naloxone and Cognitive-Dysfunction

Repeated opioids abuse may produce long-lasting and complicated cognitive deficits in individuals. Naloxone is a typical mu-opioid receptor antagonist widely used in clinical treatment for opioid overdose and opioid abuse. However, it remains unclear whether naloxone affects morphine-induced cognitive deficits. Using the 5-choice serial reaction time task (5-CSRTT), the present study investigated cognitive profiles including attention, impulsivity, compulsivity, and processing speed in repeated morphine-treated mice. Repeated morphine administration (10 mg/kg, i.p.) induced complex cognitive changes including decreased attention and increased impulsivity, compulsivity, processing speed. Systemic naloxone administration (5 mg/kg, i.p.) reversed these cognitive changes under the heavy perceptual load in 5-CSRTT. Using the novel object recognition (NOR), Y-maze and open-field test (OFT), the present study investigated the memory ability and locomotor activity. Naloxone reversed the effect of morphine on recognition memory and locomotion but had no effect on working memory. In addition, repeated morphine administration decreased the expression of postsynaptic density protein 95 (PSD95) and cAMP response element binding protein (CREB) phosphorylation in the prefrontal cortex (PFC) and hippocampus (HIP), and these effects were significantly reversed by naloxone in PFC. Our study suggests that repeated exposure to morphine affects multiple cognitive aspects and impairs synaptic functions. Systemic naloxone treatment reverses the mu-opioids-induced cognitive changes, especially under the heavy perceptual load, possibly by restoring the synaptic dysfunctions.

Topics: Analgesics, Opioid; Animals; Cognition; Cognitive Dysfunction; Cyclic AMP Response Element-Binding Protein; Disks Large Homolog 4 Protein; Hippocampus; Learning; Male; Maze Learning; Mice; Mice, Inbred C57BL; Morphine; Naloxone; Narcotic Antagonists; Prefrontal Cortex; Reaction Time; Receptors, Opioid, mu; Recognition, Psychology; Signal Transduction

Treatment of depression, a common comorbidity in patients with epilepsy, is restricted as certain antidepressants are considered to be proconvulsants. In contrast, anticonvulsant effects have been reported with some antidepressants. In the present study, the effect of tianeptine, an antidepressant, was evaluated against pentylenetetrazole (PTZ)-induced seizures, cognitive impairment and oxidative stress in rats. Tianeptine was administered in three doses (20, 40 and 80 mg/kg) 30 min before PTZ (60 mg/kg, intraperitoneally). MK801, an N-methyl-D-aspartate antagonist, and naloxone, an opioid receptor antagonist, were administered with tianeptine to evaluate the involvement of N-methyl-D-aspartate and opioid receptors, respectively. Morris water maze, elevated plus maze and passive avoidance tests were performed for behavioural assessment. Brain malondialdehyde and reduced glutathione levels were estimated as markers of oxidative stress. Tianeptine showed dose-dependent protection against PTZ seizures. Coadministration of tianeptine with MK801 potentiated the anticonvulsant effect of tianeptine. The protective effect of tianeptine against PTZ seizures was mitigated when tianeptine was administered with naloxone. Impairment of learning and memory by PTZ was prevented by tianeptine. Tianeptine also attenuated the seizure-induced increased oxidative stress. Thus, tianeptine showed an anticonvulsant effect along with amelioration of seizure-induced cognitive impairment and oxidative stress. Hence, tianeptine could be a useful drug in epileptic patients with depression, with the advantage of having both antidepressant and antiepileptic effects.

Topics: Animals; Anticonvulsants; Antidepressive Agents, Tricyclic; Avoidance Learning; Behavior, Animal; Cognitive Dysfunction; Dizocilpine Maleate; Dose-Response Relationship, Drug; Glutathione; Male; Malondialdehyde; Maze Learning; Naloxone; Oxidative Stress; Pentylenetetrazole; Rats; Rats, Wistar; Seizures; Thiazepines