G-protein coupled receptors (GPCRs) exist in an equilibrium of multiple conformational states, including different active states, which depend on the nature of the bound ligand. In consequence, different conformational states can initiate specific signal transduction pathways. The study identified compound 7e, which acts as a potent 5-hydroxytryptamine type 6 receptor (5-HT6R) neutral antagonist at Gs and does not impact neurite growth (process controlled by Cdk5). MD simulations highlighted receptor conformational changes for 7e and inverse agonist PZ-1444. In cell-based assays, neutral antagonists of the 5-HT6R (7e and CPPQ), but not inverse agonists (SB-258585, intepirdine, PZ-1444), displayed glioprotective properties against 6-hydroxydopamine-induced and doxorubicin-induced cytotoxicity. These suggest that targeting the activated conformational state of the 5-HT6R with neutral antagonists implicates the protecting properties of astrocytes. Additionally, 7e prevented scopolamine-induced learning deficits in the novel object recognition test in rats. We propose 7e as a probe for further understanding of the functional outcomes of different states of the 5-HT6R.
- MeSH
- Serotonin Receptor Agonists pharmacology MeSH
- Serotonin Antagonists chemical synthesis pharmacology MeSH
- Astrocytes drug effects MeSH
- Imidazoles chemical synthesis pharmacology MeSH
- Rats MeSH
- Humans MeSH
- Molecular Conformation MeSH
- Neurites drug effects MeSH
- Neuroglia drug effects MeSH
- Neuroprotective Agents chemical synthesis pharmacology MeSH
- Learning Disabilities chemically induced prevention & control MeSH
- Rats, Sprague-Dawley MeSH
- Pyridines chemical synthesis pharmacology MeSH
- Receptors, Serotonin drug effects MeSH
- Receptors, G-Protein-Coupled drug effects MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
The prevention of engram interference, pattern separation, flexibility, cognitive coordination and spatial navigation are usually studied separately at the behavioral level. Impairment in executive functions is often observed in patients suffering from schizophrenia. We have designed a protocol for assessing these functions all together as behavioral separation. This protocol is based on alternated or sequential training in two tasks testing different hippocampal functions (the Morris water maze and active place avoidance), and alternated or sequential training in two similar environments of the active place avoidance task. In Experiment 1, we tested, in adult rats, whether the performance in two different spatial tasks was affected by their order in sequential learning, or by their day-to-day alternation. In Experiment 2, rats learned to solve the active place avoidance task in two environments either alternately or sequentially. We found that rats are able to acquire both tasks and to discriminate both similar contexts without obvious problems regardless of the order or the alternation. We used two groups of rats, controls and a rat model of psychosis induced by a subchronic intraperitoneal application of 0.08mg/kg of dizocilpine (MK-801), a non-competitive antagonist of NMDA receptors. Dizocilpine had no selective effect on parallel/sequential learning of tasks/contexts. However, it caused hyperlocomotion and a significant deficit in learning in the active place avoidance task regardless of the task alternation. Cognitive coordination tested by this task is probably more sensitive to dizocilpine than spatial orientation because no hyperactivity or learning impairment was observed in the Morris water maze.
- MeSH
- Analysis of Variance MeSH
- Excitatory Amino Acid Antagonists toxicity MeSH
- Maze Learning drug effects MeSH
- Dizocilpine Maleate toxicity MeSH
- Rats MeSH
- Locomotion drug effects MeSH
- Disease Models, Animal MeSH
- Learning Disabilities chemically induced physiopathology MeSH
- Rats, Long-Evans MeSH
- Reaction Time drug effects MeSH
- Avoidance Learning drug effects MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
3-Quinuclidinyl benzilate (QNB) represents a non-selective, competitive antagonist of cholinergic receptors, which has been previously used to generate cognitive deficits in animal models of neurodegenerative disorders. The aim of this study was evaluation of QNB potency for creation of cognitive impairment during the acquisition, consolidation and retrieval stages of learning and memory in rats. Male Wistar rats were subjected to a water maze task with hidden platform and a step-through passive avoidance task. The water maze test was carried out in two separate experiments focused on spatial learning (acquisition test) and long-term spatial memory (retrieval test). QNB doses (0.5, 1.0, 2.0 and 5.0 mg kg(-1)) were administered to rats intraperitoneally before training sessions (acquisition test) or before probe trial (retrieval test). A QNB dose of 2.0 mg kg(-1) was administered to rats in the passive avoidance task before training (acquisition test), immediately post-training (consolidation test) or 24h pre-retention (retrieval test). QNB significantly impaired the acquisition in the water maze at doses 0.5-5.0 mg kg(-1) as well as the acquisition of passive avoidance task. In contrast, consolidation and retrieval were not affected by QNB, indicating that QNB specifically affects the stage of acquisition.
- MeSH
- Analysis of Variance MeSH
- Muscarinic Antagonists chemistry toxicity MeSH
- Maze Learning drug effects MeSH
- Time Factors MeSH
- Quinuclidinyl Benzilate chemistry toxicity MeSH
- Rats MeSH
- Disease Models, Animal MeSH
- Statistics, Nonparametric MeSH
- Motor Activity drug effects MeSH
- Learning Disabilities chemically induced MeSH
- Rats, Wistar MeSH
- Mental Recall drug effects MeSH
- Avoidance Learning drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
The military incapacitating agent BZ (3-quinuclidinyl benzilate) is an anticholinergic compound that acts at both, the peripheral and central nervous system. Effects of the agent were discovered during the Cold War and BZ became one of the most potent anticholinergic psychomimetics, characterized by low effective doses causing long-term incapacitation. History, characteristics and potential use of BZ in behavioral research are discussed throughout this review.
- MeSH
- Muscarinic Antagonists toxicity MeSH
- Chemical Warfare Agents toxicity MeSH
- Quinuclidinyl Benzilate pharmacology toxicity MeSH
- Behavior, Animal drug effects MeSH
- Rats MeSH
- Memory Disorders chemically induced MeSH
- Learning Disabilities chemically induced MeSH
- Rats, Wistar MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
Spatial learning is a widely studied type of animal behavior often considered as a model of higher human cognitive functions. Noradrenergic receptors play a modulatory role in many nerve functions, including vigilance, attention, reward, learning and memory. The present study aimed at studying the effects of separate or combined systemic administration of the alpha1-adrenergic antagonist prazosin (1 and 2 mg/kg) and beta-blocker propranolol (5 and 20 mg/kg) on the hippocampus-dependent learning in the active allothetic place avoidance (AAPA) task. Both centrally active drugs impaired spatial learning when administered together, exerting no effect in separate applications. Locomotion was impaired only in a combined application of higher doses of both drugs (2 mg/kg prazosin and 20 mg/kg propranolol). These results suggest an in vivo interaction between these two types of receptors in spatial navigation regulation.
- MeSH
- Adrenergic alpha-Antagonists administration & dosage pharmacology MeSH
- Analysis of Variance MeSH
- Adrenergic beta-Antagonists administration & dosage pharmacology MeSH
- Behavior, Animal drug effects MeSH
- Drug Combinations MeSH
- Rats MeSH
- Motor Activity drug effects MeSH
- Learning Disabilities chemically induced MeSH
- Rats, Long-Evans MeSH
- Prazosin administration & dosage pharmacology MeSH
- Propranolol administration & dosage pharmacology MeSH
- Avoidance Learning drug effects MeSH
- Space Perception drug effects MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Psychostimulancia, včetně metamfetaminu (MA), ovlivňují chování jedinců. U lidí navozují pozitivní emoce radost a štěstí, nebo potlačují negativní stavy typu anxiety či deprese. Test vyvýšeného křížového bludiště (elevated plus-maze, EPM) je nejčastěji používán k testování anxiolytických nebo anxiogenních látek, případně testování jednotlivých podtypů anxiogenních poruch. Úkolem této práce bylo otestovat vliv akutně podaného MA (1 mg/kg) na chování potkanů v EPM v protokolu s podrobnou analýzou všech vzorců chování podle studie Espejo (1998). Druhým cílem bylo zohlednit i vliv MA na učení a paméi! ve dvou fázích: akutně v „testu" a za 48 hodin a bez aplikace v „retestu". Naše výsledky ukazují, že MA ovlivňuje chování potkanů v EPM ve všech námi sledovaných kategoriích a neovlivnil učení. Prokázali jsme anxiogenní působení MA, zatímco učení nebylo M A výrazně ovlivněno.
Psychostimulants, including methamphetamine (MA), are known to influence behavior of individuals. In humans, psychostimulants i nduce positive emotions such as joy and happiness, or suppress unpleasant conditions such as anxiety and depression. Test of elevated plus-maze (EPM) is widely used test of anxiolytic and anxiogenic drugs, eventually examination of specific subtypes of anxiety disorders. The a im of the present work was to examine the effect of acutely applied MA (1 mg/kg) on rat behavior in the EPM. The detailed analysis of all behavio ral patterns was performed following the protocol based on the study of Espejo (1998). The original protocol was modified allowing to study the effect of MA on learning and memory. Our results demonstrated that MA affects rat behavior in the EPM in the most analyzed categories, al though it does not affect learning abilities. Therefor, the present protocol allowed us to determine positive anxiogenic effect of MA and exclude learning impairment.
- Keywords
- anxieta, vyvýšené křížové bludiště, metamfetamin,
- MeSH
- Maze Learning drug effects MeSH
- Behavior MeSH
- Financing, Organized MeSH
- Methamphetamine administration & dosage adverse effects MeSH
- Models, Animal MeSH
- Orientation drug effects MeSH
- Amphetamine-Related Disorders physiopathology MeSH
- Learning Disabilities chemically induced physiopathology MeSH
- Rats, Wistar MeSH
- Anxiety chemically induced MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Animals MeSH
The active place avoidance task is a cognitive task requiring spatial learning and cognitive coordination. In this task, animals are trained to move over a continuously rotating arena, on which an imperceptible to-be-avoided sector is defined, remaining stable with respect to the experimental room. The present study was aimed at evaluating the effect of GABA-B receptor agonist baclofen on locomotion and spatial behavior in active place avoidance task. Baclofen (at doses 2, 3, 3.5, 4 and 6 mg/kg) was applied 30 min prior to testing in the task. Doses 2 mg/kg and 3 mg/kg were found not to interfere with either locomotion or spatial avoidance; a dose 3.5 mg/kg disrupted selectively spatial behavior, and doses 4 mg/kg and 6 mg/kg proved to decrease both avoidance efficiency and locomotor activity. It is concluded that GABA-B receptor agonist baclofen dose-dependently disrupts spatial learning and locomotion in the place avoidance task.
- MeSH
- Analysis of Variance MeSH
- Baclofen pharmacology MeSH
- Behavior, Animal drug effects MeSH
- GABA Agonists pharmacology MeSH
- Rats MeSH
- Locomotion drug effects MeSH
- Learning Disabilities chemically induced MeSH
- Rats, Long-Evans MeSH
- Spatial Behavior MeSH
- Reaction Time drug effects MeSH
- Avoidance Learning drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
beta-Amyloid (Abeta) polypeptide plays a critical role in the pathogenesis of Alzheimer's disease (AD), which is characterized by progressive decline of cognitive functions, formation of Abeta deposits and neurofibrillary tangles, and loss of neurons. Increased genetic production or direct intracerebral administration of Abeta in animal models results in Abeta deposition, gliosis, and impaired cognitive functions. Whether aging renders the brain prone to Abeta and whether inflammation is required for Abeta-induced learning deficits is unclear. We show that intraventricular infusion of Abeta1-42 results in learning deficits in 9-month-old but not 2.5-month-old mice. Deficits that become detectable 12 weeks after the infusion are associated with a slight reduction in Cu,Zn superoxide dismutase activity but do not correlate with Abeta deposition and are not associated with gliosis. In rats, Abeta infusion induced learning deficits that were detectable 6 months after the infusion. Approximately 20% of the Abeta immunoreactivity in rats was associated with astrocytes. NMR spectrum analysis of the animals cerebrospinal fluid revealed a strong reduction trend in several metabolites in Abeta-infused rats, including lactate and myo-inositol, supporting the idea of dysfunctional astrocytes. Even a subtle increase in brain Abeta1-42 concentration may disrupt normal metabolism of astrocytes, resulting in altered neuronal functions and age-related development of learning deficits independent of Abeta deposition and inflammation.
- MeSH
- Amyloid beta-Peptides administration & dosage pharmacology MeSH
- Maze Learning drug effects MeSH
- Infusions, Intravenous MeSH
- Rats MeSH
- Magnetic Resonance Spectroscopy MeSH
- Brain cytology enzymology pathology MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Peptide Fragments administration & dosage pharmacology MeSH
- Learning Disabilities chemically induced metabolism MeSH
- Rats, Inbred SHR MeSH
- Aging physiology MeSH
- Inflammation metabolism MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- MeSH
- Maze Learning physiology drug effects MeSH
- Financing, Organized MeSH
- Rats MeSH
- Methamphetamine adverse effects MeSH
- Disease Models, Animal MeSH
- Brain physiopathology growth & development drug effects MeSH
- Orientation physiology drug effects MeSH
- Memory physiology drug effects MeSH
- Sex Characteristics MeSH
- Memory Disorders chemically induced physiopathology MeSH
- Amphetamine-Related Disorders physiopathology MeSH
- Learning Disabilities chemically induced physiopathology MeSH
- Rats, Wistar MeSH
- Sex Factors MeSH
- Central Nervous System Stimulants adverse effects MeSH
- Pregnancy MeSH
- Prenatal Exposure Delayed Effects MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Pregnancy MeSH
- Female MeSH
- Animals MeSH
