Schizophrenia dimension-specific antipsychotic drug action and failure in amphetamine-sensitized psychotic-like rats

Uzuneser, Taygun C.; Schindehütte, Magnus; Dere, Ekrem; Hörsten, Stephan von; Kornhuber, Johannes; Grömer, Teja W.; Müller, Christian P.

doi:10.1016/j.euroneuro.2018.09.005

Cited by 7 publications

(24 citation statements)

References 58 publications

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“…Then, animals received an AMPH injection (1.5 mg/kg, i.p)., and their activities were recorded for 60 min. Locomotor and central activities of the animals were analyzed using Biobserve Viewer III software (Biobserve GMBH, Germany; 44, 45).…”

Section: Methodsmentioning

confidence: 99%

“…Using piezoelectric accelerometers, acoustic startle response (ASR)-induced physical force was transformed into an electrical signal, which was measured by the TSE startle response system (TSE Systems, Bad Homburg, Germany). The prepulse inhibition (PPI) procedure was adapted from Peleg-Raibstein et al (46) and established in our previous studies (44). In brief, three prepulse intensities (74, 80, and 86 dB) and three pulse intensities (100, 110, and 120 dB) were used to assess the PPI.…”

Section: Methodsmentioning

confidence: 99%

“…In brief, three prepulse intensities (74, 80, and 86 dB) and three pulse intensities (100, 110, and 120 dB) were used to assess the PPI. Nine prepulse + pulse trials, three pulse-alone trials, three prepulse-alone trials, and one no-stimulus trial were applied in a pseudo-randomized fashion and were repeated 10 times (44, 46, 47). %PPI was calculated with the following formula: %PPI = 100 − [100 × (startle amplitude of prepulse + pulse trials/startle amplitude of pulse-alone trials)].…”

Section: Methodsmentioning

confidence: 99%

“…Dissections were performed according to the rat brain atlas (48). The monoamine content in these regions was assessed using high-performance liquid chromatography as previously described (44). In brief, dissected tissues were purified, dissolved in 0.5 M HClO 4 (Carl Roth, GmbH), and analyzed with electrochemical detection to measure the concentrations of dopamine, serotonin, and noradrenaline.…”

Section: Methodsmentioning

confidence: 99%

“…The samples were segregated on a reversed-phase column (ET 125/2, Nucleosil 120-5, C-18; Macherey and Nagel, Dueren, Germany). The working potential of the electrochemical detector (Intro, Antec, Netherlands) was set at 500 mV vs. an ISAAC reference electrode (Antec, Leyden, Netherlands) (44, 49, 50).…”

Section: Methodsmentioning

confidence: 99%

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Disrupted-in-Schizophrenia 1 (DISC1) Overexpression and Juvenile Immune Activation Cause Sex-Specific Schizophrenia-Related Psychopathology in Rats

et al. 2019

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Synaptic pruning is a critical refinement step during neurodevelopment, and schizophrenia has been associated with overpruning of cortical dendritic spines. Both human studies and animal models implicate disrupted-in-schizophrenia 1 (DISC1) gene as a strong susceptibility factor for schizophrenia. Accumulating evidence supports the involvement of DISC1 protein in the modulation of synaptic elimination during critical periods of neurodevelopment and of dopamine D2-receptor-mediated signaling during adulthood. In many species, synaptic pruning occurs during juvenile and adolescent periods and is mediated by microglia, which can be over-activated by an immune challenge, giving rise to overpruning. Therefore, we sought to investigate possible interactions between a transgenic DISC1 model (tgDISC1) and juvenile immune activation (JIA) by the bacterial cell wall endotoxin lipopolysaccharide on the induction of schizophrenia-related behavioral and neurochemical disruptions in adult female and male rats. We examined possible behavioral aberrations along three major symptom dimensions of schizophrenia including psychosis, social and emotional disruptions, and cognitive impairments. We detected significant gene–environment interactions in the amphetamine-induced locomotion in female animals and in the amphetamine-induced anxiety in male animals. Surprisingly, gene–environment interactions improved social memory in both male and female animals. JIA alone disrupted spatial memory and recognition memory, but only in male animals. DISC1 overexpression alone induced an improvement in sensorimotor gating, but only in female animals. Our neurochemical analyses detected sex- and manipulation-dependent changes in the postmortem monoamine content of animals. Taken together, we here report sex-specific effects of environment and genotype as well as their interaction on behavioral phenotypes and neurochemical profiles relevant for schizophrenia.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Disrupted-in-Schizophrenia 1 (DISC1) Overexpression and Juvenile Immune Activation Cause Sex-Specific Schizophrenia-Related Psychopathology in Rats

et al. 2019

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

et al. 2021

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Behavioural effects of APH199, a selective dopamine D4 receptor agonist, in animal models

et al. 2023

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Rationale The dopamine D4 receptors (DRD4) play a key role in numerous brain functions and are involved in the pathogenesis of various psychiatric disorders. DRD4 ligands have been shown to moderate anxiety, reward and depression-like behaviours, and cognitive impairments. Despite a series of promising but ambiguous findings, the therapeutic advantages of DRD4 stimulation remain elusive. Objectives The investigation focused on the behavioural effects of the recently developed DRD4 agonist, APH199, to evaluate its impact on anxiety, anhedonia, behavioural despair, establishment and retrieval of alcohol reinforcement, and amphetamine (AMPH)-induced symptoms. Methods Male C57BL/6 J mice and Sprague–Dawley rats were examined in five independent experiments. We assessed APH199 (0.1–5 mg/kg, i.p.) effects on a broad range of behavioural parameters in the open field (OF) test, conditioned place preference test (CPP), elevated plus maze (EPM), light–dark box (LDB), novelty suppressed feeding (NSF), forced swim test (FST), sucrose preference test (SPT), AMPH-induced hyperlocomotion test (AIH), and prepulse inhibition (PPI) of the acoustic startle response in AMPH-sensitized rats. Results APH199 caused mild and sporadic anxiolytic and antidepressant effects in EPM and FST, but no remarkable impact on behaviour in other tests in mice. However, we found a significant increase in AMPH-induced hyperactivity, suggesting an exaggeration of the psychotic-like responses in the AMPH-sensitized rats. Conclusions Our data challenged the hypothesis of the therapeutic benefits of DRD4 agonists, pointing out a possible aggravation of psychosis. We suggest a need for further preclinical studies to ensure the safety of antipsychotics with DRD4 stimulating properties.

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Schizophrenia dimension-specific antipsychotic drug action and failure in amphetamine-sensitized psychotic-like rats

Cited by 7 publications

References 58 publications

Disrupted-in-Schizophrenia 1 (DISC1) Overexpression and Juvenile Immune Activation Cause Sex-Specific Schizophrenia-Related Psychopathology in Rats

Disrupted-in-Schizophrenia 1 (DISC1) Overexpression and Juvenile Immune Activation Cause Sex-Specific Schizophrenia-Related Psychopathology in Rats

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

Behavioural effects of APH199, a selective dopamine D4 receptor agonist, in animal models

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