- Email: [email protected]
Tzschentke and Schmidt reply
L was cited but its important conclusions were not conveyed. A fact rarely raised in debates about dizocilpine is the steepness of its doseresponse curve. In the strain of rats used in our lab, dizolcipine ranges from having few behavioural effects at 0.1 mg kg21 (but nevertheless prevents sensitization when co-administered with psychomotor stimulants) to having profound and bizarre behavioural effects at 0.25 mg kg21 (yet still preventing sensitization). Clearly, this is a tool to be used cautiously, and all findings should certainly be confirmed with other classes of NMDA receptor antagonists (which we have always done). Nevertheless, early
studies with this drug provided the impetus for many subsequent behavioural and cellular studies that have now led to the realization that drug addiction should be viewed as a form of glutamate-dependent plasticity. This is an important advance, because it has opened the door to the search for glutamate-based pharmacotherapies for addiction. Thus, dizocilpine showed us the path to take, but we shouldnÕt expect it to carry us through the whole journey. It is time to move on to better and more selective drugs and see what we can learn about sensitization itself, not sensitization as it interacts with a peculiar pharmacological agent.
Tzschentke and Schmidt reply In our recent article1 we cited the paper by Gambarana et al.2 as one example of a sensitization study the results of which could be explained by state-dependency (SD) effects. These authors now argue that due to the particular design of their study the SD interpretation may not be applicable in this case. We do not claim to be experts on the topic of SD, but it is not clear to us why under the experimental conditions of Gambarana et al. the SD interpretation should not be appropriate. The core feature of SD is that retrieval of information or the performance of a learned task is impaired when expression is tested in a state different from the one under which acquisition took place. And in this context it does not make a difference whether the Ôacquisition stateÕ is acutely induced by bolus drug injections or whether it is a chronic state induced by continuous drug infusion. If the drug infusion is terminated and sufficient time for washout is allowed before expression is tested, then the state of the animal will be different, hence the requirements for possible statedependent effects are met. In fact, the authors2 themselves seem to be inclined towards an SD explanation since they write: Ô...the complete
expression of cocaine sensitization seems to depend on the state under which sensitization developed. The state effected by dizocilpine favours the expression of cocaine sensitization if sensitization is induced under dizocilpine infusion whereas the same state, induced by dizocilpine, reduces the response to cocaine if sensitization has developed under cocaine alone.Õ [our italics] (Ref. 2, p. 66). It is true that in the vast majority of studies on SD, a «state« was induced by acute drug administration, but this does not mean that SD effects only occur under these conditions. In fact, such effects have been demonstrated in cases where the Ôacquisition stateÕ was induced by chronic rather than acute drug administration (yet different from the state under which expression was tested3,4); SD has even been shown in cases where a ÔstateÕ was implemented after the training experience (F. Colpaert, pers. commun.). In our article1, we tried to make a clear distinction between dizocilpine and other classes of NMDA receptor blockers, as should have been apparent from the title. One of our aims was to reinforce the view that dizocilpine might be a very ÔatypicalÕ drug, even within the group of noncompetitive NMDA receptor antag-
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Marina E. Wolf Department of Neuroscience, FUHS/The Chicago Medical School, 3333 Green Bay Road, North Chicago, IL 60064-3095, USA.
References 1 Tzschentke, T. M. and Schmidt, W. J. (1998) Trends Pharmacol. Sci. 19, 447Ð451 2 Wolf, M. E. (1998) Prog. Neurobiol. 54, 679Ð720 3 Li, Y. and Wolf, M. E. (1999) Psychopharmacology 141, 351Ð361 4 Wolf, M. E., White, F. J. and Hu, X-T. (1994) J. Neurosci. 14, 1735Ð1745 5 Li, Y. et al. Synapse (in press) 6 Carlezon, W. A., Jr, Mendrek, A. and Wise, R. A. (1995) Synapse 20, 1Ð9 7 Wise, W. A., Mendrek, A. and Carlezon, W. A., Jr (1996) Synapse 22, 362Ð368 8 Stewart, J. and Druhan, J. P. (1993) Psychopharmacology 100, 125Ð132
onists, and that results generated with this drug may not justify broad generalizations with respect to the role of the glutamatergic system. This view has been detailed by others in this journal recently5. Dr Wolf mentioned a recent study in her lab where the competitive NMDA receptor antagonist CGS19755 was used. It was found that co-treatment with this compound prevented amphetamine sensitization during the induction phase as well as during subsequent amphetamine challenges. Unfortunately it was not mentioned whether dizocilpine was used in that study as well. If it was, we would have expected the animals to exhibit a day-to-day increase in locomotion during the induction phase but no sensitized response on a subsequent amphetamine challenge. Such a pattern of results was reported by the same group previously for morphine in combination with dizocilpine and CGS19755 (Ref. 6), highlighting the importance of NMDA-receptor activation in the development of sensitization, but also showing that dizocilpine did not block the behavioural plasticity per se during the induction phase. Nevertheless, the conclusion of most workers in the field from findings like these was not only that NMDA receptors are important for sensitization, but also that dizocilpine itself
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was able to block behavioural plasticity; this latter conclusion is, in our view, not justified by the experimental evidence. Other than the field of the neuropharmacology of glutamate and its use of dizocilpine, there are few areas of pharmacological research that have relied so heavily on the use of just one single compound to achieve a particular pharmacological effect, and it is an unfortunate fact that only a few groups have tested NMDA antagonists other than dizocilpine, the group of Dr Wolf being one of the notable exceptions. We absolutely agree with Dr Wolf in that it will be very important in the future to move on to other, ÔbetterÕ NMDA receptor antagonists that allow for an improved dissociation of pharmacological effect and side-effects. If animals that have received amphetamine plus dizocilpine during the induction phase and that do not show the cellular changes normally associated with sensitization (as shown by Dr WolfÕs group7) are challenged with amphetamine plus dizocilpine, it is very likely that they would show a strong, sensitized behavioural response (in the absence of cellular adaptations). Therefore, we cannot see why our statement that block of the cellular changes is clearly not reflected at the behavioural level should be puzzling. Of course, the very experiments that would show that this dissociation does indeed exist have not been carried out. However, the available data show that dizocilpine blocks the cellular changes, but does not block the concurrent day-to-day increase in locomotion occurring during repeated treatment and the sensitized locomotion occurring in response to a subsequent challenge with the sensitizing drug plus dizocilpine. Leaving SD or alternative interpretations aside, one could still maintain the notion that dizocilpine blocks behavioural sensitization to amphetamine or morphine (as evidenced by the lack of a sensitized response to a subsequent challenge with the sensitizing drug), but it cannot block behavioural sensitization per se, because the treatment with amphetamine or morphine plus dizocilpine can 190
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S produce very clear sensitized responses. Apparently, this may be quite different, e.g. for competitive NMDA receptor antagonists which have been shown not only to block sensitized responses to a subsequent drug challenge but also to prevent the day-to-day increases in locomotion during the induction phase6. We are sure that everybody working in the field knows about the respectability of certain groups. Nevertheless it is not quite clear to us how the conclusions from the paper by Stewart and Druhan8 are essential for our discussion. The main conclusion from this paper is that sensitization is a phenomenon which consists of a conditioned and a nonconditioned component and that both of these components can be influenced independently from each other and can also be blocked by dizocilpine. This shows that sensitization is not a simple, unitary phenomenon, and it also suggests that for both components, conditioned and non-conditioned, NMDA receptor-mediated processes are important. Of course, the findings of Stewart and Druhan8 do not fit at all with the SD hypothesis, and they are in stark contrast to the findings of another highly respected group9,10. We cannot offer an explanation for these conflicting results other than procedural differences in the experimental design, which appear to be particularly important in studies with dizocilpine. Nevertheless, this very case can serve as an interesting lesson for the ÔawkwardnessÕ of the results sometimes generated with dizocilpine and, once more, reinforces the view that one should be extremely cautious when generalizing from findings with dizocilpine, in particular with regard to the functional significance of NMDA receptor blockade in general. References 1 Tzschentke, T. M. and Schmidt, W. J. (1998) Trends Pharmacol. Sci. 19, 447Ð451 2 Gambarana, C. et al. (1998) Behav. Pharmacol. 9, 61Ð68 3 Overton, D. A. (1984) in Drugs, Neurotransmitters and Behavior (Iversen, L. L., Iversen, S. D. and Snyder, S. H., eds), pp. 59Ð127, Plenum Press
4 Weingartner, H., Murphy, D. L. and Stillman, R. C. (1978) in Stimulus Properties of Drugs: Ten Years of Progress (Colpaert, F. C. and Rosecrans, J. A., eds), pp. 445Ð453, Elsevier 5 Vanderschuren, L. J. M. J. et al. (1998) Trends Pharmacol. Sci. 19, 79Ð81 6 Jeziorski, M., White, F. J. and Wolf, M. E. (1994) Synapse 16, 137Ð147 7 Wolf, M. E., White, F. J. and Hu, X-T. (1994) J. Neurosci. 14, 1735Ð1745 8 Stewart, J. and Druhan, J. P. (1993) Psychopharmacology 110, 125Ð132 9 Wise, R. A., Mendrek, A. and Carlezon, W. A., Jr (1996) Synapse 22, 362Ð368 10 Ranaldi, R., Neklesa, T. and Wise, R. A. (1997) Soc. Neurosci. Abstr. 23, 1091
Thomas M. Tzschentke and Werner J. Schmidt Department of Neuropharmacology, University of Tübingen, Zoological Institute, Mohlstr. 54/1, 72074 Tübingen, Germany.
Chemical name CGS19755: cis-4-(phosphonomethyl)2-piperidine carboxylic acid
Note added in proof Since the submission of this letter, the paper by Li and Wolf [Li and Wolf (1999) Psychopharmacology 141, 351Ð361) has been published, in which the authors argue strongly against SD effects. Nevertheless, the basic situation remains unchanged: although there was no day-today increase in locomotion in animals receiving amphetamine plus CGP19755, there was a very clear sensitization of animals receiving amphetamine plus dizocilpine. Thus, these results confirm the differential effects of different NMDA receptor antagonists on the development of sensitization. But, because the results for dizocilpine were ÔcomplexÕ, they do not provide an explanation for the findings and do not unequivocally rule out SD effects. Li and Wolf argue that the sensitization seen in the amphetamine plus dizocilpine group might be due to sensitization to the locomotor activating effects of dizocilpine itself. Although this interpretation would explain the absence of a sensitized response to a subsequent amphetamine challenge (as the animals would be sensitized to dizocilpine but not to amphetamine) it sharply conflicts with the idea that NMDA receptor activation is necessary for the induction of sensitization, as Li and Wolf themselves suggest. This would imply that the dizocilpine-induced sensitization is independent of NMDA receptor activation.
studies with this drug provided the impetus for many subsequent behavioural and cellular studies that have now led to the realization that drug addiction should be viewed as a form of glutamate-dependent plasticity. This is an important advance, because it has opened the door to the search for glutamate-based pharmacotherapies for addiction. Thus, dizocilpine showed us the path to take, but we shouldnÕt expect it to carry us through the whole journey. It is time to move on to better and more selective drugs and see what we can learn about sensitization itself, not sensitization as it interacts with a peculiar pharmacological agent.
Tzschentke and Schmidt reply In our recent article1 we cited the paper by Gambarana et al.2 as one example of a sensitization study the results of which could be explained by state-dependency (SD) effects. These authors now argue that due to the particular design of their study the SD interpretation may not be applicable in this case. We do not claim to be experts on the topic of SD, but it is not clear to us why under the experimental conditions of Gambarana et al. the SD interpretation should not be appropriate. The core feature of SD is that retrieval of information or the performance of a learned task is impaired when expression is tested in a state different from the one under which acquisition took place. And in this context it does not make a difference whether the Ôacquisition stateÕ is acutely induced by bolus drug injections or whether it is a chronic state induced by continuous drug infusion. If the drug infusion is terminated and sufficient time for washout is allowed before expression is tested, then the state of the animal will be different, hence the requirements for possible statedependent effects are met. In fact, the authors2 themselves seem to be inclined towards an SD explanation since they write: Ô...the complete
expression of cocaine sensitization seems to depend on the state under which sensitization developed. The state effected by dizocilpine favours the expression of cocaine sensitization if sensitization is induced under dizocilpine infusion whereas the same state, induced by dizocilpine, reduces the response to cocaine if sensitization has developed under cocaine alone.Õ [our italics] (Ref. 2, p. 66). It is true that in the vast majority of studies on SD, a «state« was induced by acute drug administration, but this does not mean that SD effects only occur under these conditions. In fact, such effects have been demonstrated in cases where the Ôacquisition stateÕ was induced by chronic rather than acute drug administration (yet different from the state under which expression was tested3,4); SD has even been shown in cases where a ÔstateÕ was implemented after the training experience (F. Colpaert, pers. commun.). In our article1, we tried to make a clear distinction between dizocilpine and other classes of NMDA receptor blockers, as should have been apparent from the title. One of our aims was to reinforce the view that dizocilpine might be a very ÔatypicalÕ drug, even within the group of noncompetitive NMDA receptor antag-
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Marina E. Wolf Department of Neuroscience, FUHS/The Chicago Medical School, 3333 Green Bay Road, North Chicago, IL 60064-3095, USA.
References 1 Tzschentke, T. M. and Schmidt, W. J. (1998) Trends Pharmacol. Sci. 19, 447Ð451 2 Wolf, M. E. (1998) Prog. Neurobiol. 54, 679Ð720 3 Li, Y. and Wolf, M. E. (1999) Psychopharmacology 141, 351Ð361 4 Wolf, M. E., White, F. J. and Hu, X-T. (1994) J. Neurosci. 14, 1735Ð1745 5 Li, Y. et al. Synapse (in press) 6 Carlezon, W. A., Jr, Mendrek, A. and Wise, R. A. (1995) Synapse 20, 1Ð9 7 Wise, W. A., Mendrek, A. and Carlezon, W. A., Jr (1996) Synapse 22, 362Ð368 8 Stewart, J. and Druhan, J. P. (1993) Psychopharmacology 100, 125Ð132
onists, and that results generated with this drug may not justify broad generalizations with respect to the role of the glutamatergic system. This view has been detailed by others in this journal recently5. Dr Wolf mentioned a recent study in her lab where the competitive NMDA receptor antagonist CGS19755 was used. It was found that co-treatment with this compound prevented amphetamine sensitization during the induction phase as well as during subsequent amphetamine challenges. Unfortunately it was not mentioned whether dizocilpine was used in that study as well. If it was, we would have expected the animals to exhibit a day-to-day increase in locomotion during the induction phase but no sensitized response on a subsequent amphetamine challenge. Such a pattern of results was reported by the same group previously for morphine in combination with dizocilpine and CGS19755 (Ref. 6), highlighting the importance of NMDA-receptor activation in the development of sensitization, but also showing that dizocilpine did not block the behavioural plasticity per se during the induction phase. Nevertheless, the conclusion of most workers in the field from findings like these was not only that NMDA receptors are important for sensitization, but also that dizocilpine itself
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was able to block behavioural plasticity; this latter conclusion is, in our view, not justified by the experimental evidence. Other than the field of the neuropharmacology of glutamate and its use of dizocilpine, there are few areas of pharmacological research that have relied so heavily on the use of just one single compound to achieve a particular pharmacological effect, and it is an unfortunate fact that only a few groups have tested NMDA antagonists other than dizocilpine, the group of Dr Wolf being one of the notable exceptions. We absolutely agree with Dr Wolf in that it will be very important in the future to move on to other, ÔbetterÕ NMDA receptor antagonists that allow for an improved dissociation of pharmacological effect and side-effects. If animals that have received amphetamine plus dizocilpine during the induction phase and that do not show the cellular changes normally associated with sensitization (as shown by Dr WolfÕs group7) are challenged with amphetamine plus dizocilpine, it is very likely that they would show a strong, sensitized behavioural response (in the absence of cellular adaptations). Therefore, we cannot see why our statement that block of the cellular changes is clearly not reflected at the behavioural level should be puzzling. Of course, the very experiments that would show that this dissociation does indeed exist have not been carried out. However, the available data show that dizocilpine blocks the cellular changes, but does not block the concurrent day-to-day increase in locomotion occurring during repeated treatment and the sensitized locomotion occurring in response to a subsequent challenge with the sensitizing drug plus dizocilpine. Leaving SD or alternative interpretations aside, one could still maintain the notion that dizocilpine blocks behavioural sensitization to amphetamine or morphine (as evidenced by the lack of a sensitized response to a subsequent challenge with the sensitizing drug), but it cannot block behavioural sensitization per se, because the treatment with amphetamine or morphine plus dizocilpine can 190
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S produce very clear sensitized responses. Apparently, this may be quite different, e.g. for competitive NMDA receptor antagonists which have been shown not only to block sensitized responses to a subsequent drug challenge but also to prevent the day-to-day increases in locomotion during the induction phase6. We are sure that everybody working in the field knows about the respectability of certain groups. Nevertheless it is not quite clear to us how the conclusions from the paper by Stewart and Druhan8 are essential for our discussion. The main conclusion from this paper is that sensitization is a phenomenon which consists of a conditioned and a nonconditioned component and that both of these components can be influenced independently from each other and can also be blocked by dizocilpine. This shows that sensitization is not a simple, unitary phenomenon, and it also suggests that for both components, conditioned and non-conditioned, NMDA receptor-mediated processes are important. Of course, the findings of Stewart and Druhan8 do not fit at all with the SD hypothesis, and they are in stark contrast to the findings of another highly respected group9,10. We cannot offer an explanation for these conflicting results other than procedural differences in the experimental design, which appear to be particularly important in studies with dizocilpine. Nevertheless, this very case can serve as an interesting lesson for the ÔawkwardnessÕ of the results sometimes generated with dizocilpine and, once more, reinforces the view that one should be extremely cautious when generalizing from findings with dizocilpine, in particular with regard to the functional significance of NMDA receptor blockade in general. References 1 Tzschentke, T. M. and Schmidt, W. J. (1998) Trends Pharmacol. Sci. 19, 447Ð451 2 Gambarana, C. et al. (1998) Behav. Pharmacol. 9, 61Ð68 3 Overton, D. A. (1984) in Drugs, Neurotransmitters and Behavior (Iversen, L. L., Iversen, S. D. and Snyder, S. H., eds), pp. 59Ð127, Plenum Press
4 Weingartner, H., Murphy, D. L. and Stillman, R. C. (1978) in Stimulus Properties of Drugs: Ten Years of Progress (Colpaert, F. C. and Rosecrans, J. A., eds), pp. 445Ð453, Elsevier 5 Vanderschuren, L. J. M. J. et al. (1998) Trends Pharmacol. Sci. 19, 79Ð81 6 Jeziorski, M., White, F. J. and Wolf, M. E. (1994) Synapse 16, 137Ð147 7 Wolf, M. E., White, F. J. and Hu, X-T. (1994) J. Neurosci. 14, 1735Ð1745 8 Stewart, J. and Druhan, J. P. (1993) Psychopharmacology 110, 125Ð132 9 Wise, R. A., Mendrek, A. and Carlezon, W. A., Jr (1996) Synapse 22, 362Ð368 10 Ranaldi, R., Neklesa, T. and Wise, R. A. (1997) Soc. Neurosci. Abstr. 23, 1091
Thomas M. Tzschentke and Werner J. Schmidt Department of Neuropharmacology, University of Tübingen, Zoological Institute, Mohlstr. 54/1, 72074 Tübingen, Germany.
Chemical name CGS19755: cis-4-(phosphonomethyl)2-piperidine carboxylic acid
Note added in proof Since the submission of this letter, the paper by Li and Wolf [Li and Wolf (1999) Psychopharmacology 141, 351Ð361) has been published, in which the authors argue strongly against SD effects. Nevertheless, the basic situation remains unchanged: although there was no day-today increase in locomotion in animals receiving amphetamine plus CGP19755, there was a very clear sensitization of animals receiving amphetamine plus dizocilpine. Thus, these results confirm the differential effects of different NMDA receptor antagonists on the development of sensitization. But, because the results for dizocilpine were ÔcomplexÕ, they do not provide an explanation for the findings and do not unequivocally rule out SD effects. Li and Wolf argue that the sensitization seen in the amphetamine plus dizocilpine group might be due to sensitization to the locomotor activating effects of dizocilpine itself. Although this interpretation would explain the absence of a sensitized response to a subsequent amphetamine challenge (as the animals would be sensitized to dizocilpine but not to amphetamine) it sharply conflicts with the idea that NMDA receptor activation is necessary for the induction of sensitization, as Li and Wolf themselves suggest. This would imply that the dizocilpine-induced sensitization is independent of NMDA receptor activation.