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

Nitrous oxide (N(2)O), 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 N(2)O effects are unknown. The aim of the present studies was to examine the effect of N(2)O 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 N(2)O during the conditioning phase (acquisition of CPP) or during postconditioning phase (expression of CPP). The same protocol was used to evaluate the impact of N(2)O 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. N(2)O 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 N(2)O, ruling out an effect of this gas on attention, anxiety, depression, locomotion and anhedonia. These studies raise the possibility that N(2)O could have a clinical benefit in the management of morphine and cocaine addiction.

Analysis of transcriptional responses in the mouse dorsal striatum following acute 3,4-methylenedioxymethamphetamine (ecstasy): identification of extracellular signal-regulated kinase-controlled genes.

3,4-Methylenedioxymethamphetamine (ecstasy), a widely used recreational drug with psychoactive properties, induces both serotonin and dopamine release in the brain. However, little is known about its intracellular effects. We previously showed that 3,4-methylenedioxymethamphetamine rewarding effects in mice were dependent upon extracellular signal-regulated kinase activation and that dorsal striatum was a critical region for mediating extracellular signal-regulated kinase-dependent Egr1 3,4-methylenedioxymethamphetamine-induced transcription. Here, we extend these findings by showing that 3,4-methylenedioxymethamphetamine is indeed able to activate extracellular signal-regulated kinase within this structure. To identify genes regulated by acute 3,4-methylenedioxymethamphetamine in the mice dorsal striatum, and selectively controlled by this kinase, we performed microarray experiments by using a selective inhibitor of extracellular signal-regulated kinase activation, SL327. Of the approximately 24,000 genes from the microarray, 27 showed altered expression after exposure to 3,4-methylenedioxymethamphetamine, and among these, 59% were partially or totally inhibited by SL327 pretreatment. Our results showed that the genes regulated by 3,4-methylenedioxymethamphetamine encode proteins that belong to transcription factors family, signaling pathways (phosphatases, cytoskeleton regulation), and synaptic functions. These early changes, and especially those controlled by extracellular signal-regulated kinase activation might play significant roles in the expression of many of the behaviors that occur following 3,4-methylenedioxymethamphetamine taking.