Haloperidol rescues the schizophrenia-like phenotype in adulthood after rotenone administration in neonatal rats.

Neuropsychiatric disorders are multifactorial disturbances that encompass several hypotheses, including changes in neurodevelopment. It is known that brain development disturbances during early life can predict psychosis in adulthood. As we have previously demonstrated, rotenone, a mitochondrial complex I inhibitor, could induce psychiatric-like behavior in 60-day-old rats after intraperitoneal injections from the 5th to the 11th postnatal day. Because mitochondrial deregulation is related to psychiatric disorders and the establishment of animal models is a high-value preclinical tool, we investigated the responsiveness of the rotenone (Rot)-treated newborn rats to pharmacological agents used in clinical practice, haloperidol (Hal), and methylphenidate (MPD). Taken together, our data show that Rot-treated animals exhibit hyperlocomotion, decreased social interaction, and diminished contextual fear conditioning response at P60, consistent with positive, negative, and cognitive deficits of schizophrenia (SZ), respectively, that were reverted by Hal, but not MPD. Rot-treated rodents also display a prodromal-related phenotype at P35. Overall, our results seem to present a new SZ animal model as a consequence of mitochondrial inhibition during a critical neurodevelopmental period. Therefore, our study is crucial not only to elucidate the relevance of mitochondrial function in the etiology of SZ but also to fulfill the need for new and trustworthy experimentation models and, likewise, provide possibilities to new therapeutic avenues for this burdensome disorder.

Neonatal Rotenone Administration Induces Psychiatric Disorder-Like Behavior and Changes in Mitochondrial Biogenesis and Synaptic Proteins in Adulthood.

Since psychiatric disorders are associated with changes in the development of the nervous system, an energy-dependent mechanism, we investigated whether mitochondrial inhibition during the critical neurodevelopment window in rodents would be able to induce metabolic alterations culminating in psychiatric-like behavior. We treated male Wistar rat puppies (P) with rotenone (Rot), an inhibitor of mitochondrial complex I, from postnatal days 5 to 11 (P5-P11). We demonstrated that at P60 and P120, Rot-treated animals showed hyperlocomotion and deficits in social interaction and aversive contextual memory, features observed in animal models of schizophrenia, autism spectrum disorder, and attention deficit hyperactivity disorder. During adulthood, Rot-treated rodents also presented modifications in CBP and CREB levels in addition to a decrease in mitochondrial biogenesis and Nrf1 expression. Additionally, NFE2L2-activation was not altered in Rot-treated P60 and P120 animals; an upregulation of pNFE2L2/ NFE2L2 was only observed in P12 cortices. Curiously, ATP/ADP levels did not change in all ages evaluated. Rot administration in newborn rodents also promoted modification in Rest and Mecp2 expression, and in synaptic protein levels, named PSD-95, Synaptotagmin-1, and Synaptophysin in the adult rats. Altogether, our data indicate that behavioral abnormalities and changes in synaptic proteins in adulthood induced by neonatal Rot administration might be a result of adjustments in CREB pathways and alterations in mitochondrial biogenesis and Nrf1 expression, rather than a direct deficiency of energy supply, as previously speculated. Consequently, Rot-induced psychiatric-like behavior would be an outcome of alterations in neuronal paths due to mitochondrial deregulation.

Potential beneficial effects of caffeine administration in the neonatal period of an animal model of schizophrenia.

Obstetric complications, like maternal hypertension and neonatal hypoxia, disrupt brain development, leading to psychiatry disorders later in life, like schizophrenia. The exact mechanisms behind this risk are not yet well known. Spontaneously hypertensive rats (SHR) are a well-established model to study neurodevelopment of schizophrenia since they exhibit behavioral alterations mimicking schizophrenia that can be improved with antipsychotic drugs. SHR mothers are hypertensive, and the SHR offspring develop in preeclampsia-like conditions. Hypoxic conditions increase levels of adenosine, which play an important role in brain development. The enhanced levels of adenosine at birth could be related to the future development of schizophrenia. To investigate this hypothesis adenosine levels of brain neonatal Wistar rats and SHR were quantified. After that, caffeine, an antagonist of adenosinergic system, was administrated on PND (postnatal day) 7 (neurodevelopmental age similar to a human at delivery) and rats were observed at adolescent and adult ages. We also investigated the acute effects of caffeine at adolescent and adult ages. SHR control adolescent and adult groups presented behavioral deficits like hyperlocomotion, deficit in social interaction (SI), and contextual fear conditioning (CFC). In SHR, neonatal caffeine treatment on PND 7 normalized hyperlocomotion, improved SI, and CFC observed at adolescent period and adult ages, showing a beneficial effect on schizophrenia-like behaviors. Wistar rats neonatally treated with caffeine exhibited hyperlocomotion, deficit in SI and CFC when observed at adolescent and adult ages. Acutely caffeine treatment administrated at adolescent and adult ages increased locomotion and decreased SI time of Wistar rats and impair CFC in adult Wistars. No effects were observed in SHR. In conclusion, caffeine can be suggested as a useful drug to prevent behavioral deficits observed in this animal model of prenatal hypoxia-induced schizophrenia profile when specifically administered on PND 7.

Effects of maternal exposure to extract of Trichilia catigua on antibody production in the offspring of Wistar rats.

It was evaluated the effects of maternal treatment with the Trichilia catigua (ExTc) crude extract on the antibodies' production by their offspring. Female rats received ExTc or saline from the first day of pregnancy until the twenty-first day after the birth of the pups, when the pups were weaned. All pups were inoculated with two doses of 50 µg of IgY diluted in aluminium hydroxide/PBS on days 26 and 40 of life. Antibody levels were analysed by ELISA. Our results show an increase in levels of IgG1 and IgG2a anti-IgY in female offspring of mothers treated with ExTc compared to female offspring of untreated mothers. Furthermore, ExTc treatment suppressed the production of IgG2a anti-IgY antibodies in males. The data show that maternal exposure to ExTc can modulate the production of antibodies in the offspring.

The exposure to Trichilia catigua (catuaba) crude extract impairs fertility of adult female rats but does not cause reproductive damage to male offspring.

ETHNOPHARMACOLOGICAL RELEVANCE: Trichilia catigua is broadly used in folk medicine due to its mental and physical tonic activities and stimulant effects. In animal models, its antidepressant-like effects have been associated with the dopaminergic (DA) system modulation, which has an important role on maternal behavior and male offspring reproductive development. AIM OF THE STUDY: Since little is known about the adverse effects of the exposure to T. catigua crude extract (CAT) in rats, specially regarding maternal homeostasis and offspring development, the aim of the present study was to evaluate whether CAT exposure may influence maternal toxicity parameters and behavior or disrupt male offspring physical and reproductive development. MATERIAL AND METHODS: Dams were treated daily (by gavage) with 400mg/kg of CAT or vehicle (control=CTR) throughout pregnancy and lactation. Fertility and maternal behavior tests were conducted in dams. Male offspring reproductive and behavioral parameters were analyzed. RESULTS: Dams exposed to CAT showed increased pre- and post-implantation losses rates when compared to CTR group. No significant changes regarding maternal behavior or male offspring parameters were observed. CONCLUSION: In conclusion, maternal exposure to CAT interfered with implantation during the initial phases of pregnancy but did not induce changes on maternal behavior or male offspring reproductive and behavioral parameters.