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The potential protective effect of citicoline on aluminum chloride-induced cognitive deficits was investigated in rats. In a Morris water maze, administration of aluminum chloride to rats for 90 days resulted in increased escape latency to reach the platform and decreased swimming speed in acquisition trials. Similarly, in probe trials, the time required to reach the hidden platform was increased and the time spent in the target quadrant was reduced. Also, administration of aluminum chloride to rats for 90 days increased the reference and working memory errors and time required to end the task in the radial arm maze. In addition, this treatment decreased the step-through latency in the passive avoidance test. Concurrently, treatment of rats with aluminum chloride for 90 days increased hippocampal glutamate, malondialdehyde, and nitrite levels and decreased intracellular reduced glutathione level. In the citicoline-treated group, aluminum chloride-induced learning and memory impairments as assessed by the Morris water maze, radial arm maze, and passive avoidance tests were inhibited. At the same time, treatment of rats with citicoline prevented the biochemical alterations induced by aluminum chloride in the hippocampus. It can be concluded that elevation of hippocampal glutamate level with consequent oxidative stress and nitric oxide (NO) overproduction may play an important role in aluminum-induced cognitive impairments. Also, our results suggest, for the first time, that citicoline can protect against the development of these cognitive deficits through inhibition of aluminum-induced elevation of glutamate level, oxidative stress, and NO overproduction in the hippocampus.

Bupropion efficacy in attenuation of morphine tolerance and dependence with its high safety and tolerability profile provide an alternative option to conventional agents e.g., ketamine and clonidine to modulate these phenomena.

Fluoxetine, a commonly prescribed antidepressant, use in nociceptive pain management represents one of the unsettled issues of fluoxetine therapeutics. By reviewing the literature about fluoxetine's possible roles in this setting, those could be solitary antinociceptive effect, enhancement of acute morphine analgesia, blocking morphine tolerance development, and blocking dependence development and associated abstinence syndrome. In this study, we examined those four alleged roles of fluoxetine. Moreover, as effective alleviation of morphine tolerance, dependence, and abstinence syndrome represents one of the most challenging medical needs, we biochemically analyzed fluoxetine effect on these phenomena. Fluoxetine (10 mg/kg, IP) was examined in hot plate test for assessment of possible analgesic activity and enhancement of morphine acute analgesia (1 and 5 mg/kg, SC). Repeated morphine (5 mg/kg, SC) administration for 9 days developed tolerance and dependence; fluoxetine was co-administered to evaluate its potential to modulate these processes. We also determined concomitant changes in neurotransmitters (glutamate and noradrenaline), inflammatory status, and prooxidant-antioxidant balance. Our results indicated that fluoxetine did not possess significant analgesia solely and did not enhance acute morphine analgesia. However, fluoxetine administration with morphine significantly attenuated tolerance and dependence development and abstinence syndrome with corresponding suppression of morphine-induced changes in neurotransmitters (glutamate and noradrenaline), inflammatory status, and prooxidant-antioxidant balance. These biochemical results may reflect both direct and indirect effects of fluoxetine. Our conclusion is that despite fluoxetine possesses low - if any - analgesic activity, it significantly adds to opioids not via enhancing analgesic activity but through modulation of tolerance and dependence development.