Dopaminergic and glutamatergic models of psychosis show differential sensitivity to aripiprazole and a novel experimental compound modulating D2/5-HT receptor activity.

Dopamine type 2 receptors (D2Rs) constitute the main molecular target in the pharmacotherapy of schizophrenia. However, the second and third generation of antipsychotics comprises multi-target ligands, also binding serotonin type 3 receptors (5-HT3Rs) and other receptor classes as well. Here, we examined two experimental compounds (marked compound K1697 and K1700) from the group of 1,4-di-substituted aromatic piperazines, previously described in the study of Juza et al., 2021, and compared them with the chosen reference antipsychotic, aripiprazole. Their efficacy against schizophrenia-like behavior was tested in two different models of psychosis in the rat, induced by acute administration of either amphetamine (1.5 mg/kg) or dizocilpine (0.1 mg/kg), reflecting the dopaminergic and glutamatergic hypotheses of schizophrenia. The two models exhibited broadly similar behavioral manifestations: hyperlocomotion, disrupted social behavior and impaired prepulse inhibition of the startle response. However, they differed in their treatment responses as hyperlocomotion and prepulse inhibition deficit in the dizocilpine model were resistant to antipsychotic treatment, unlike the amphetamine model. One of the experimental compounds, K1700, ameliorated all the observed schizophrenia-like behaviors in the amphetamine model with an efficacy comparable to or greater than aripiprazole. Whereas social impairments caused by dizocilpine were strongly suppressed by aripiprazole, K1700 was less efficient. Taken together, K1700 showed antipsychotic properties comparable to those of aripiprazole, although the efficacy of the two drugs differed in specific domains of behavior and was also model-dependent. Our present results highlight the differences in these two schizophrenia models and their responsiveness to pharmacotherapy, and confirm compound K1700 as a promising drug candidate.

Developmental effects of constitutive mTORC1 hyperactivity and environmental enrichment on structural synaptic plasticity and behaviour in a rat model of autism spectrum disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental condition causing a range of social and communication impairments. Although the role of multiple genes and environmental factors has been reported, the effects of the interplay between genes and environment on the onset and progression of the disease remains elusive. We housed wild-type (Tsc2+/+) and tuberous sclerosis 2 deficient (Tsc2+/-) Eker rats (ASD model) in individually ventilated cages or enriched conditions and conducted a series of behavioural tests followed by the histochemical analysis of dendritic spines and plasticity in three age groups (days 45, 90 and 365). The elevated plus-maze test revealed a reduction of anxiety by enrichment, whereas the mobility of young and adult Eker rats in the open field was lower compared to the wild type. In the social interaction test, an enriched environment reduced social contact in the youngest group and increased anogenital exploration in 90- and 365-day-old rats. Self-grooming was increased by environmental enrichment in young and adult rats and decreased in aged Eker rats. Dendritic spine counts revealed an increased spine density in the cingulate gyrus in adult Ekers irrespective of housing conditions, whereas spine density in hippocampal pyramidal neurons was comparable across all genotypes and groups. Morphometric analysis of dendritic spines revealed age-related changes in spine morphology and density, which were responsive to animal genotype and environment. Taken together, our findings suggest that under TSC2 haploinsufficiency and mTORC1 hyperactivity, the expression of behavioural signs and neuroplasticity in Eker rats can be differentially influenced by the developmental stage and environment.

Behavioral Alterations and Decreased Number of Parvalbumin-Positive Interneurons in Wistar Rats after Maternal Immune Activation by Lipopolysaccharide: Sex Matters.

Maternal immune activation (MIA) during pregnancy represents an important environmental factor in the etiology of schizophrenia and autism spectrum disorders (ASD). Our goal was to investigate the impacts of MIA on the brain and behavior of adolescent and adult offspring, as a rat model of these neurodevelopmental disorders. We injected bacterial lipopolysaccharide (LPS, 1 mg/kg) to pregnant Wistar dams from gestational day 7, every other day, up to delivery. Behavior of the offspring was examined in a comprehensive battery of tasks at postnatal days P45 and P90. Several brain parameters were analyzed at P28. The results showed that prenatal immune activation caused social and communication impairments in the adult offspring of both sexes; males were affected already in adolescence. MIA also caused prepulse inhibition deficit in females and increased the startle reaction in males. Anxiety and hypolocomotion were apparent in LPS-affected males and females. In the 28-day-old LPS offspring, we found enlargement of the brain and decreased numbers of parvalbumin-positive interneurons in the frontal cortex in both sexes. To conclude, our data indicate that sex of the offspring plays a crucial role in the development of the MIA-induced behavioral alterations, whereas changes in the brain apparent in young animals are sex-independent.

mTOR inhibitor improves autistic-like behaviors related to Tsc2 haploinsufficiency but not following developmental status epilepticus.

BACKGROUND: Tuberous sclerosis complex (TSC), a multi-system genetic disorder often associated with autism spectrum disorder (ASD), is caused by mutations of TSC1 or TSC2, which lead to constitutive overactivation of mammalian target of rapamycin (mTOR). In several Tsc1+/- and Tsc2+/- animal models, cognitive and social behavior deficits were reversed by mTOR inhibitors. However, phase II studies have not shown amelioration of ASD and cognitive deficits in individuals with TSC during mTOR inhibitor therapy. We asked here if developmental epilepsy, common in the majority of individuals with TSC but absent in most animal models, could explain the discrepancy. METHODS: At postnatal day P12, developmental status epilepticus (DSE) was induced in male Tsc2+/- (Eker) and wild-type rats, establishing four experimental groups including controls. In adult animals (n = 36), the behavior was assessed in the paradigms of social interaction test, elevated plus-maze, light-dark test, Y-maze, and novel object recognition. The testing was carried out before medication (T1), during a 2-week treatment with the mTOR inhibitor everolimus (T2) and after an 8-week washing-out (T3). Electroencephalographic (EEG) activity was recorded in a separate set of animals (n = 18). RESULTS: Both Tsc2+/- mutation and DSE caused social behavior deficits and epileptiform EEG abnormalities (T1). Everolimus led to a persistent improvement of the social deficit induced by Tsc2+/-, while deficits related to DSE did not respond to everolimus (T2, T3). CONCLUSIONS: These findings may contribute to an explanation why ASD symptoms in individuals with TSC, where comorbid early-onset epilepsy is common, were not reliably ameliorated by mTOR inhibitors in clinical studies.