Behavioural and biochemical adaptations to nicotine in rats: influence of MK801, an NMDA receptor antagonist

Chronic exposure of rats to nicotine can result in sensitization to the stimulant effects of nicotine on locomotor activity. At a biochemical level, chronic exposure to nicotine increases the number of CNS nicotinic binding sites, and this has been suggested as the basis for sensitization to nicotine. The present experiment was conducted to examine the effects of MK801, an NMDA receptor antagonist, on sensitization to nicotine. In addition, the hypothesis that MK801 may block behavioural sensitization by preventing the up-regulation of nicotinic receptors was tested by measuring receptor numbers in the same individuals using quantitative autoradiography with [3H]-cytisine and [3H]-MK801. Male Sprague-Dawley rats were chronically treated with nicotine (0.4 mg/kg s.c.) or saline daily for 7 days. Over the next 2 days, in a counterbalanced order, rats were challenged with nicotine (0.4 mg/kg s.c.) or saline and locomotor activity was monitored. In saline-pretreated rats, nicotine produced a small increase in activity. Nicotine-pretreated rats exhibited higher levels of activity following a nicotine challenge. This sensitized response was attenuated in rats administered MK801 (0.3 mg/kg i.p.) 30 min before each daily nicotine injection. Rats pretreated with MK801 alone showed activity scores no different from saline pretreated control groups. Biochemical studies revealed increased [3H]-cytisine binding following chronic nicotine treatment; however, receptor increases were significantly attenuated by MK801 pretreatment. Binding of [3H]-MK801 remained unchanged across the four groups. The results suggest that MK801 prevents behavioural sensitization to nicotine via the prevention of receptor up-regulation. Although the findings support the notion that receptor up-regulation may be the basis for the increased responsiveness to nicotine, other interpretations are possible.