Specific blockade of morphine- and cocaine-induced reinforcing effects in conditioned place preference by nitrous oxide in mice

Nitrous oxide (N2O), a pharmacological active gas and an antagonist of N-methyl-D-aspartic acid receptors, has been reported to be effective in the treatment of alcohol and tobacco withdrawal syndrome. However, the neurobiological bases of N2O effects are unknown. The aim of the present studies was to examine the effect of N2O on acquisition and expression of morphine- (10 mg/kg; s.c.) and cocaine- (20 mg/kg; i.p.) induced conditioned place preference (CPP) in mice. Unbiased place conditioning method was used. Mice were exposed to N2O during the conditioning phase (acquisition of CPP) or during postconditioning phase (expression of CPP). The same protocol was used to evaluate the impact of N2O on locomotor activity, two-trial recognition task (memory), spontaneous alternation, sucrose consumption (anhedonic state), forced swim (depressive state) and elevated O-maze tests (anxiety state). In all these tests, mice were treated with morphine (10 mg/kg, s.c.) the first day, the following day mice were given saline. This sequence alternated during the next 4 days. Control animals received saline every day. The behavior of animals was evaluated on day 8. N2O did not induce CPP but impaired the acquisition of morphine-induced CPP and blocked the expression of cocaine- and morphine-induced CPP. The effects of the gas were long lasting and persist 4 days following the exposure. Moreover no behavioral modifications in tests usually used to investigated emotional state as compared with control mice were observed in animals exposed to N2O, ruling out an effect of this gas on attention, anxiety, depression, locomotion and anhedonia. These studies raise the possibility that N2O could have a clinical benefit in the management of morphine and cocaine addiction.