BEHAVIORAL 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 th e stimulant effects of nicotine on locomotor activity. At a biochemica l level, chronic exposure to nicotine increases the number of CNS nico tinic binding sites, and this has been suggested as the basis for sens itization to nicotine. The present experiment was conducted to examine the effects of MK801, an NMDA receptor antagonist, on sensitization t o nicotine. In addition, the hypothesis that MK801 may block behaviour al sensitization by preventing the up-regulation of nicotinic receptor s was tested by measuring receptor numbers in the same individuals usi ng quantitative autoradiography with [H-3]-cytisine and [H-3]-MK801. M ale Sprague-Dawley rats were chronically treated with nicotine (0.4 mg /kg SC) or saline daily for 7 days. Over the next 2 days, in a counter balanced order, rats were challenged with nicotine (0.4 mg/kg SC) or s aline and locomotor activity was monitored. In saline-pretreated rats, nicotine produced a small increase in activity. Nicotine-pretreated r ats exhibited higher levels of activity following a nicotine challenge . This sensitized response was attenuated in rats administered MK801 ( 0.3 mg/kg IP) 30 min before each daily nicotine injection. Rats pretre ated with MK801 alone showed activity scores no different from saline pretreated control groups. Biochemical studies revealed increased [H-3 ]-cytisine binding following chronic nicotine treatment; however recep tor increases were significantly attenuated by MK801 pretreatment. Bin ding of [H-3]-MK801 remained unchanged across the four groups, The res ults suggest that MK801 prevents behavioural sensitization to nicotine via the prevention of receptor up-regulation. Although the findings s upport the notion that receptor up-regulation may be the basis for the increased responsiveness to nicotine, other interpretations are possi ble.