الفهرس 
IntroductionOnly 14 pages are availabe for public view
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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.
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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.
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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.