LACK OF IFENPRODIL ANXIOLYTIC ACTIVITY AFTER ITS MULTIPLE TREATMENT IN CHRONICALLY ETHANOL-TREATED RATS

P. Mikolajczak*, I. Okulicz-Kozaryn, E. Kaminska, M. Szulc, W. Dyr1 and W. Kostowski1

Department of Pharmacology, K. Marcinkowski University of Medical Sciences, Rokietnicka 5a, 60-806 Poznan and
1 Department of Pharmacology and Physiology of the Nervous System, Institute of Psychiatry and Neurology, Al. Sobieskiego 1-9, 02-957 Warsaw, Poland

Received 7 February 2002; in revised form 18 December 2002; accepted 27 February 2003


    ABSTRACT
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Aims: The purpose of this study was to assess the anxiolytic activity of ifenprodil in Warsaw high-preferring (WHP) and low-preferring (WLP) rats after chronic ethanol treatment. Methods: WHP and WLP animals, their paired-ethanol-naive groups and control Wistar rats were treated with ifenprodil (1.0 mg/kg, intraperitoneally) for 21 consecutive days. Anxiolytic activity was evaluated by using the two-compartment exploratory test. In addition, the locomotor activity paradigm was also assessed. Results: Ifenprodil did not affect this paradigm in all investigated groups. The ethanol treatment led to lowering of anxiolytic scores in WHP rats. Multiple ifenprodil administration showed an anxiogenic-like activity in both WHP- and WLP-ethanol-treated groups. Conclusions: Our results suggest that, under some conditions, the role of ifenprodil in the treatment of alcoholism may be insufficient to support its use.


    INTRODUCTION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
It is known that, upon chronic treatment, alcohol produces a withdrawal syndrome characterized by distinct, often physical, signs and symptoms. Moreover, withdrawal is associated with a negative affective state including various negative emotions, such as dysphoria, irritability, restlessness, sleep disorders, depressive symptoms and anxiety (Kreek and Koob, 1998Go). Recently, it was postulated that anxiety could be a predictor of relapse to uncontrolled drinking in detoxified alcohol-dependent patients (Willinger et al., 2002Go), although the relationship between alcohol dependence and anxiety is sometimes questionable (Schuckit and Hesselbrock, 1994Go).

In rats, it has been observed that the basal level of anxiety is an important predictor of vulnerability to ethanol intake (Spanagel et al., 1995Go), alcohol treatment leads to anxiety-related reactions (Poelchen et al., 2001Go; Boehm II et al., 2002Go), and many lines of ethanol-preferring and non-preferring rats show significant anxiogenic-like responses (Stewart et al., 1993Go; Colombo et al., 1995Go; Overstreet et al., 1997Go; McMillen et al., 1998Go; Salimov, 1999Go; Kampov-Polevoy et al., 2000Go). It is now clear that the GABAA system is involved in the pathophysiology of anxiety disorders (Clement and Chapouthier, 1998Go) and that chronic ethanol administration decreases GABAergic neurotransmission (Grobin et al., 1998Go; Kreek and Koob, 1998Go). On the other hand, the role of glutamatergic transmission in anxiety is also recognized (Meldrum, 2000Go; Jetty et al., 2001Go) and N-methyl-d-aspartate (NMDA) competitive and non-competitive antagonists appear to have anti-anxiety effects in animal models of anxiety, although many of them cannot be regarded as potential anxiolytic drugs, due to their side-effect profiles (Chojnacka-Wojcik et al., 2001Go).

It is also known that chronic ethanol exposure is associated with upregulation of NMDA receptor function (Davis and Wu, 2001Go) and NMDA receptor antagonists may have potential therapeutic implications for ethanol addiction (Bisaga and Popik, 2000Go), but their role in the treatment of ethanol-induced anxiety disorder is an open question.

Polyamines can alter the function of NMDA receptors via the polyamine site(s) and the NR2B subunit renders NMDA receptors particularly sensitive to potentiation by polyamines (Yamamura and Shimoji, 1999Go). It is generally accepted that chronic ethanol treatment of rats leads to progressive increases in the NR1, NR2A, NR2B subunits of the NMDA receptor complex (Davis and Wu, 2001Go) and the involvement of polyamines in ethanol dependence and withdrawal has been postulated (Littleton et al., 2001Go). Ifenprodil or eliprodil (an analogue of ifenprodil), competitive antagonists at the spermine site of the NMDA complex acting via NR2B subunit of the NMDA receptor (Yamamura and Shimoji, 1999Go), significantly suppress ethanol withdrawal signs (Kotlinska and Liljequist, 1996Go; Narita et al., 2000Go; Nagy et al., 2001Go; Mayer et al., 2002Go). Concerning the effects of polyamine ligands in anxiolytic testing procedures, it is known that ifenprodil does not produce antipunishment effects in rats (Sanger and Jackson, 1989Go; Koek and Colpaert, 1991Go) and a similar effect after eliprodil was observed (Wiley et al., 1998Go), whereas a very low dose (0.0195 mg/kg, intraperitoneally) of ifenprodil was found to have a marked anxiolytic profile in mice using the plus-maze paradigm (Fraser et al., 1996Go). Moreover, it has recently been shown that the NR2B subunit is involved in the expression of ethanol withdrawal symptoms in rodents, including anxiety, and that some of these effects can be affected by ifenprodil treatment (Stork et al., 2002Go).

Nevertheless, it must be emphasized that all the above-mentioned effects were obtained after a single administration of these polyamine ligands and, to our knowledge, no data are available concerning prolonged treatment with ifenprodil on anxiolytic activity. Therefore, we considered it of interest to investigate the effects of repeated administration of ifenprodil on anxiety test procedures in chronically ethanol-treated rats.

A preliminary account of part of this present work has been presented (Mikolajczak et al., 2001Go).


    MATERIALS AND METHODS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Animals
The experiments were performed on WHP (Warsaw high-preferring) (n = 37) and WLP (Warsaw low-preferring) (n = 31) (17th generation) male lines of Wistar rats housed individually in their home cages and kept on a reversed 12 h/12 h night/day cycle under constant ambient conditions (20 ± 2°C, relative humidity 65%). All rats had free access to standard laboratory diet [pellets: Labofeed B (LSM); Feeds and Concentrates Production Plant, Poland].

Two groups of animals were presented with a free choice paradigm between tap water and ethanol solution [12% (w/w) solution from 95% stock ethanol] for 4 weeks (ethanol-treated groups: WHP: n = 18; WLP: n = 14). The procedure was continued during the following 3 weeks (drug treatment period). The other two groups of WHP (n = 19) and WLP (n = 17) rats were presented freely with tap water during the whole experiment period and were used as inbred control groups (ethanol-naive WHP or WLP, respectively). Additionally, 16 Wistar male outbred control rats (CR), housed also individually in their home cages, were presented freely with tap water. The ethanol and water intakes (ml) were measured every day during the drug treatment period for individual rats. The volume of ethanol intake was converted to a value in g/kg/24 h and expressed as a mean ± SEM for the group during the last week of drug treatment. Similarly, total fluid intake (sum of water and ethanol solution intakes) was also expressed in ml/kg/24 h for the groups during the last week of drug administration. Preference (in %) was calculated as the amount of ethanol consumed (100 x ml/kg/24 h)/total fluid intake (ml/kg/24 h). The body weight of animals after the drug treatment period was also measured.

Drug treatment
After 4 weeks of voluntary ethanol intake, the groups of rats were treated with ifenprodil (ifenprodil tartrate; RBI, USA) (1.0 mg/kg, intraperitoneally) dissolved in water for injection (vehicle) (Aqua pro injectione, Polfa, Poland) for 21 consecutive days. The control groups were given the corresponding volume of vehicle. The dose of ifenprodil was chosen according to our previous experiments (Mikolajczak et al., 2002aGo,bGo) and in agreement with others (Malinowska et al., 1999Go; Napiorkowska-Pawlak et al., 2000Go).

Locomotor activity
Effect of 21x ifenprodil or 21x vehicle on locomotor activity was measured in all investigated groups of rats as the number of impulses produced by their spontaneous movements during 5 min using a ‘PAN — licensed activity meter’, Poland, as described in our previous experiments (Mikolajczak et al., 2002aGo).

Anxiolytic test
The anxiolytic effects were assessed according to the two-compartment exploratory test (Crawley and Goodwin, 1980Go; Crawley, 1981Go; Merlo-Pich and Samani, 1989Go). Briefly, the surface of the apparatus was divided into 25 equal squares consisting of two compartments: one (4 squares) was black and the other (21 squares) was white. At the beginning of the test, all rats were placed in the same peripheral lit ‘white’ square near to the ‘black’ compartment. The numbers of transitions between the two compartments (BWT), square entries in the black compartment (BSE) and square entries in the white compartment (WSE) were recorded for 5 min by an observer sitting 2 m away, unaware of the treatment. Whenever the animal crossed the transition line with all four legs, an event was recorded. All investigations were conducted during the dark phase in a dimly illuminated, sound-proof room 30 min after the last dose (21) of daily ifenprodil administration.

Statistical analysis
All values are expressed as means ± SEM. The statistical comparison of results was carried out using one-way analysis of variance (ANOVA) followed by Duncan post-hoc test to analyse the ethanol intake and locomotor activity data. Kruskal– Wallis non-parametric ANOVA followed by a Mann–Whitney test was applied for anxiolytic data (WSE, BSE and BWT scores) analysis.


    RESULTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Our results show, that the animals used in this study differed in voluntary ethanol intake, since there were statistically significant differences between all ethanol-treated groups [ANOVA: F(3, 28) = 7.58; P < 0.001] (Table 1Go). The observed effect was produced by ethanol-treated WHP animals, which consumed significantly more ethanol than the corresponding ethanol-treated WLP rats (P < 0.01). The rats of the ethanol-treated WHP line also showed higher ethanol preference as compared with appropriate ethanol-treated WLP animals (P < 0.05) (Table 1Go). The total fluid intake was lower in ethanol-naive and ethanol-treated groups of WHP or WLP rats when compared with the appropriate CR group; however, the differences were not statistically significant [ANOVA: F(9, 74) = 1.39; P > 0.1] (Table 1Go). Moreover, there were no differences in total fluid intake between either appropriate ethanol-naive or ethanol-treated animals. Multiple ifenprodil administration did not alter any of the above parameters of drinking behaviour, since there were no statistically significant differences between ifenprodil- and vehicle-treated rats (Table 1Go).


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Table 1. Parameters of alcohol intake after multiple ifenprodil treatment in ethanol-high-preferring (WHP), ethanol-non-preferring (WLP) and control Wistar (CR) rats
 
In the experiment, when testing the sedative action of chronic ethanol treatment on the basis of the assessment of rats’ locomotor activity, it was found that there were statistically significant differences between all investigated groups [ANOVA: F(9, 74) = 2.61; P < 0.05] (Fig. 1Go). However, using detailed analysis we found that these differences were produced mainly by ethanol-treated WLP rats, because the ethanol-treated WLP+vehicle rats had lower values, in comparison to appropriate CR (P < 0.05), ethanol-naive WLP (P < 0.05) or ethanol-treated WHP rats (P < 0.05), whereas the ethanol-naive WHP+vehicle or ethanol-treated WHP+vehicle rats showed similar activities as CR animals. Moreover, the multiple ifenprodil treatment did not affect the locomotor activity paradigm in all investigated animals (Fig. 1Go).



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Fig. 1. Effect of multiple ifenprodil treatment on locomotor activity in ethanol-high-preferring (WHP), ethanol-low-preferring (WLP) and control (CR) rats.

Rats were treated with ifenprodil (1 mg/kg intraperitoneally) or an equal volume (X ml/kg) of vehicle (sterile water for injection) for 21 days. Data are expressed as means ± SEM of 7–10 animals; one-way ANOVA: F(9, 74) = 2.61; P < 0.05; **, statistically significant difference vs CR+vehicle group, P < 0.05 (Duncan post-hoc test); ##, statistically significant difference vs ethanol-naive WLP+vehicle group, P < 0.05 (Duncan post-hoc test); ++, statistically significant difference vs ethanol-treated WLP+vehicle group, P < 0.05 (Duncan post-hoc test).

 
The results of the effects of ifenprodil treatment on anxiolytic activity in ethanol-naive, chronically ethanol-treated, and in CR, animals are shown in Fig. 2Go. It was found that chronic ethanol treatment and multiple ifenprodil administration led to statistically significant changes in the test values when expressed as WSE [Kruskal–Wallis ANOVA: H(9, 74) = 28.5; P < 0.001] (Fig. 2AGo), BSE [Kruskal–Wallis ANOVA: H(9, 74) = 47.9; P < 0.001] (Fig. 2BGo) or BWT scores [Kruskal–Wallis ANOVA: H(9, 74) = 35.6; P < 0.001] (Fig. 2CGo).



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Fig. 2. Effect of multiple ifenprodil treatment on anxiolytic activity expressed as WSE scores (A), BSE scores (B) or BWT scores (C) in ethanol-high-preferring (WHP), ethanol-non-preferring (WLP) and control (CR) rats.

Details as in Fig. 1Go. Data are expressed as means ± SEM of 7–10 animals. (A) Kruskal–Wallis ANOVA: H(9, 74) = 28.5; P < 0.001; *, statistically significant difference vs CR+vehicle group, P < 0.1 (Mann–Whitney test); ###,#, statistically significant difference vs ethanol-naive WLP+vehicle group, P < 0.01 or P < 0.1, respectively (Mann–Whitney test). (B) Kruskal–Wallis ANOVA: H(9, 74) = 47.9; P < 0.001; **,*, statistically significant difference vs CR+vehicle group, P < 0.05 or P < 0.1, respectively (Mann–Whitney test); ###, statistically significant difference vs ethanol-naive WLP+vehicle group, P < 0.01 (Mann–Whitney test); ++, statistically significant difference vs ethanol-treated WLP+vehicle group, P < 0.05 (Mann–Whitney test); &&&, statistically significant difference vs ethanol-naive WHP+vehicle group, P < 0.01 (Mann–Whitney test). (C) Kruskal–Wallis ANOVA: H(9, 74) = 35.6; P < 0.001; *, statistically significant difference vs CR+vehicle group, P < 0.1 (Mann–Whitney test); ##, statistically significant difference vs ethanol-naive WLP+vehicle group, P < 0.05 (Mann–Whitney test); &, statistically significant difference vs ethanol-naive WHP+vehicle group, P < 0.1 (Mann–Whitney test); @@, statistically significant difference vs appropriate vehicle-treated group, P < 0.05 (Mann–Whitney test).

 
Using detailed analysis, we found that the ethanol-treated WHP+vehicle animals showed anxiogenic-like activity expressed by decrease of BSE scores (P < 0.01) or BWT scores (P < 0.1), when compared with the ethanol-naive WHP+vehicle group (Fig. 2B and CGo, respectively), whereas the decreasing test values expressed by WSE, which was also measured, was not statistically significant (Fig. 2AGo). Moreover, the test values in ethanol-naive WHP+vehicle rats were lower than those of ethanol-naive WLP animals, but comparable with those of the CR group; however, the effects were also insignificant (BSE, BWT) or reached near significance (BSE, P < 0.1) (Fig. 2AGo–C). Similarly, the ethanol-treated WLP+vehicle rats had lower WSE (P < 0.01), BSE (P < 0.01) and BWT (P < 0.05) scores, when compared with ethanol-naive WLP rats (Fig. 2AGo–C). Generally, all test values in ethanol-naive WLP+vehicle animals were the highest in comparison to appropriate CR group, although the differences did not reach statistical significance (P < 0.1) (Fig. 2AGo–C).

Detailed analysis showed that, when test values were expressed by BWT scores, statistically significant effects of multiple ifenprodil treatment on performance of the anxiolytic task leading to lowering of test scores in ethanol-treated WLP (P < 0.05) and ethanol-treated WHP animals (P < 0.05) were noticed, when compared with appropriate vehicle-treated rats (Fig. 2CGo). However, ifenprodil involvement expressed by WSE or BSE scores did not reach a statistical significance (Fig. 2A and BGo, respectively).


    DISCUSSION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
The two groups of rats differing in voluntary ethanol intake used in the present work (WHP and WLP) exhibited differences in drinking behaviour, which were in line with our previous report (Dyr and Kostowski, 2000Go). The choice of the free choice paradigm as a method for chronic ethanol treatment corresponds with some criteria in humans (Koob, 2000Go). Thus, it has been postulated that oral ethanol self-administration in ethanol-preferring animals is closely related to the criterion ‘A great deal of time spent in activities necessary to obtain substance, to use substance, or to recover from its effect’, whereas ethanol intake corresponds to the criterion ‘Substance used in larger amounts or over a longer period than the person intended’. Therefore we believe that the rats used in this study fulfil at least one of the two criteria for an animal model of alcoholism.

With respect to the drinking pattern in the investigated rats, we found that there were no significant statistical differences in daily total fluid intake. Therefore, it can be concluded that the animals used in our study were not dehydrated and probably not undernourished.

The lowering of locomotor activity observed in ethanol-treated WLP rats, compared with ethanol-treated WHP, ethanol-naive WLP or CR animals was in line with the results concerning the differences between many ethanol-preferring and non-preferring rat lines bred for alcohol preference, since ‘preferring’ animals were more reactive than their counterparts or possessed the same activity as the heterogeneous Wistar animals (Badishtov et al., 1995Go; McMillen et al., 1998Go; Nowak et al., 2000Go). However, multiple ifenprodil treatment did not affect the locomotor activity paradigm in our rats. It is interesting that the multiple treatment produced a similar effect in CR animals after a single ifenprodil administration (i.e. there was no tolerance-like effect) (Mikolajczak et al., 2002aGo). Similar effects in ethanol-naive WHP and ethanol-naive WLP rats were found. This suggests that ifenprodil does not produce a sedative activity after the dose used in this study, whereas, at higher doses (e.g. 10 mg/kg, intraperitoneally), ifenprodil shows a tendency to reduce locomotor activity or the prolongation of ethanol-induced sleeping time in CR animals (Mikolajczak et al., 2002aGo), which is in agreement with data presented by others (Sanger and Joly, 1991Go; Ginski and Witkin, 1994Go; Doyle and Shaw, 1998Go; Malinowska et al., 1999Go).

Ethanol-treated WHP animals showed anxiogenic-like activity expressed by a significant decrease of BSE scores, when compared with the ethanol-naive WHP or CR groups, using the two-compartment exploratory test. The results showed that ethanol-treated WHP animals were more ‘anxious’ and this effect was not affected by the locomotor activity of these animals. Also in ethanol-treated WLP rats, a decrease in test parameters was found, in comparison with ethanol-naive WLP animals. Chronic ethanol treatment of WLP rats led to a lowering of locomotor activity and the decrease in test scores in ethanol-treated WLP animals was probably due to involvement of ethanol-induced motor impairment and did not show the true anxiolytic effects. On the other hand, it is known that the light–dark box test of anxiety is allegedly less influenced by differences in activity (Crawley and Goodwin, 1980Go), and this test was helpful in the assessment of anxiolytic activity of mouse lines selectively bred for sensitivity to ethanol locomotor stimulant effects (Boehm II et al., 2002Go). Therefore, the nature of ethanol-induced events in WLP animals is difficult to explain directly on the basis of our data.

It is also possible to conclude that, due to continuous availability of ethanol intake during the experiments, any eventual withdrawal symptoms may not have influenced these rats’ activity. So the data obtained in our ethanol-treated WHP rats support the hypothesis that these animals exhibit, after ethanol treatment, more anxiogenic behaviour, which is in agreement with the results of others (Stewart et al., 1993Go; Colombo et al., 1995Go). However, it has to be emphasized that there are also data showing that ethanol-preferring rats exhibit lower measures of experimental anxiety, than ethanol-non-preferring subjects (Baldwin et al., 1991Go; Badishtov et al., 1995Go; Moller et al., 1997Go; McMillen et al., 1998Go). In the opinion of many authors (Overstreet et al., 1997Go; McMillen et al., 1998Go; Salimov, 1999Go), these discrepancies may be due to the different behavioural phenotypes and breeding processes and/or different anxiety tests used in the cited studies.

Multiple ifenprodil treatment led to the worse fulfilment of the BWT task in ethanol-treated WHP and ethanol-treated WLP rats, whereas ifenprodil did not cause any significant alterations in the scores in ethanol-naive WLP and WHP, or CR, animals. After ifenprodil administration, there were no differences between WSE and BSE scores in ethanol-treated WHP animals. In the ethanol-treated WLP group, ifenprodil treatment showed the lowering of WSE and BSE tasks, but the effects were statistically insignificant. However, since the BWT task [number of transitions between a brightly lit (aversive) and a dark (safe) compartment] represents probably the most specific parameter of the two-compartment test (Clement and Chapouthier, 1998Go), therefore the effect ex-pressed by lowering of BWT scores after ifenprodil treatment seems to be important. In this study, one of the questions is whether the test used here is valuable for assessment of ifenprodil anxiolytic activity. It is known that benzodiazepines show their anxiolytic activity in the two-compartment exploratory test (Crawley, 1981Go; Costall et al., 1989Go). Moreover, in one of our previous studies, diazepam expressed its anxiolytic activity by increases in WSE, BSE and BWT scores in CR animals and, additionally, in ethanol-preferring rats (BWT scores) (Okulicz-Kozaryn et al., 1999Go). It is also known that compounds from a class different from benzodiazepines show their anxiolytic profile in this test (Nowakowska et al., 1998Go, 1999Go). Therefore, we believe that the procedure used in this study is valid enough to predict the eventual anxiolytic activity of ifenprodil in our experiments.

It is sometimes postulated that NMDA antagonists appear to have anti-anxiety effects (Chojnacka-Wojcik et al., 2001Go). It is also known, as mentioned earlier, that ifenprodil, in a relatively low dose, has an anxiolytic profile (Fraser et al., 1996Go), whereas, at higher doses, the drug did not produce such effects (Sanger and Jackson, 1989Go). In the present study, ifenprodil, in the dose used here, did not show a significant anxiolytic activity per se, which is in agreement with other results (Sanger and Jackson, 1989Go; Stork et al., 2002Go). By contrast, in both ethanol-treated groups of rats, ifenprodil treatment led to a decrease in BWT scores, which may be interpreted as an anxiogenic activity. Additionally, due to the fact that the multiple ifenprodil treatment did not alter ethanol-drinking behaviour or total fluid intake, it seems that the observed effect of ifenprodil expressed by lowering of BWT scores is not altered by drinking behavioural patterns.

It is proposed that a non-receptor protein tyrosine kinase Fyn-mediated phosphorylation of the NMDA receptor subunit NR2B may be a crucial factor for alcohol withdrawal-induced anxiety in mice (Stork et al., 2002Go). Moreover, a stronger response after acute ifenprodil administration in transgenic Fyn alcohol-withdrawn mice in comparison to their wild-type counterparts was observed and the findings were indicative of an anxiogenic-like response of ethanol-withdrawn in transgenic Fyn mice to NR2B antagonism expressed by ifenprodil (Stork et al., 2002Go). It can, therefore, be speculated that the reaction after ifenprodil administration obtained in our ethanol-treated rats may be associated with the above-mentioned effect, and that this effect is observed not only after ethanol discontinuation, but also as a result of ethanol–ifenprodil interaction. However, from our data, it is difficult to explain the nature of ifenprodil-induced anxiogenic activity in ethanol-treated WHP and WLP rats.

Applying the other tests for detailed assessment of ifenprodil-induced anxiogenic activity in chronically ethanol-treated animals and determining the molecular characteristics of the ethanol-sensitive polyamine site of NMDA receptor in WHP and WLP rats after subchronic ifenprodil treatment is thus an important subject for future investigation. In conclusion, because of the anxiogenic-like activity of ifenprodil in chronically ethanol-treated rats, use of the drug in the treatment of alcoholism should be considered carefully.


    ACKNOWLEDGEMENTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
This work was partially supported by grants 501-3-10-02 and 501-3-10-05 from K. Marcinkowski University of Medical Sciences in Poznan, Poland.


    FOOTNOTES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
* Author to whom correspondence should be addressed. Back


    REFERENCES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Badishtov, B. A., Overstreet, D. H., Kashevskaya, O. P., Vigilinskaya, I. V., Kampov-Polevoy, A. B., Seredenin, S. B. and Halikas, J. A. (1995) To drink or not to drink: Open field behavior in alcohol-preferring and non-preferring rat strains. Physiology and Behavior 57, 585–589.[CrossRef][ISI][Medline]

Baldwin, H. A., Wall, T. L., Schuckit, M. A. and Koob, G. F. (1991) Differential effects of ethanol on punished responding in the P and NP rats. Alcoholism: Clinical and Experimental Research 15, 700–704.[ISI][Medline]

Bisaga, A. and Popik, P. (2000) In search of a new pharmacological treatment for drug and alcohol addiction: N-methyl-D-aspartate (NMDA) antagonists. Drug and Alcohol Dependence 59, 1–15.[ISI][Medline]

Boehm II, S. L., Reed, C. L., McKinnon, C. S. and Phillips, T. J. (2002) Shared genes influence sensitivity to the effects of ethanol on locomotor and anxiety-like behaviors, and the stress axis. Psychopharmacology 161, 54–63.[CrossRef][ISI][Medline]

Chojnacka-Wojcik, E., Klodzinska, A. and Pilc, A. (2001) Glutamate receptor ligands as anxiolytics. Current Opinion in Investigational Drugs 2, 1112–1119.[Medline]

Clement, Y. and Chapouthier, G. (1998) Biological bases of anxiety. Neuroscience and Biobehavioral Reviews 22, 623–633.[CrossRef][ISI][Medline]

Colombo, G., Agabio, R., Lobina, C., Reali, R., Zocchi, A., Fadda, F. and Gessa, G. L. (1995) Sardinian alcohol-preferring rats: a genetic animal model of anxiety. Physiology and Behavior 57, 1181–1185.[CrossRef][ISI][Medline]

Costall, B., Jones, B. J., Kelly, M. E., Naylor, R. J. and Tomkins, D. M. (1989) Exploration of mice in a black and white test box: Validation as a model of anxiety. Pharmacology, Biochemistry and Behavior 32, 777–785.[CrossRef][ISI][Medline]

Crawley, J. N. (1981) Neuropharmacological specificity of a single animal model for the behavioral action of benzodiazepines. Pharmacology, Biochemistry and Behavior 15, 695–699.[CrossRef][ISI][Medline]

Crawley, J. N. and Goodwin, F. K. (1980) Preliminary report of a simple animal behavior model for anxiolytic effects of benzodiazepines. Pharmacology, Biochemistry and Behavior 13, 167–170.[CrossRef][ISI][Medline]

Davis, K. M. and Wu, J. Y. (2001) Role of glutamatergic and GABAergic systems in alcoholism. Journal of Biomedical Science 8, 7–19.[CrossRef][ISI][Medline]

Doyle, K. M. and Shaw, G. G. (1998) Investigation of the actions and antagonistic activity of some polyamine analogues in vivo. British Journal of Pharmacology 124, 386–390.[Abstract]

Dyr, W. and Kostowski, W. (2000) Animal model of ethanol abuse: Rats selectively bred for high and low voluntary alcohol intake. Acta Poloniae Pharmaceutica — Drug Research 57 (Suppl.), 90–92.

Fraser, C. M., Cooke, M. J., Fisher, A., Thompson, I. D. and Stone, T. W. (1996) Interactions between ifenprodil and dizocilpine on mouse behaviour in models of anxiety and working memory. European Neuropsychopharmacology 6, 311–316.[CrossRef][ISI][Medline]

Ginski, M. J. and Witkin, J. M. (1994) Sensitive and rapid behavioral differentiation of N-methyl-D-aspartate receptor antagonists. Psychopharmacology 114, 574–582.

Grobin, A. C., Matthews, D. B., Devaud, L. L. and Morrow, A. L. (1998) The role of GABAA receptors in the acute and chronic effects of ethanol. Psychopharmacology 139, 2–19.[CrossRef][ISI][Medline]

Jetty, P. V., Charney, D. S. and Goddard, A. W. (2001) Neurobiology of generalized anxiety disorder. Psychiatric Clinics of North America 24, 75–97.[ISI][Medline]

Kampov-Polevoy, A., Matthews, D. B., Gause, L., Morrow, A. L. and Overstreet, D. H. (2000) P rats develop physical dependence on alcohol via voluntary drinking: changes in seizure thresholds, anxiety and patterns of alcohol drinking. Alcoholism: Clinical and Experimental Research 24, 278–284.[CrossRef][ISI][Medline]

Koek, W. and Colpaert, F. C. (1991) Use of a conflict procedure in pigeons to characterize anxiolytic drug activity: evaluation of N-methyl-D-aspartate antagonists. Life Sciences 49, PL37–PL42.[CrossRef][ISI][Medline]

Koob, G. F. (2000) Animal models of craving for ethanol. Addiction 95, S73–S81.[ISI][Medline]

Kotlinska, J. and Liljequist, S. (1996) Oral administration of glycine and polyamine receptor antagonists blocks ethanol withdrawal seizures. Psychopharmacology 127, 238–244.[CrossRef][ISI][Medline]

Kreek, M. J. and Koob, G. F. (1998) Drug dependence: stress and dysregulation of brain reward pathways. Drug and Alcohol Dependence 51, 23–47.[CrossRef][ISI][Medline]

Littleton, J. M., Lovinger, D., Liljequist, S., Ticku, R., Matsumoto, I. and Barron S. (2001) Role of polyamines and NMDA receptors in ethanol dependence and withdrawal. Alcoholism: Clinical and Experimental Research 25, 132S–136S.[CrossRef][ISI][Medline]

Malinowska, B., Napiorkowska-Pawlak, D., Pawlak, R., Buczko, W. and Gothert, M. (1999) Ifenprodil influences changes in mouse behaviour related to acute and chronic ethanol administration. European Journal of Pharmacology 377, 13–19.[CrossRef][ISI][Medline]

Mayer, S., Harris, B. R., Gibson, D. A., Blanchard, J. A., Prendergast, M. A., Holley, R. C. and Littleton, J. (2002) Acamprosate, MK-801, and ifenprodil inhibit neurotoxicity and calcium entry induced by ethanol withdrawal in organotypic slice cultures from neonatal rat hippocampus. Alcoholism: Clinical and Experimental Research 26, 1468–1478.[ISI][Medline]

McMillen, B. A., Means, L. W. and Matthews, J. D. (1998) Comparison of the alcohol-preferring P rat to the Wistar rat in behavioral tests of impulsivity and anxiety. Physiology and Behavior 63, 371–375.[CrossRef][ISI][Medline]

Meldrum, B. S. (2000) Glutamate as a neurotransmitter in the brain: review of physiology and pathology. Journal of Nutrition 130, 1007S–1015S.[ISI][Medline]

Merlo-Pich, E. and Samani, R. (1989) A two-compartment exploratory model to study anxiolytic/anxiogenic effects of drugs in the rat. Pharmacology Research 21, 595–602.

Mikolajczak, P., Okulicz-Kozaryn, I., Kaminska, E., Dyr, W. and Kostowski, W. (2001) Anxiogenic-like effect after multiple ifenprodil treatment in chronically ethanol treated rats. Behavioural Pharmacology 12 (Suppl. 1), S66.

Mikolajczak, P., Okulicz-Kozaryn, I., Kaminska, E., Niedopad, L., Polanska, A. and Gebka, J. (2002a) Effects of acamprosate and some polyamine site ligands of NMDA receptor on short-term memory in rats. European Journal of Pharmacology 444, 83–96.[CrossRef][ISI][Medline]

Mikolajczak, P., Okulicz-Kozaryn, I., Szczawinska, K., Polanska, A. and Bobkiewicz-Kozlowska, T. (2002b) Effects of multiple ifenprodil and spermidine treatment on social recognition in rats. Journal of Basic and Clinical Physiology and Pharmacology 13, 61–67.[Medline]

Moller, C., Wiklund, L., Thorsell, A., Hyytia, P. and Heilig, M. (1997) Decreased measures of experimental anxiety in rats bred for high alcohol preference. Alcoholism: Clinical and Experimental Research 21, 656–660.[ISI][Medline]

Nagy, J., Muller, F. and Laszlo, L. (2001) Cytotoxic effect of alcohol-withdrawal on primary cultures of cortical neurones. Drug and Alcohol Dependence 61, 155–162.[CrossRef][ISI][Medline]

Napiorkowska-Pawlak, D., Malinowska, B., Pawlak, R., Buczko, W. and Gothert, M. (2000) Attenuation of acute amnestic effect of ethanol by ifenprodil: comparison with ondansetron and dizocilpine. Fundamental and Clinical Pharmacology 14, 125–131.[ISI][Medline]

Narita, M., Soma, M., Narita, M., Mizoguchi, H., Tseng, L. F. and Suzuki, T. (2000) Implications of the NR2B subunit-containing NMDA receptor localized in mouse limbic forebrain in ethanol dependence. European Journal of Pharmacology 401, 191–195.[CrossRef][ISI][Medline]

Nowak, K. L., Ingraham, C. M., McKinzie, D. L., McBride, W. J., Lumeng, L., Li, T.-K. and Murphy, J. M. (2000) An assessment of novelty-seeking behavior in alcohol-preferring and -nonpreferring rats. Pharmacology, Biochemistry and Behavior 66, 113–121.[CrossRef][ISI][Medline]

Nowakowska, E., Chodera, A. and Kus, K. (1998) An anxiolyticlike effect of ondansetron disappears in oxazepam-tolerant rats. Pharmacology, Biochemistry and Behavior 59, 935–938.[CrossRef][ISI][Medline]

Nowakowska, E., Chodera, A. and Kus, K. (1999) Influence of olanzapine on cognitive functions and catalepsy in rats after single and chronic administration. Polish Journal of Pharmacology 51, 295–300.[ISI][Medline]

Okulicz-Kozaryn, I., Mikolajczak, P., Szczawinska, K. and Kaminska, E. (1999) Lack of zolpidem anxiolytic activity in comparison to diazepam effects in chronically ethanol treated rats. In Fifth International Brain Research Organization World Congress of Neuroscience, Jerusalem, July 11–15, Israel. Abstracts, p. 112.

Overstreet, D. H., Halikas, J. A., Seredenin, S. B., Kampov-Polevoy, A., Viglinskaya, I. V., Kashevskaya, O., Badishtov, B. A., Knapp, D. J., Mormede, P., Kiianmaa, K., Li, T.-K. and Rezvani, A. H. (1997) Behavioral similarities and differences among alcohol-preferring and -nonpreferring rats: confirmation by factor analysis and extension by additional groups. Alcoholism: Clinical and Experimental Research 21, 840–848.[ISI][Medline]

Poelchen, W., Knitter, H., Sieler, D., Regenthal, R., Preiss, R. and Illes, P. (2001) In vitro tolerance to inhibition by ethanol of N-methyl-D-aspartate-induced depolarization in locus coeruleus neurons of behaviorally ethanol-tolerant rats. Neurochemistry International 39, 51–58.[CrossRef][ISI][Medline]

Salimov, R. M. (1999) Different behavioral patterns related to alcohol use in rodents: a factor analysis. Alcohol 17, 157–162.[CrossRef][ISI][Medline]

Sanger, D. J. and Jackson, A. (1989) Effects of phencyclidine and other N-methyl-D-aspartate antagonists on the schedule-controlled behavior of rats. Journal of Pharmacology and Experimental Therapeutics 248, 1215–1221.[Abstract]

Sanger, D. J. and Joly, D. (1991) Effects of NMDA receptor antagonists and sigma ligands on the acquisition of conditioned fear in mice. Psychopharmacology 104, 27–34.[ISI][Medline]

Schuckit, M. A. and Hesselbrock, V. (1994) Alcohol dependence and anxiety disorders: what is the relationship? American Journal of Psychiatry 151, 1723–1734.[Abstract]

Spanagel, R., Montkowski, A., Allingham, K., Stohr, T., Shoaib, M., Holsboer, F. and Landgraf, R. (1995) Anxiety: a potential predictor of vulnerability to the initiation of ethanol self-administration. Psychopharmacology 122, 369–372.[ISI][Medline]

Stewart, R. B., Gatto, G. J., Lumeng, L., Li, T.-K. and Murphy, J. M. (1993) Comparison of alcohol preferring P and -non-preferring NP rats on test of anxiety and the anxiolytic effects of ethanol. Alcohol 10, 1–10.[CrossRef][ISI][Medline]

Stork, O., Kojima, N., Stork, S., Kume, N. and Obata, K. (2002) Resistance to alcohol withdrawal-induced behaviour in Fyn transgenic mice and its reversal by ifenprodil. Molecular Brain Research 105, 126–135.[ISI][Medline]

Wiley, J. L., Compton, A. D., Holcomb, J. D., McCallum, S. E., Varvel, S. A., Porter, J. H. and Balster, R. L. (1998) Effects of modulation of NMDA neurotransmission on response rate and duration in a conflict procedure of rats. Neuropharmacology 37, 1527–1534.[CrossRef][ISI][Medline]

Willinger, U., Lenzinger, E., Hornik, K., Fischer, G., Schonbeck, G., Aschauer, H. N. and Meszaros, K. (2002) Anxiety as a predictor of relapse in detoxified alcohol-dependent patients. Alcohol and Alcoholism 37, 609–612.[Abstract/Free Full Text]

Yamamura, T. and Shimoji, K. (1999) Subunit- and site-specific pharmacology of the NMDA receptor channel. Progress in Neurobiology 59, 279–298.[CrossRef][ISI][Medline]





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