Low doses of dizocilpine block the development and subsequent expression of locomotor sensitization to nicotine in rats

Rationale and objectives: We attempted to determine if the effects of the glutamate NMDA receptor blocker dizocilpine (MK-801) on nicotine locomotor sensitization were due to a blockade of the development of sensitization or to state-dependency. Methods and results: In experiment 1, repeated co-administration of a high dose of dizocilpine (0.25 mg/ka) along with 0.4 mg/kg nicotine enhanced locomotion, failed to alter the development of locomotor sensitization to nicotine, but completely blocked the subsequent expression of sensitization to a challenge injection of nicotine alone. However, repeated injections of this dose of dizocilpine alone produced locomotion and sensitization that was equivalent to that produced by the dizocilpine/nicotine combination. In four separate replications in experiments 2 and 3, co-administration of a low dose of dizocilpine (0.075 mg/kg), which did not produce sensitization to itself, blocked both the development of nicotine sensitization and its subsequent expression in response to a challenge injection of nicotine. Moreover, this repeated dizocilpine/nicotine administration did not affect the subsequent development of sensitization to nicotine alone (experiment 3). Suggesting that these effects of dizocilpine may be confined to the development of sensitization, challenge injections of dizocilpine failed to block the capacity to express previously nicotine-sensitized locomotion (experiment 2). Conclusions: Co-administration of a low dose of dizocilpine can block the development of locomotor sensitization to repeated injections of nicotine without producing state-dependency. Thus, NMDA receptor activation appears to be critical for the development, but not the subsequent expression, of nicotine locomotor sensitization.