Br. J. Pharmacol. (1992), 105, 514-515
SPECIAL REPORT
© Macmillan Press Ltd, 1992
MK801 attenuates behavioural adaptation to chronic nicotine administration in rats Mohammed Shoaib & 1Ian P. Stolerman Department of Psychiatry, Institute of Psychiatry, London, SE5 8AF
The effect of administering MK801 (0.3mgkg-1) during chronic nicotine (0.4mgkg-1) treatment was studied on locomotor activity in rats. Sensitization of the locomotor activity response to nicotine was seen with chronic nicotine treatment. This sensitization was attenuated in rats that had received MK801 30 min before the daily nicotine injections during chronic treatment. These results suggest that the NMDA receptor may be involved in the adaptive processes seen with chronic nicotine administration. Keywords: Nicotine; locomotor activity; MK801; NMDA receptor
Introduction The N-methyl-D-aspartate (NMDA) antagonist MK801 [( + )-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine] was developed initially for its ability in preventing neurological disorders such as epileptogenesis and neurodegeneration. However with the increasing number of behavioural studies, it is becoming evident that excitatory amino acid systems have a more central role in other behaviours and in learning and memory (Ward et al., 1990). Many responses of rats to morphine, amphetamines and cocaine are known to exhibit behavioural plasticity, and thus may show either tolerance or sensitization (reverse tolerance) with repeated exposures to the drugs (Goudie & EmmettOglesby, 1989). A recent series of reports has shown that MK801 blocks the development of sensitization or tolerance to several psychoactive substances. Both amphetamine- and cocaine-induced sensitization of locomotor stimulation in mice have been blocked (Karler et al., 1989), as well as sensitization to cocaine-induced convulsions and stereotypy in rats (Karler et al., 1989). Tolerance to the analgesic effects of morphine in rats can be attenuated by MK801 (Trujillo & Akil, 1991). In addition, MK801 attenuated the development of morphine-dependence as assessed by naloxone-precipitated withdrawal (Trujillo & Akil, 1991). Such findings suggest that diverse drugs can trigger a common mechanism of adaptation that is sensitive to MK801. It was our aim to extend these findings by investigating whether MK801 could also attenuate an adaptive response seen with chronic administration of nicotine. Repeated exposures of rats to small doses of nicotine can produce sensitization to the locomotor stimulant effect (Clarke & Kumar, 1983; Ksir et al., 1987). Larger doses of nicotine produce a strong depressant effect on locomotor activity to which tolerance develops rapidly with repeated exposures, thus unmasking the underlying locomotor stimulation (Clarke & Kumar, 1983; Ksir et al., 1987).
MK-N) or saline (MK-S). The other two groups received saline injection (i.p.) followed by nicotine (0.4mgkg-', s.c.; S-N) or saline (SC; S-S). Rats were chronically treated daily as described above for 14 days, receiving half of their treatments before they were placed in locomotor activity cages for 60min immediately after injection of nicotine or saline; on alternate days, they were returned to their home cages immediately after injection. Following chronic treatment, each rat was tested with a randomised sequence of doses of nicotine (0.1, 0.2, 0.4, 0.8 mg kg -1) and saline. Successive treatments were tested on alternate days, with only the usual chronic treatments given on intervening days. Rats were injected with nicotine or saline and were immediately placed into photocell activity cages (Clarke & Kumar, 1983). The number of cage crosses (movements from one beam of infra-red light to another) was recorded over 60 min. Results were analysed by one- and twofactor analyses of variance for repeated measures. Dunnett's t test was used as a test of significance at each dose utilised.
Results Illustrated in Figure 1 are activity scores for doses of nicotine in the four chronically treated groups. An initial twofactor analysis of variance for repeated measures showed a significant interaction of the chronic treatment regimen with
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SPECIAL REPORT
© Macmillan Press Ltd, 1992
MK801 attenuates behavioural adaptation to chronic nicotine administration in rats Mohammed Shoaib & 1Ian P. Stolerman Department of Psychiatry, Institute of Psychiatry, London, SE5 8AF
The effect of administering MK801 (0.3mgkg-1) during chronic nicotine (0.4mgkg-1) treatment was studied on locomotor activity in rats. Sensitization of the locomotor activity response to nicotine was seen with chronic nicotine treatment. This sensitization was attenuated in rats that had received MK801 30 min before the daily nicotine injections during chronic treatment. These results suggest that the NMDA receptor may be involved in the adaptive processes seen with chronic nicotine administration. Keywords: Nicotine; locomotor activity; MK801; NMDA receptor
Introduction The N-methyl-D-aspartate (NMDA) antagonist MK801 [( + )-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine] was developed initially for its ability in preventing neurological disorders such as epileptogenesis and neurodegeneration. However with the increasing number of behavioural studies, it is becoming evident that excitatory amino acid systems have a more central role in other behaviours and in learning and memory (Ward et al., 1990). Many responses of rats to morphine, amphetamines and cocaine are known to exhibit behavioural plasticity, and thus may show either tolerance or sensitization (reverse tolerance) with repeated exposures to the drugs (Goudie & EmmettOglesby, 1989). A recent series of reports has shown that MK801 blocks the development of sensitization or tolerance to several psychoactive substances. Both amphetamine- and cocaine-induced sensitization of locomotor stimulation in mice have been blocked (Karler et al., 1989), as well as sensitization to cocaine-induced convulsions and stereotypy in rats (Karler et al., 1989). Tolerance to the analgesic effects of morphine in rats can be attenuated by MK801 (Trujillo & Akil, 1991). In addition, MK801 attenuated the development of morphine-dependence as assessed by naloxone-precipitated withdrawal (Trujillo & Akil, 1991). Such findings suggest that diverse drugs can trigger a common mechanism of adaptation that is sensitive to MK801. It was our aim to extend these findings by investigating whether MK801 could also attenuate an adaptive response seen with chronic administration of nicotine. Repeated exposures of rats to small doses of nicotine can produce sensitization to the locomotor stimulant effect (Clarke & Kumar, 1983; Ksir et al., 1987). Larger doses of nicotine produce a strong depressant effect on locomotor activity to which tolerance develops rapidly with repeated exposures, thus unmasking the underlying locomotor stimulation (Clarke & Kumar, 1983; Ksir et al., 1987).
MK-N) or saline (MK-S). The other two groups received saline injection (i.p.) followed by nicotine (0.4mgkg-', s.c.; S-N) or saline (SC; S-S). Rats were chronically treated daily as described above for 14 days, receiving half of their treatments before they were placed in locomotor activity cages for 60min immediately after injection of nicotine or saline; on alternate days, they were returned to their home cages immediately after injection. Following chronic treatment, each rat was tested with a randomised sequence of doses of nicotine (0.1, 0.2, 0.4, 0.8 mg kg -1) and saline. Successive treatments were tested on alternate days, with only the usual chronic treatments given on intervening days. Rats were injected with nicotine or saline and were immediately placed into photocell activity cages (Clarke & Kumar, 1983). The number of cage crosses (movements from one beam of infra-red light to another) was recorded over 60 min. Results were analysed by one- and twofactor analyses of variance for repeated measures. Dunnett's t test was used as a test of significance at each dose utilised.
Results Illustrated in Figure 1 are activity scores for doses of nicotine in the four chronically treated groups. An initial twofactor analysis of variance for repeated measures showed a significant interaction of the chronic treatment regimen with
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