Abstract
MK-801, an NMDA receptor antagonist, and scopolamine, a cholinergic receptor blocker, are widely used as tool compounds to induce learning and memory deficits in animal models to study schizophrenia or Alzheimer-type dementia (AD), respectively. Memory impairments are observed after either acute or chronic administration of either compound. The present experiments were performed to study the nitric oxide (NO)-related mechanisms underlying memory dysfunction induced by acute or chronic (14 days) administration of MK-801 (0.3 mg/kg, i.p.) or scopolamine (1 mg/kg, i.p.). The levels of L-arginine and its derivatives, L-citrulline, L-glutamate, L-glutamine and L-ornithine, were measured. The expression of constitutive nitric oxide synthases (cNOS), dimethylaminohydrolase (DDAH1) and protein arginine N-methyltransferases (PMRTs) 1 and 5 was evaluated, and the impact of the studied tool compounds on cGMP production and NMDA receptors was measured. The studies were performed in both the cortex and hippocampus of mice. S-nitrosylation of selected proteins, such as GLT-1, APP and tau, was also investigated. Our results indicate that the availability of L-arginine decreased after chronic administration of MK-801 or scopolamine, as both the amino acid itself as well as its level in proportion to its derivatives (SDMA and NMMA) were decreased. Additionally, among all three methylamines, SDMA was the most abundant in the brain (~70%). Administration of either compound impaired eNOS-derived NO production, increasing the monomer levels, and had no significant impact on nNOS. Both compounds elevated DDAH1 expression, and slight decreases in PMRT1 and PMRT5 in the cortex after scopolamine (acute) and MK-801 (chronic) administration were observed in the PFC, respectively. Administration of MK-801 induced a decrease in the cGMP level in the hippocampus, accompanied by decreased NMDA expression, while increased cGMP production and decreased NMDA receptor expression were observed after scopolamine administration. Chronic MK-801 and scopolamine administration affected S-nitrosylation of GLT-1 transport protein. Our results indicate that the analyzed tool compounds used in pharmacological models of schizophrenia or AD induce changes in NO-related pathways in the brain structures involved in cognition. To some extent, the changes resemble those observed in human samples.
Highlights
Learning and memory processes are crucial for the interaction of individuals with their environments and involve the coordination of large, widely distributed brain networks.Memory is often understood as an information processing system with explicit and implicit functioning that comprises a sensory processor, short-term memory (STM) and long-term memory (LTM) [1]
MK-801 at the dose of 0.3 mg/kg induced cognitive deficits in CD1 mice both after acute and prolonged administration [17–21], and scopolamine was used at the dose of 1 mg/kg [22]
Concomitant experiments aimed to assess the main factors mediating nitric oxide (NO)-induced effects, i.e., the cyclic guanosine monophosphate (cGMP) level accompanied by NMDA receptor expression, and the results reveal that cGMP production was abolished in the hippocampus with increased NMDA receptor expression, indicating the attenuation of cGMP synthesis in the MK-801-based model, followed by the diminution of long-term potentiation (LTP)
Summary
Learning and memory processes are crucial for the interaction of individuals with their environments and involve the coordination of large, widely distributed brain networks.Memory is often understood as an information processing system with explicit and implicit functioning that comprises a sensory processor, short-term memory (STM) and long-term memory (LTM) [1]. Learning and memory processes are crucial for the interaction of individuals with their environments and involve the coordination of large, widely distributed brain networks. Long-term memory, once consolidated, can store much larger quantities of information and is persistent and stable for a potentially unlimited duration [1]. In contrast to STM, LTM is maintained by stable and permanent changes in neural connections that are widely distributed throughout the brain. Consolidation of STM into LTM at the molecular level presumably involves synaptic consolidation and system consolidation The former involves alterations in synaptic protein synthesis, activation of the intracellular transduction cascade and changes in membrane potential [7]. Synaptic plasticity and synaptic strength, which underlie memory formation, are regulated by long-term potentiation (LTP), which is considered to be an important mechanism in learning and memory processes [7]. The hippocampus is essential to the consolidation of information from STM to LTM [8]
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