sigma-frequency (10-17 Hz) oscillations. Unilateral and bipolar frontoparietal (FP), transcranial anodal stimulation by direct current (<+1 mA) was applied in ketamine-treated rats. A concomitant bilateral electroencephalographic recording of the parietal cortex measured the stimulation effects on its spontaneously occurring oscillations. A 5 min FP anodal tDCS immediately and quickly reduced, significantly with an intensity-effect relationship, the ketamine-induced gamma hyperactivity, and sigma hypoactivity at least in the bilateral parietal cortex. A duration effect was also recorded. The tDCS also tended to diminish the ketamine-induced delta hypoactivity. These preliminary neurophysiological findings are promising for developing a therapeutic proof-of-concept against neuropsychiatric disorders.