Ales Stuchlik

Dynamic learning and memory, synaptic plasticity and neurogenesis: an update.

Mammalian memory is the result of the interaction of millions of neurons in the brain and their coordinated activity. Candidate mechanisms for memory are synaptic plasticity changes, such as long-term potentiation (LTP). LTP is essentially an electrophysiological phenomenon manifested in hours-lasting increase on postsynaptic potentials after synapse tetanization. It is thought to ensure long-term changes in synaptic efficacy in distributed networks, leading to persistent changes in the behavioral patterns, actions and choices, which are often interpreted as the retention of information, i.e., memory. Interestingly, new neurons are born in the mammalian brain and adult hippocampal neurogenesis is proposed to provide a substrate for dynamic and flexible aspects of behavior such as pattern separation, prevention of interference, flexibility of behavior and memory resolution. This work provides a brief review on the memory and involvement of LTP and adult neurogenesis in memory phenomena.

Application of a novel Active Allothetic Place Avoidance task (AAPA) in testing a pharmacological model of psychosis in rats: comparison with the Morris Water Maze

Administration of a non-competitive NMDA antagonist dizocilpine (MK-801) was proposed to be an animal model of psychosis. NMDA-receptor blockade is accompanied by increased locomotion, behavioral deficits, and other changes resembling psychotic symptoms. However, the role of NMDA-receptors in organizing brain representations is not understood yet. We tested the effect of NMDA-receptor blockade by systemic administration of dizocilpine at two different doses (0.1 or 0.2 mg/kg) in a recently designed Active Allothetic Place Avoidance (AAPA), a task which requires rats to separate spatial stimuli from two continuously dissociated subsets. The effect of dizocilpine on learning in the AAPA task was compared with its effect on acquisition of the reference memory version of the Morris Water Maze task. Both doses impaired performance in the Morris Water Maze task, whereas only the higher dose impaired performance in the AAPA task. The Morris Water Maze appears to be more sensitive to dizocilpine-induced behavioral deficit than the AAPA task. These findings support the notion that these two tasks are differentially dependent on the NMDA-receptor function.

The difference in effect of mGlu2/3 and mGlu5 receptor agonists on cognitive impairment induced by MK-801.

The manipulation of glutamate neurotransmission could represent a potential strategy for the pharmacotherapy of schizophrenic symptoms. Preclinical studies suggest that two subtypes of metabotropic glutamate (mGlu) receptors such as mGlu2/3 and mGlu5 receptors have the potential to ameliorate deficits in schizophrenia. In our study we evaluated the role of a non-specific mGlu receptor agonist ((1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid; 1S,3R-ACPD), mGlu5 receptor agonist or positive modulators ((RS)-2-Chloro-5-hydroxyphenylglycine;CHPG; [(3-Fluoro-phenyl)methylene]hydrazone-3-fluorobenzaldehyde; DFB; 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide; CDPPB) and a mGlu2/3 receptor agonist (2,2,2-Trifluoro-N-[4-(2-methoxyphenoxy)phenyl]-N-(3-pyrdinylmethyl)ethanesulfonamide hydrochloride; LY-487379) on performance in a cognitive task (Active Allothetic Place Avoidance) after sub-chronic administration of 5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cyclo-hepten-5,10-imine; MK-801 . The Active Allothetic Place Avoidance task is suitable for assessing the executive function and attention of animals and was previously validated for testing the effect of anti-psychotics. Application of the mGlu2/3 receptor agonist had no effect on cognitive impairment induced by MK-801. However, the mGlu5 receptor agonists ameliorated cognitive impairment induced by MK-801 without affecting locomotion. In conclusion, the mGlu5 receptor agonists could be effective in the treatment of cognitive deficits in patients with schizophrenia. However, the pro-cognitive effect of the agonist of mGlu2/3 receptors was not demonstrated in the present study.

Risperidone and ritanserin but not haloperidol block effect of dizocilpine on the active allothetic place avoidance task

Spatial working memory or short-term place memory is impaired in schizophrenia. The efficiency of antipsychotic drugs, particularly of typical antipsychotics, on cognitive deficit in schizophrenia remains disputable. Inhibition of serotonin (5-HT) 2A/2C receptors is important for cognitive improvement in schizophrenic patients treated with antipsychotics. The aim of the present work was to establish the effect of the 5-HT2A/2C receptor antagonist ritanserin (2.5 or 5 mg/kg), the dopamine D2 antagonist haloperidol (0.1 or 1 mg/kg), and the atypical antipsychotic risperidone (0.1 mg/kg or 1 mg/kg), which is an antagonist of both 5-HT2A/2C and D2 receptors, on cognitive deficit induced by subchronic administration of dizocilpine (MK-801, 0.1 mg/kg). We used the active allothetic place avoidance (AAPA) task, requiring the rat to differentiate between relevant and irrelevant stimuli, in a way similar to disruption of information processing disturbed in schizophrenic patients. Our results show that treatment with 5-HT2A/2C receptor antagonists, regardless of their effect on D2 receptors, blocked the cognitive impairment produced by MK-801. Haloperidol did not sufficiently reduce the deficit in AAPA induced by MK-801. Interestingly, administration of risperidone and haloperidol alone, but not ritanserin, impaired the AAPA performance in intact rats. Ritanserin and risperidone actually improve cognition independently of their effect on locomotor activity in an animal model of schizophrenia-like behavior. This finding is in accordance with the assumption that some antipsychotics are primarily effective against cognitive dysfunction in schizophrenia.

MORRIS WATER MAZE LEARNING IN LONG-EVANS RATS IS DIFFERENTIALLY AFFECTED BY BLOCKADE OF D1-LIKE AND D2-LIKE DOPAMINE RECEPTORS

Dopaminergic neurotransmission is involved in several brain functions including spatial cognition. In the present study we examine the effects of systemic administration of D1-like receptor antagonist SCH23390 and D2-like receptor antagonist sulpiride on the acquisition of the Morris water maze task. We used visible versus hidden platform versions of the MWM in order to distinguish between the effects of the drugs on the procedural versus cognitive aspects of the task. SCH23390 was found to prolong escape latencies to the visible platform at a higher dose (0.05mg/kg), whilst the lower dose (0.02mg/kg) left both procedural and cognitive functions almost unchanged. SCH23390 was also found to reduce swimming speed. Sulpiride did not affect the visible platform learning at any of three doses studied (30, 60 and 100mg/kg); the highest dose of sulpiride (100mg/kg) impaired place navigation to the hidden platform, without affecting the swim speed. The results of the present study show a difference in the involvement of D1-like and D2-like receptors in the MWM acquisition.

Neurosteroid modulation of N-methyl-D-aspartate receptors: Molecular mechanism and behavioral effects

Glutamate is the main neurotransmitter released at synapses in the central nervous system of vertebrates. Its excitatory role is mediated through activation of specific glutamatergic ionotropic receptors, among which the N-methyl-D-aspartate (NMDA) receptor subtype has attracted considerable attention in recent years. Substantial progress has been made in elucidating the roles these receptors play under physiological and pathological conditions and in our understanding of the functional, structural, and pharmacological properties of NMDA receptors. Many pharmacological compounds have been identified that affect the activity of NMDA receptors, including neurosteroids. This review summarizes our knowledge about molecular mechanisms underlying the neurosteroid action at NMDA receptors as well as about the action of neurosteroids in animal models of human diseases.

Manipulation of D2 receptors with quinpirole and sulpiride affects locomotor activity before spatial behavior of rats in an active place avoidance task

Dopamine-mediated neurotransmission is widely studied with respect to motivation, motor activity and cognitive processes. The aim of the present study was to evaluate the role of D2 receptors in the behavior of rats in the active allothetic place avoidance (AAPA) task. D2 receptor agonist quinpirole and antagonist sulpiride were administered intraperitoneally 20min prior to behavioral testing. Administration of quinpirole led to dose-dependent increase of locomotion; the spatial efficiency was spared across the dose range studied (0.05-1.0mg/kg). In contrast, sulpiride decreased locomotor activity at a dose not influencing spatial efficiency (60mg/kg); the highest dose of sulpiride (100mg/kg) caused a deficit in both locomotor and spatial behaviors. The results suggest a relatively lesser importance of D2 receptors for spatial efficiency in the AAPA task, with a predominant influence of D2 receptor ligands on motor activity.

Two learning tasks provide evidence for disrupted behavioural flexibility in an animal model of schizophrenia-like behaviour induced by acute MK-801: a dose-response study.

Schizophrenia is a chronic and devastating illness. Exact causes of the disease remain elusive; however, neurodevelopmental changes in the brain glutamate system are recognized to play an important role. Several animal models of the disease are induced by a systemic blockade of N-methyl-d-aspartate (NMDA) receptors. This study examined the animal model of schizophrenia-like behaviours induced by acute treatment with MK-801, a non-competitive NMDA-receptor antagonist. Behavioural flexibility is an ability to adapt to the changes in environment, and schizophrenia is often accompanied by its decrease. The study tested the effect of MK-801 on behavioural flexibility in an active place avoidance task and the Morris water maze (MWM). Flexibility was tested under reversal conditions, i.e., after changing the location of the target. Each spatial task addressed different functions; continuous coordinate-frame segregation was present in the active place avoidance and precise place representation in the MWM. Results showed that reversal was altered in both tasks by MK-801 at doses of 0.10-0.15 mgkg(-1). Some impairment was observed in the active place avoidance task at 0.08 mgkg(-1). Swimming towards a visible platform was impaired only by the highest dose (0.15 mgkg(-1)). The results demonstrate that a significant impairment of behavioural flexibility accompanies this acute animal model of schizophrenia-like behaviours, and that active place avoidance had higher sensitivity for such deficits than the MWM. This suggests the usefulness of the reversal paradigm in both tasks for examining novel drugs with antipsychotic and procognitive actions.

Central muscarinic blockade interferes with retrieval and reacquisition of active allothetic place avoidance despite spatial pretraining

Animal navigation to hidden goals (place navigation) ranks among the most intensively studied types of behaviour because it requires brain representations of environments in the form of cognitive maps, demonstrated to depend on hippocampal function. Intact function of muscarinic receptors in the brain was originally assumed to be crucial for place navigation, however, recent studies using non-spatial pretraining demonstrated that animals with central blockade of muscarinic acetylcholine receptors can also learn and retrieve spatial memory engrams. In the present study we addressed whether navigation in the active allothetic place avoidance (AAPA) task, which requires animals to separate spatial stimuli into coherent representations and navigate according to the representation relevant for the task, is dependent on intact muscarinic receptors in the brain. We studied the effect of three doses of scopolamine (0.5, 1.0 and 2.0mg/kg) administered 20 min prior to training on the retention of the AAPA and re-acquisition of the AAPA in a new environment. The dose of 2.0mg/kg was found to impair both AAPA retention and re-acquisition of the AAPA in a new environment, whereas the 1.0mg/kg dose only impaired the reinforced retention of AAPA. It is concluded that, unlike navigation in classic paradigms, efficient orientation in the AAPA task is critically dependent on muscarinic receptors in the brain.

Common mechanisms of pain and depression: are antidepressants also analgesics?

Neither pain, nor depression exist as independent phenomena per se, they are highly subjective inner states, formed by our brain and built on the bases of our experiences, cognition and emotions. Chronic pain is associated with changes in brain physiology and anatomy. It has been suggested that the neuronal activity underlying subjective perception of chronic pain may be divergent from the activity associated with acute pain. We will discuss the possible common pathophysiological mechanism of chronic pain and depression with respect to the default mode network of the brain, neuroplasticity and the effect of antidepressants on these two pathological conditions. The default mode network of the brain has an important role in the representation of introspective mental activities and therefore can be considered as a nodal point, common for both chronic pain and depression. Neuroplasticity which involves molecular, cellular and synaptic processes modifying connectivity between neurons and neuronal circuits can also be affected by pathological states such as chronic pain or depression. We suppose that pathogenesis of depression and chronic pain shares common negative neuroplastic changes in the central nervous system (CNS). The positive impact of antidepressants would result in a reduction of these pathological cellular/molecular processes and in the amelioration of symptoms, but it may also increase survival times and quality of life of patients with chronic cancer pain.