ABSTRACT
Glutamatergic processes are strongly implicated in the pathophysiology and treatment of depression, including the antidepressant effects of N-methyl-D-aspartate (NMDA) receptor antagonists. This study was designed to see whether memantine, a noncompetitive NMDA antagonist, has antidepressant effects in behaviors and synaptic plasticity. Rats were randomly divided into control, stressed, and stressed+memantine groups. The animal model was established by chronic unpredictable stress. Memantine (20 mg/kg) was administrated i.p. for 21 days. Weight, sucrose consumption, water maze behavior and prefrontal cortical long-term potentiation (LTP) were measured, followed by immunohisotchemistry test of NR2B expression. Results showed that rats' weight and sucrose consumption were significantly lower in stressed group than those in control group, while the last time of sucrose consumption was improved by memantine. Rats in stressed group performed worse in reversal learning related stages, while rats in stressed+memantine group performed worse in spatial memory related stages. LTP test showed lower amplitude of field excitatory postsynaptic potential in prefrontal cortex in stressed group. Immunohistochemistry showed lower expression of NR2B receptor in prefrontal cortex in stressed group, and higher expression in hippocampus in stressed+memantine group. In conclusion, memantine in dose of 20 mg/kg improves the sucrose consumption, reversal learning and prefrontal cortical synaptic plasticity, but impairs spatial memory, which is probably due to different extent of up-regulating NR2B receptor expression in prefrontal cortex and hippocampus in stressed rats.
Subject(s)
Antidepressive Agents/pharmacology , Behavior, Animal/drug effects , Depressive Disorder/drug therapy , Memantine/pharmacology , Neuronal Plasticity/drug effects , Animals , Behavior, Animal/physiology , Depressive Disorder/psychology , Disease Models, Animal , Excitatory Amino Acid Antagonists/pharmacology , Male , Neuronal Plasticity/physiology , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Prefrontal Cortex/physiopathology , Rats , Rats, Wistar , Stress, Psychological/complicationsABSTRACT
Post weaning isolation-reared rats show deficits in learning and memory, which are also seen in many psychiatric disorders like schizophrenia. The present study utilized behavioral and electrophysiological tests to further characterize cognitive disorders in this rat model, and to explore possible neurobiological mechanisms associated with them. Isolation rearing was performed in male Wistar rats from weaning for 8 weeks. Spatial memory and reversal learning were assessed using Morris water maze (MWM); synaptic plasticity was assessed by recording long-term potentiation (LTP) from thalamus to prefrontal cortex; and potassium ion channel currents were tested using the cerebrospinal fluid (CSF) of different groups in hippocampal slices by patch clamp. The results of MWM showed that isolation-reared rats performed worse in probe trials and memory retention tests. The LTP tests showed that the prefrontal cortical postsynaptic potential slopes were significantly lower in isolated rats than group housed ones. The patch clamp recording showed that the amplitudes of hippocampal voltage-dependent transient outward K(+) currents (I(A)) were enhanced, and the steady inactivation curve of I(A) was shifted towards positive potential by CSF of isolated rats. These data suggested that isolation rearing can impair the spatial cognition of rats, with the possible mechanisms of affecting prefrontal cortical synaptic plasticity and hippocampal potassium ion channel currents.
