Synergistic effect between citalopram and citicoline on anxiolytic effect in non-sensitized and morphine-sensitized mice: An isobologram analysis.

In the present study, the effects of intraperitoneal (i.p.) injections of citalopram and citicoline on morphine-induced anxiolytic effects were investigated in non-sensitized and morphine-sensitized mice using elevated plus-maze (EPM). Subcutaneous (s.c.) administration morphine (5 mg/kg) increased the percentage of open arm time (%OAT, in morphine-sensitized mice), and open arm entries (%OAE, in non-sensitized mice), but not a locomotor activity, indicating an anxiolytic response to morphine. On the other hand, i.p. administration of naloxone decreased %OAT (morphine-sensitized mice), and %OAE (non-sensitized and morphine-sensitized mice), but not a locomotor activity, showing an anxiogenic effect to naloxone. Moreover, i.p.co-administration of citalopram (5 and 10 mg/kg) and citicoline (75 mg/kg) induced the anxiolytic effect. Interestingly, i.p. co-administration of low doses of citalopram (0.5, 1 and 2.5 mg/kg) and citicoline (25 mg/kg) significantly increased %OAT and %OAE in non-sensitized as well as %OAT in morphine-sensitized mice, indicating an anxiolytic effect. An isobolographic analysis of data was performed, presenting a synergistic interaction between citalopram and citicoline upon the production of anxiolytic effect in non-sensitized and morphine-sensitized mice. In conclusion, it seems that (1) morphine sensitization affects the anxiety behavior in the EPM, (2) μ-opioid receptors play an important role in morphine anxiolytic effect, (3) citalopram and citicoline induced anti-anxiety effect, (4) a synergistic effect of citalopram and citicoline upon induction of anti-anxiety behavior in non-sensitized and morphine-sensitized mice.