الفهرس | Only 14 pages are availabe for public view |
Abstract Anxiety disorders are the most common psychiatric illnesses encountered in clinical medicine. Most of the current treatments for anxiety disorders target limited number of neurotransmitter systems in the CNS, including the amino acid transmitters (GABA and glutamate) and the monoamine transmitters (Norepinephrine, serotonin and to a lesser extent dopamine). The intolerability to the adverse effects of the current pharmacological treatments for anxiety disorders drives the search for novel anxiolytic agents with lower incidence of adverse effects that could target other neurotransmitter systems in the CNS. Recently, it has been demonstrated that acetaminophen, the most widely prescribed analgesic and antipyretic agent, undergoes a two-step metabolic transformation to form N-arachidonoyl phenolamine (AM404). Acetaminophen is first de-acetylated to p-aminophenol, which is then conjugated with arachidonic acid in the CNS by the action of fatty acid amide hydrolase (FAAH) to form AM404. This metabolite, which acts as an anandamide uptake inhibitor, interferes with several important molecular targets and provides an interesting link between acetaminophen and the endocannabinoid system. In view of the fact that acetaminophen favours the accumulation of anandamide via AM404; and that anandamide can produce anxiolytic-like effects, the aim of this study was to investigate the effect of acetaminophen on anxiety-related behaviour in mice using two animal models of anxiety; the elevated plus-maze (EPM) and the Vogel conflict test. The involvement of AM404, the active metabolite of acetaminophen, in this effect was investigated using the CB 1 blocker, rimonabant, and the fatty acid amide hydrolase inhibitor, URB597. Furthermore, the effect of acetaminophen on serum corticosterone level of mice tested in both models was also investigated. 105 Summary and Conclusion The main findings of the present study were as the following: Systemic administration of acetaminophen induced a dose-dependent anxiolytic- like effect in mice tested in the EPM. The observed effect was prominent on both spatiotemporal and ethological indices of anxiety in that model. Pretreatment with the CB 1 blocker; rimonabant, antagonized the anxiolytic-like effect of acetaminophen in mice tested in the EPM. Similarly, pretreatment with the FAAH inhibitor; URB597, attenuated the anxiolytic-like effect of acetaminophen in mice tested in the EPM. The selected doses of acetaminophen in this study did not induce a significant change in locomotor activity of mice tested in the open field test. In the Vogel conflict test, systemic administration of acetaminophen induced a dose-dependent anxiolytic-like effect in mice. Pretreatment with the CB 1 blocker; rimonabant, antagonized the anxiolytic-like effect of acetaminophen in mice tested in the Vogel conflict test. Similarly, pretreatment with the FAAH inhibitor; URB597, attenuated the anxiolytic-like effect of acetaminophen in mice tested in the Vogel conflict test. The selected doses of acetaminophen in this study did not induce a significant change in the number of unpunished licks taken by mice tested in the water consumption test. Furthermore, the selected doses of acetaminophen in this study did not induce a significant change in the latencies for hind paw licking of mice tested in the hot-plate test. Acetaminophen, at its highest selected dose, was able to reduce serum corticosterone level in mice tested in the EPM. The effect of acetaminophen on serum corticosterone level was reversed by the use of the CB 1 blocker; rimonabant. Similarly, acetaminophen at its highest selected dose was also able to reduce serum corticosterone levels in mice tested in the Vogel conflict test. Again, the effect of acetaminophen on serum corticosterone levels of mice tested in the Vogel conflict test was reversed by the use of the CB 1 blocker, rimonabant. 106 Summary and Conclusion Based on the previous findings in this study, it can be concluded that: Acetaminophen exerted a dose-dependent anxiolytic-like effect in mice tested in two of the most commonly employed animal models of anxiety; the EPM and the Vogel conflict test. The fact that these two models reflect different aspects of anxiety, may suggest that acetaminophen could play a promising role in the treatment of different types of anxiety disorders, alone or in combination with other clinically used anxiolytics. The findings that acetaminophen did not significantly affect mice behaviours in the open field, water consumption or hot-plate tests, support the main finding of this study and rule out any conflicting parameters that could confound the observed anxiolytic-like effect of acetaminophen. The ability of the CB 1 blocker; rimonabant and the FAAH inhibitor; URB597, to antagonise the anxiolytic-like effect of acetaminophen in both models, suggest the involvement of AM404-mediated synaptic accumulation of anandamide and the subsequent activation of the CB 1 receptors in the observed anxiolytic-like effect. Another interesting finding in this study was the ability of acetaminophen to reduce serum corticosterone level of mice tested in both models. This finding may suggest that acetaminophen could negatively modulate the activity of the hypothalamo- pituitary-adrenal axis through its CNS active metabolite; AM404. The finding that rimonabant was able to reverse the effect of acetaminophen on serum corticosterone, may suggest the involvement of the endocannabinoid system in this effect. |