Cardiac and hepatic side effects of fluoxetine in male and female adolescent rats.

BACKGROUND: Fluoxetine (FLX) is widely prescribed as an antidepressant medicine in the juvenile population. OBJECTIVES: Although some adverse effects of FLX have been reported in adults, the present study aimed to investigate the side effects of FLX treatment during adolescence on the cardiac and hepatic systems. METHODS: Male and female rats were gavaged with FLX (5 mg/kg/day) on postnatal days (PND) 21 to PND 60. Following treatment, blood samples were collected and hepatic enzymes were evaluated. The specimens of the liver and heart of animals were subjected to histopathological assessment. RESULTS: Fluoxetine significantly raised serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) in males, whereas the aspartate aminotransferase (AST) level increased in both male and female animals. In the histopathological study, hepatic plates were more seriously affected, and the sinusoids were irregular in adolescent male rats. Degenerative changes were observed especially in the first and second hepatic zones of FLX-treated male rats. Signs of inflammation and accumulation of lymphoid groups were frequently observed in the portal triad of the hepatic lobules. These alterations were more severe in male livers. Minimum or nearly normal changes were observed in female liver slides. In addition, the histological assessment indicated that treatment with FLX during adolescence also increased the heart's weight and the wall thickness of the right and left ventricles (hypertrophy) in male and especially female animals. CONCLUSION: Our findings may provide new insights into the cardiac and hepatic adverse effects of FLX.

Beneficial effects of enriched environment on behavior, cognitive functions, and hippocampal brain-derived neurotrophic factor level following postnatal serotonin depletion in male rats.

The neurotransmitter serotonin (5-HT) is one of the most important modulators of neural circuitry and has a critical role in neural development and functions. Previous studies indicated that changes in serotonergic system signaling in early life critically impact mental health, behavior, the morphology of hippocampal neurons, and cognitive functions across the lifespan. The enriched environment (EE) has indicated beneficial effects on behavior and cognitive functions in the developmental period of life, but its impacts on cognitive impairments and behavioral changes following postnatal serotonin depletion are unknown. Therefore, the present study aimed to evaluate the influences of the EE housing (postnatal days [PNDs] 21-60) following postnatal serotonin depletion (by para-chlorophenylalanine [PCPA], 100 mg/kg, s.c, in PNDs 10-20) on anxiety-related behaviors, cognitive functions, and brain-derived neurotrophic factor (BDNF) mRNA expression in the hippocampus of male rats. Memory and behavioral parameters were examined in early adulthood and after that, the hippocampi of rats were removed to determine the BDNF mRNA expression by PCR (PNDs 60-70). The findings of the present work indicated that adolescent EE exposure alleviated memory impairment, decreased BDNF levels, and anxiety disorders induced by experimental depletion of serotonin. Overall, these results indicate that serotonergic system dysregulation during the developmental periods can be alleviated by adolescent EE exposure.

Postnatal depletion of serotonin affects the morphology of neurons and the function of the hippocampus in male rats.

Serotonin (5-HT) is an essential neurotransmitter for the refined organization of the cerebral cortex. Studies have suggested that altered serotonin signaling contributes to cognitive impairment and psychiatric disorders. However, the exact role of this neurotransmitter on the development of hippocampal neurons is not recognized. Here we aimed to examine the effects of the para-chlorophenylalanine (PCPA; 100 mg/kg/daily, s.c. during the postnatal days 10-20), a reversible inhibitor of 5-HT synthesis, on the serotonin level of the hippocampal and prefrontal cortex. We also focused on the morphology of the neurons in the hippocampus and spatial learning and memory. Our results indicated that the administration of PCPA led to a decrease in serotonin levels in the hippocampus and prefrontal cortex. Postnatal serotonin depletion also induced subtle alterations in the neuronal populations of the hippocampus and impaired spatial memory in the adulthood period of life. We found that critical developmental periods of serotonin depletion caused degeneration and swelling of neurons as well as significant neuronal loss in the hippocampal CA1, CA3, and dentate gyrus (DG) areas. Thus, serotonin, a strikingly important neurotransmitter, can affect neuronal morphology, development, and hippocampal-dependent memory.

Alterations in the behavior, cognitive function, and BDNF level in adult male rats following neonatal blockade of GABA-A receptors.

Gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the mature brain. At an early developmental period, it acts in an excitatory manner that influences many processes of proliferation, migration, and differentiation of the neurons. Previous evidence indicated that manipulation of the GABAergic system function by activation or blockade of its receptors during developmental periods leads to behavioral and cognitive abnormality in adulthood. Therefore, we examined the effects of neonatal blockade of GABA-A receptors by bicuculline on behavior, cognitive function, and hippocampal and prefrontal cortex (PFC) brain-derived neurotrophic factors level (BDNF) in adulthood. As a result, neonatal rats were treated with either bicuculline (75,150, and 300 µg/kg) or DMSO on postnatal days 7,9, and 11. These groups underwent the behavioral (open field, elevated plus maze, and hot plate) and learning and memory (passive avoidance learning and memory) tests in postnatal days (PNDs) 61-70. After the ending of the behavioral tests, the rats were sacrificed under deep anesthesia and the hippocampi and prefrontal cortex (PFC) of the brain were removed for assessing the BDNF mRNA expression. Our results indicated that neonatal administration of bicuculline at the highest dose increased passive avoidance memory and hippocampal BDNF level. Meanwhile, this drug at a low dose impaired this type of memory and increased PFC BDNF level. Besides, treatment with bicuculline during postnatal days increased anxiety and pain sensitivity in a dose-dependent manner. Taken together, these findings confirmed the notion that GABA-A receptors during the developmental period are important for programming neurobehavioral phenotypes in adult life.

Serotonin depletion during the postnatal developmental period causes behavioral and cognitive alterations and decreases BDNF level in the brain of rats.

A survey of the literature indicates that the developmental disruptions in serotonin (5-HT) levels can influence the brain development and the function. To the best of our knowledge, so far, there are a few studies about the effects of developmental period 5-HT depletion on cognition and behavior of adult male and female rats. Therefore, in the present study, we examined the effects of postnatal days (PND 10-20) administration of para-chlorophenylalanine (PCPA, 100 mg/kg, s.c) a 5-HT synthesis inhibitor, on anxiety-related behaviors, pain sensitivity, short-term recognition memory, and hippocampal and prefrontal cortex (PFC) brain-derived neurotrophic factor (BDNF) mRNA expression in adult male and female rats. Novel object recognition memory (NORM) and behavioral parameters (anxiety-like behaviors and pain sensitivity) were evaluated in early adulthood and after that, the hippocampi and PFC of the rat's brain were removed for the determination of BDNF mRNA expression. Our results indicated that the postnatal period administration of PCPA impaired short-term NORM. The postnatal developmental period treatment with PCPA also increased anxiety-like behaviors in the open field and elevated plus maze (EPM) tests. Postnatal PCPA treatment increased pain sensitivity in the hot plate test in both male and female rats, especially in female animals. In addition, postnatal days serotonin depletion decreased BDNF level in the hippocampus and PFC of both male and female rats. These findings demonstrate that serotonin plays the main role in neurodevelopment, cognitive functions, and behavior. Therefore, serotonergic system dysregulation during the developmental periods may have more adverse influences on the brain development of rats.

Effects of adolescent administration of fluoxetine on novel object recognition memory, anxiety-like behaviors, and hippocampal brain-derived neurotrophic factor level.

AIMS: Fluoxetine (FLX) is a common selective serotonin reuptake inhibitor, which is used in adolescents with psychiatric disorders. Controversial results have been obtained in different studies about the effects of FLX on cognitive functions. The present study was designed to examine the effects of chronic FLX exposure during adolescence on cognitive function, anxiety-like behaviors, and hippocampal brain-derived neurotrophic factor (BDNF) mRNA expression among adult male and female rats. MAIN METHODS: The sex-dependent effects of FLX chronic administration during adolescence (5 mg/kg/day, gavage) on short-term novel object recognition memory (NORM), anxiety-like behaviors, and BDNF mRNA expression in the hippocampus were examined. NORM and anxiety-like behaviors were assessed by novel object recognition, open field, and elevated plus-maze (EPM) tests, respectively. The expression of BDNF mRNA was also evaluated by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). KEY FINDINGS: The present findings revealed the dysfunction of short-term NORM among the adolescent male and female rats exposed to FLX, while the mRNA expression of BDNF was significantly higher among the males. Moreover, adolescent FLX administration had different effects on the anxiety-like behaviors of the male and female rats. Adolescent FLX treatment also decreased the body weight of the male animals. SIGNIFICANCE: In conclusion, adolescent FLX treatment impairs cognitive functions in both sexes and increases BDNF mRNA expression in the hippocampus of the male animals. FLX administration during adolescence has sex-dependent effects on anxiety-like behaviors. These findings indicate that the impairment of cognitive functions can occur following the adolescent manipulation of the serotonergic system. Therefore, the side effects of chronic FLX administration during adolescence should be more considered.

Effects of exposure to enriched environment during adolescence on passive avoidance memory, nociception, and prefrontal BDNF level in adult male and female rats.

Previous studies demonstrated that an enriched environment (EE) exposure improves cognitive functions, synaptic plasticity, neurogenesis, and induction of brain-derived neurotrophic factor (BDNF) in multiple brain regions of laboratory animal models. Also, studies on the sex-dependent effects of exposure to EE during adolescence on adult cognitive functions are less. Therefore, the present experiment was aimed to assess the effects of EE during adolescence on passive avoidance learning and memory, nociception, and prefrontal cortex (PFC) BDNF mRNA levels in the adult male and female rats. Our results indicated that housing in the EE during adolescence improves passive avoidance memory and increases nociceptive response against thermal stimulus in both sexes. Findings of our study also showed an increased BDNF level in the PFC of female animals. As a result, sex differences can affect the expression of BDNF mRNA in the PFC. Further research concerning the precise mechanisms underlying sex hormone-dependent production of BDNF in PFC is critical.

Sex-dependent effects of chronic fluoxetine exposure during adolescence on passive avoidance memory, nociception, and prefrontal brain-derived neurotrophic factor mRNA expression.

Fluoxetine, a common antidepressant drug, is widely used for mental disorders therapy in adolescents. Previous animal experiments have indicated that exposure to fluoxetine during adolescence leads to persistent behavioral changes and neuroplasticity in the hippocampal formation and cortex which may continue until adulthood. Therefore, in the present experimental study, we examined the effects of chronic fluoxetine exposure (5 mg/kg/day, gavage) throughout adolescence (postnatal day 21-60) on passive avoidance learning and memory, pain sensitivity, and brain-derived neurotrophic factor (BDNF) level in the prefrontal cortex of young adult male and female rats. Passive avoidance learning, memory, and nociception were assessed by the shuttle box and hot plate tests respectively. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was applied to estimate the BDNF mRNA expression. Our data showed that chronic administration of fluoxetine had an increasing effect on passive avoidance memory in female animals. As well as, chronic fluoxetine treatment decreased latency of response to thermal stimulus in male and female rats. The mRNA expression of BDNF in the prefrontal cortex significantly increased in fluoxetine- exposed female rats. In conclusion, chronic fluoxetine treatment has sex-dependent effects on passive avoidance memory and BDNF mRNA expression, but the pain threshold decreases in both sexes. Therefore, passive avoidance memory, pain sensitivity, and the BDNF level are influenced by the manipulation of the serotonergic system.

Sex-dependent effects of postweaning exposure to an enriched environment on novel objective recognition memory and anxiety-like behaviors: The role of hippocampal BDNF level.

Exposure to enriched environment (EE) has been indicated to enhance cognitive functions, hippocampal neural plasticity, neurogenesis, long-term potentiation, and levels of the brain-derived neurotrophic factor (BDNF) in laboratory animals. Also, studies on the sex-dependent effects of exposure to EE during adolescence on adult cognitive functions are less. This is important because the beneficial effects of EE may be predominant in the adolescence stage. Therefore, the present study was designed to compare the effects of EE during adolescence (PND21-PND60) on novel objective recognition memory (NORM), anxiety-like behaviors, and hippocampal BDNF mRNA level in the adult male and female rats. Assessment of NORM and anxiety-like behaviors has been done by novel objective recognition task, open field (OF), and elevated plus maze (EPM), respectively. The expression of BDNF mRNA level was also evaluated by quantitative RT-PCR. Our findings demonstrated that housing in the EE during adolescence improves NORM in adult male rats. Also, exposure to EE during adolescence had a different effect on anxiety-like behaviors in both sexes. Additionally, our results indicated an augmented BDNF level in the hippocampus of male and female rats. In conclusion, adolescent exposure to EE has sex-dependent effects on cognitive functions and anxiety-like behaviors and increases BDNF mRNA expression in the hippocampus of both male and female rats; thus, BDNF is an important factor that can mediate the beneficial effects of EE and running exercise on cognitive functions and psychiatric traits.