scholarly journals 1MeTIQ and olanzapine, despite their neurochemical impact, did not ameliorate performance in fear conditioning and social interaction tests in an MK-801 rat model of schizophrenia

2021 ◽  
Author(s):  
Magdalena Białoń ◽  
Agnieszka Chocyk ◽  
Iwona Majcher-Maślanka ◽  
Marcelina Żarnowska ◽  
Krzysztof Michalski ◽  
...  
Keyword(s):  
Social Interaction ◽  
Fear Conditioning ◽  
Negative Symptoms ◽  
Brain Structures ◽  
Fear Memory ◽  
Contextual Fear Conditioning ◽  
Acute Administration ◽  
Sprague Dawley ◽  
Mk 801 ◽  
Serotonin System

Abstract Background The aim of the present study was to evaluate the effect of 1MeTIQ on fear memory and social interaction in an MK-801-induced model of schizophrenia. The results obtained after administration of 1MeTIQ were compared with those obtained with olanzapine, an antipsychotic drug. Methods Sprague–Dawley rats received a single injection of MK-801 to induce behavioral disorders. 1MeTIQ was given either acutely in a single dose or chronically for 7 consecutive days. Olanzapine was administered once. In groups receiving combined treatments, 1MeTIQ or olanzapine was administered 20 min before MK-801 injection. Contextual fear conditioning was used to assess disturbances in fear memory (FM), and the sociability of the rats was measured in the social interaction test (SIT). Biochemical analysis was carried out to evaluate monoamine levels in selected brain structures after treatment. Results Our results are focused mainly on data obtained from neurochemical studies, demonstrating that 1MeTIQ inhibited the MK-801-induced reduction in dopamine levels in the frontal cortex and increased the 5-HT concentration. The behavioral tests revealed that acute administration of MK-801 caused disturbances in both the FM and SIT tests, while neither 1MeTIQ nor olanzapine reversed these deficits. Conclusion 1MeTIQ, although pharmacologically effective (i.e., it reverses MK-801-induced changes in monoamine activity), did not influence MK-801-induced social and cognitive deficits. Thus, our FM tests and SIT did not support the main pharmacological hypotheses that focus on dopamine system stabilization and dopamine–serotonin system interactions as probable mechanisms for inhibiting the negative symptoms of schizophrenia.

scholarly journals Lack of drug-induced post-retrieval amnesia for auditory fear memories in rats

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Laura Luyten ◽  
Anna Elisabeth Schnell ◽  
Natalie Schroyens ◽  
Tom Beckers
Keyword(s):  
Fear Conditioning ◽  
Critical Time ◽  
Fear Memory ◽  
Time Frame ◽  
Long Term Memory ◽  
Sprague Dawley ◽  
Drug Induced ◽  
Pharmacological Agents ◽  
Administration Routes ◽  
Permanent Storage

Abstract Background Long-term memory formation is generally assumed to involve the permanent storage of recently acquired memories, making them relatively insensitive to disruption, a process referred to as memory consolidation. However, when retrieved under specific circumstances, consolidated fear memories are thought to return to a labile state, thereby opening a window for modification (e.g., attenuation) of the memory. Several interventions during a critical time frame after this destabilization seem to be able to alter the retrieved memory, for example by pharmacologically interfering with the restabilization process, either by direct protein synthesis inhibition or indirectly, using drugs that can be safely administered in patients (e.g., propranolol). Here, we find that, contrary to expectations, systemic pharmacological manipulations in auditory fear-conditioned rats do not lead to drug-induced post-retrieval amnesia. Results In a series of well-powered auditory fear conditioning experiments (four with propranolol, 10 mg/kg, two with rapamycin, 20–40 mg/kg, one with anisomycin, 150 mg/kg and cycloheximide, 1.5 mg/kg), we found no evidence for reduced cued fear memory expression during a drug-free test in adult male Sprague-Dawley rats that had previously received a systemic drug injection upon retrieval of the tone fear memory. All experiments used standard fear conditioning and reactivation procedures with freezing as the behavioral read-out (conceptual or exact replications of published reports) and common pharmacological agents. Additional tests confirmed that the applied drug doses and administration routes were effective in inducing their conventional effects on expression of fear (propranolol, acutely), body weight (rapamycin, anisomycin, cycloheximide), and consolidation of extinction memories (cycloheximide). Conclusions In contrast with previously published studies, we did not find evidence for drug-induced post-retrieval amnesia, underlining that this effect, as well as its clinical applicability, may be considerably more constrained and less readily reproduced than what the current literature would suggest.

scholarly journals S218. TAURINE DOES NOT PREVENT SOCIAL DEFICITS INDUCED BY MK-801 IN ADULT ZEBRAFISH

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S121-S122
Author(s):  
Franciele Kich Giongo ◽  
Radharani Benvenutti ◽  
Matheus Gallas-Lopes ◽  
Adrieli Sachett ◽  
Angelo Piato ◽  
...  
Keyword(s):  
Social Interaction ◽  
Animal Models ◽  
Negative Symptoms ◽  
Acute Exposure ◽  
First Episode ◽  
Social Deficits ◽  
Zebrafish Model ◽  
Mk 801 ◽  
Total Distance ◽  
The Social

Abstract Background Cognitive and negative symptoms are the core reason for the functional deficits experienced by patients with schizophrenia. Drugs that can modulate these symptoms are especially needed since no progress has been achieved in the last few decades with currently available antipsychotics. Taurine is an amino acid not used for protein synthesis but widely distributed in mammalian tissues. In the central nervous system, it has been shown to act as an inhibitory neuromodulator and possess neuroprotective, antioxidant and immunomodulatory properties. Decreased plasma and brain levels of taurine have been reported in patients as well as in animal models of schizophrenia. Furthermore, taurine improved symptoms and was well tolerated in a clinical trial of patients with first-episode psychosis. We investigated whether taurine counteracts social deficits in a zebrafish model of social interaction following acute exposure to MK-801 (dizocilpine), an NDMA antagonist commonly used in schizophrenia animal models. Methods Ninety-six 3-month-old wild-type zebrafish (Danio rerio, 50:50 male:female ratio) were used. For the social interaction test, animals were individually placed in a beaker with 200 mL of tank water (control) or taurine solution (42, 150 and 400 mg/L) for 20 minutes, and then exposed to water or MK-801 (5 µM) for another 20 minutes (n = 12 animals per group). Immediately after the treatments, zebrafish were transferred to the social interaction apparatus, a tank virtually divided in 3 vertical zones and sided by an empty tank and a tank containing 10 zebrafish. Behavior was recorded for 7 minutes and the last 5 were analyzed by automated tracking with the software ANY-Maze. The time spent in the stimulus zone was measured as a proxy for social interaction; total distance traveled was also computed. Data were analyzed by two-way ANOVA. Results MK-801 increased the total distance traveled (F1,88 = 4.935, p = 0.0289) and reduced the time spent in the tank zone next to the conspecifics (F1,88 = 23.14, p < 0.0001). No main effects of taurine or interaction effects were observed on locomotor or social interaction parameters. Discussion Although taurine has been shown to increase social interaction in rats and modulate shoaling behavior in ethanol-exposed zebrafish, it had not been tested against social deficits induced by NMDA antagonists. We observed that taurine did not counteract the hyperlocomotion and social deficit induced by acute exposure to MK-801 in zebrafish. As schizophrenia etiology has been linked to cortical and hippocampal disruption in GABAergic signaling, taurine may be effective as a preventive treatment in early neurodevelopmental stages. Further testing using animal models that more closely resemble the course of schizophrenia are thus needed to investigate the potential of this molecule.

scholarly journals S179. ADMINISTRATION OF ROTENONE DURING NEONATAL PERIOD INDUCES SCHIZOPHRENIA-LIKE BEHAVIOR

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S106-S106
Author(s):  
Amanda Siena ◽  
Thiago Varga ◽  
Juan Simões ◽  
Elisandra Henrique ◽  
Aline Camargo Ramos ◽  
...  
Keyword(s):  
Nervous System ◽  
Social Interaction ◽  
Fear Conditioning ◽  
Young Adulthood ◽  
Emotional Memory ◽  
Contextual Fear Conditioning ◽  
Behavioral Tests ◽  
Prodromal Phase ◽  
Behavioral Deficits ◽  
Contextual Fear

Abstract Background The neurodevelopment refers to the process that generates and shapes the nervous system of animals. It begins during the earliest stages of embryonic development and it is the last system to be completed after birth, which occurs during the end of adolescence. The majority of mechanisms that constitutes neurodevelopment, such as cell proliferation, migration and neural differentiation, axon growth cone and dendritic filopodia formation as well as synapse are ATP dependents, therefore mitochondria dependents. Hence, disturbs during nervous system development can lead to behavioral deficits and neuropsychiatric disorders, such as schizophrenia. Results of our research group showed that a mitochondria dysfunction during neurodevelopment, by Rotenone (a complex I inhibitor) administration, induces behavioral deficits, such as hyperlocomotion and decreased social interaction, when the rats were young adults (60 days old). Thus, the objective of this study was to evaluate the behavioral deficits in an early age (prodromal phase) and if the behavioral deficits presented at young adulthood could be attenuated or reverted by antipsychotic (Haldol – Hal) or psychostimulant (Metilphenidate – MPD). Notwithstanding, draw a parallel between this animal model and a neuropsychiatric disorder. Methods To reach this goal, we treated intraperitoneally wistar puppies (P) with Rotenone 0.1mg/kg (Rot), Saline (Sal) or Vehicle (Veh) (DMSO) during P5-P11. To verify the prodromal phase, we performed behavioral tests (open field, social interaction and contextual fear conditioning) at P35. Therefore, in order to analyze the behavior during the young adulthood (P60), each animal previously treated with Sal, Veh or Rot was then treated intraperitoneally, 30 min before the behavioral tests (open field, social interaction and contextual fear conditioning), with either Saline (Sal-Sal, Veh-Sal, Rot-Sal), Hal (Sal-Hal, Veh-Hal, Rot-Hal) or MPD (Sal-MPD, Veh-MPD, Rot-MPD). Results Results showed mean±SEM (n=8 for each group) and analyzed by One-Way Anova and Duncan post-hoc compared to control group (Sal-Sal 100%). At P35, we verified: i) no significant changes in locomotor activity between Rot and Sal; ii) decrease in social interaction after treatment with Rot (68.40%±3.077; p<0.05 in relation to Sal); iii) a reduction in freezing time in contextual fear conditioning task to Rot group (45.20±8.03; p<0.05 when compared to Sal). At P60, we noticed i) an increase in locomotor activity after treatment with Rot-Sal (134.88%±3.95; p<0.05 when compared to Sal-Sal) that was decreased by treatment with Rot-Hal (94.76%±15.74; p<0.05 when compared to Rot-Sal), but not with Rot-MPD (compared to Rot-Sal); ii) a decrease in social interaction at P60 after treatment with Rot-Sal (68.35%±5.87; p<0.05 when compared to Sal-Sal) that was reverted by treatment with Rot-Hal (100.80%±6.66; p<0.05 when compared to Rot-Sal) and also with Rot-MPD (100.6%±6,89; p<0.05 when compared to Rot-Sal); iii) in contextual fear conditioning the animals treated with Rot presented a decrease in freezing response (31.50%±7.36; p<0.05 when compared to Sal-Sal) that was reverted by treatment with Rot-Hal (81.21%±16.65; p<0.05 when compared to Rot-Sal). Discussion We concluded that neonatal treatment with Rot promote behavior deficits at young age (P35), such as deficit in social interaction and emotional memory; in young adulthood (P60) we also verified deficit in social interaction and emotional memory, in addition to hyperlocomotion, that are mostly reverted with treatment with Hal, but not with MPD. Altogether our data suggest a relationship between mitochondria inhibition during neurodevelopment leading to schizophrenia-like behavior.

FC29-03 - Effects of chronic oral treatment with aripiprazole on expression of nmda receptor subunits and binding sites in rat brain

2011 ◽  
Vol 26 (S2) ◽  
pp. 1979-1979
Author(s):  
M. Zink ◽  
N. Segnitz ◽  
T. Ferbert ◽  
A. Schmitt ◽  
P. Gass ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Negative Symptoms ◽  
Oral Treatment ◽  
Antipsychotic Agents ◽  
Brain Regions ◽  
Relative Increase ◽  
Receptor Expression ◽  
Sprague Dawley ◽  
Adult Type ◽  
Mk 801

IntroductionThe glutamatergic theory of schizophrenia proposes a dysfunction of ionotropic N-Methyl-D-aspartate (NMDA)-receptors (NR). Several therapeutic strategies address NR function and effects of antipsychotic agents on NR expression have been described.ObjectivesThe partial dopaminergic and serotonergic agonist aripiprazole (APZ) was able to counteract behavioural effects of NR antagonists, but effects of APZ on NR expression have not been investigated.AimsTo evaluate effects of APZ on NR mRNA and protein expressionMethodsWe treated Sprague-Dawley rats for 4 weeks or 4 months with APZ in daily oral doses of 10 and 40 mg per kg body weight. Expression of the NR subunits NR1, NR2A, NR2B, NR2C and NR2D was assessed by semiquantitative radioactive in situ-hybridization, and in parallel receptor binding using 3H-MK-801 receptor autoradiography.ResultsIncreased expression levels of NR1 (4 weeks), NR2A (4 weeks), NR2C (4 weeks and 4 months) and NR2D (4 months) were observed in several hippocampal and cortical brain regions. The parallel reduced expression of NR2B mRNAs (4 months) resulted in a relative increase of the NR2A/NR2B ratio. Marked differences between specific brain regions, the doses and time points of assessment became obvious. On the receptor level, increased MK-801-binding was found after 4 weeks in the 40 mg-group and after 4 months in the 10 mg-group.ConclusionsThe effects of APZ converge in enhanced NMDA-receptor expression and a shift of subunit-composition towards adult-type receptors. Our results confirm regulatory connections between dopaminergic, serotonergic and glutamatergic neurotransmission with relevance for cognitive and negative symptoms of schizophrenia.

scholarly journals Fear Memory

2016 ◽  
Vol 96 (2) ◽  
pp. 695-750 ◽  
Author(s):  
Ivan Izquierdo ◽  
Cristiane R. G. Furini ◽  
Jociane C. Myskiw
Keyword(s):  
Fear Conditioning ◽  
Basolateral Amygdala ◽  
Inhibitory Avoidance ◽  
Long Term Potentiation ◽  
Fear Memory ◽  
Contextual Fear Conditioning ◽  
Fear Learning ◽  
Term Potentiation ◽  
Mechanisms Of Memory

Fear memory is the best-studied form of memory. It was thoroughly investigated in the past 60 years mostly using two classical conditioning procedures (contextual fear conditioning and fear conditioning to a tone) and one instrumental procedure (one-trial inhibitory avoidance). Fear memory is formed in the hippocampus (contextual conditioning and inhibitory avoidance), in the basolateral amygdala (inhibitory avoidance), and in the lateral amygdala (conditioning to a tone). The circuitry involves, in addition, the pre- and infralimbic ventromedial prefrontal cortex, the central amygdala subnuclei, and the dentate gyrus. Fear learning models, notably inhibitory avoidance, have also been very useful for the analysis of the biochemical mechanisms of memory consolidation as a whole. These studies have capitalized on in vitro observations on long-term potentiation and other kinds of plasticity. The effect of a very large number of drugs on fear learning has been intensively studied, often as a prelude to the investigation of effects on anxiety. The extinction of fear learning involves to an extent a reversal of the flow of information in the mentioned structures and is used in the therapy of posttraumatic stress disorder and fear memories in general.

scholarly journals Proteomic Analysis Reveals Sex-Specific Protein Degradation Targets in the Amygdala During Fear Memory Formation

2021 ◽  
Vol 14 ◽  
Author(s):  
Kayla Farrell ◽  
Madeline Musaus ◽  
Shaghayegh Navabpour ◽  
Kiley Martin ◽  
W. Keith Ray ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Fear Conditioning ◽  
Degradation Process ◽  
Fear Memory ◽  
Memory Formation ◽  
Contextual Fear Conditioning ◽  
Female Rats ◽  
Protein Targets ◽  
Male And Female Rats ◽  
Ubiquitin Proteasome

Ubiquitin-proteasome mediated protein degradation has been widely implicated in fear memory formation in the amygdala. However, to date, the protein targets of the proteasome remain largely unknown, limiting our understanding of the functional significance for protein degradation in fear memory formation. Additionally, whether similar proteins are targeted by the proteasome between sexes has yet to be explored. Here, we combined a degradation-specific K48 Tandem Ubiquitin Binding Entity (TUBE) with liquid chromatography mass spectrometry (LC/MS) to identify the target substrates of the protein degradation process in the amygdala of male and female rats following contextual fear conditioning. We found that males (43) and females (77) differed in the total number of proteins that had significant changes in K48 polyubiquitin targeting in the amygdala following fear conditioning. Many of the identified proteins (106) had significantly reduced levels in the K48-purified samples 1 h after fear conditioning, suggesting active degradation of the substrate due to learning. Interestingly, only 3 proteins overlapped between sexes, suggesting that targets of the protein degradation process may be sex-specific. In females, many proteins with altered abundance in the K48-purified samples were involved in vesicle transport or are associated with microtubules. Conversely, in males, proteins involved in the cytoskeleton, ATP synthesis and cell signaling were found to have significantly altered abundance. Only 1 protein had an opposite directional change in abundance between sexes, LENG1, which was significantly enhanced in males while lower in females. This suggests a more rapid degradation of this protein in females during fear memory formation. Interestingly, GFAP, a critical component of astrocyte structure, was a target of K48 polyubiquitination in both males and females, indicating that protein degradation is likely occurring in astrocytes following fear conditioning. Western blot assays revealed reduced levels of these target substrates following fear conditioning in both sexes, confirming that the K48 polyubiquitin was targeting these proteins for degradation. Collectively, this study provides strong evidence that sex differences exist in the protein targets of the degradation process in the amygdala following fear conditioning and critical information regarding how ubiquitin-proteasome mediated protein degradation may contribute to fear memory formation in the brain.

scholarly journals Histaminergic ligands injected into the nucleus basalis magnocellularis differentially affect fear conditioning consolidation

2013 ◽  
Vol 16 (3) ◽  
pp. 575-582 ◽  
Author(s):  
Fernando Benetti ◽  
Elisabetta Baldi ◽  
Corrado Bucherelli ◽  
Patrizio Blandina ◽  
Maria Beatrice Passani
Keyword(s):  
Fear Conditioning ◽  
Memory Consolidation ◽  
Present Report ◽  
Fear Memory ◽  
Brain Regions ◽  
Contextual Fear Conditioning ◽  
Nucleus Basalis ◽  
Nucleus Basalis Magnocellularis ◽  
Endogenous Histamine ◽  
Male Wistar Rats

Abstract The role of the nucleus basalis magnocellularis (NBM) in fear conditioning encoding is well established. In the present report, we investigate the involvement of the NBM histaminergic system in consolidating fear memories. The NBM was injected bilaterally with ligands of histaminergic receptors immediately after contextual fear conditioning. Histaminergic compounds, either alone or in combination, were stereotaxically administered to different groups of adult male Wistar rats and memory was assessed as conditioned freezing duration 72 h after administration. This protocol prevents interference with NBM function during either acquisition or retrieval phases, hence restricting the effect of pharmacological manipulations to fear memory consolidation. The results presented here demonstrate that post-training H3 receptors (H3R) blockade with the antagonist/inverse agonist thioperamide or activation with immepip in the NBM potentiates or decreases, respectively, freezing response at retrieval. Thioperamide induced memory enhancement seems to depend on H2R, but not H1R activation, as the H2R antagonist zolantidine blocked the effect of thioperamide, whereas the H1R antagonist pyrilamine was ineffective. Furthermore, the H2R agonist ampthamine improved fear memory expression independently of the H3R agonist effect. Our results indicate that activation of post-synaptic H2R within the NBM by endogenous histamine is responsible for the potentiated expression of fear responses. The results are discussed in terms of activation of H3 auto- and heteroreceptors within the NBM and the differential effect of H3R ligands on fear memory consolidation in distinct brain regions.

Sign in / Sign up

Export Citation Format

Share Document