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Neuromodulatory effects of dextromethorphan: role of NMDA receptors in responses
TiPS - April 2990 [Vol. 1 II
146 The most impressive and extensive group of secondary metabelites resulting from decarboxyl-
ation are the alkaloids. Most of this disparate group probably serve as plant defenses, their formation consti~ting one of the mechanisms whereby the highly successful angiosperms evolved in the face of predation by large bacterial viral, animals and and fungal onslaughts. The mammalian pharmacology of alkaloids is extensive; it is difficult to think of an alkaloid lacking in activity (Table III). Carboxylation and decarboxylation - these two processes, so simple in principle, have shaped and determined the respective
disc:plines
and
of biochemistry
pharmacology. 8.
MAX
References 1 winter, c. c. (1981) j. L&of. 125,212 2 Wasmer, 1. MM.,Carrion, H. M., Mekras, G. and Po&ano, V. A. (1981) J. UroI. 125, 204-207 3 Bafios, J. E., Bosch, F. and Far& M. (1989) Med. Toxicol. Adverse Dru.q Exper. 4,464 4 Starmers, A. and Colin-Jones, D. (1984) Latxrf ii, 978 5 Brindiey, G. S. (1983) Br. J. Ps~c;~iat~ 143,332-337 6 Krane, R. J., Goldstein, I. and Saenz de Tejada. I. (1989) N. Eql. I. Med. 321, 1648-1659 7 Ne!!ans, R. E., ELIis, L. R. and KramerLevien, D. (1987) J. Ural. 138, 52-54 8 Michal. V., Kramer, R., F’opischai,J. and
_ETTERS Dextromethoxphan, dysphoria and NMDA receptors
Neuromodulatoryeffects of dextromethorphan: role of NMDA receptors in responses I read with interest the recent article by Tortella and colleagues (Tips, December 1989)’ conceming the central actions of dextromethorphan. I agree with many of their points, but others require comment. Firstly, the authors’ statement that dextromethorphan is not psychotomimetic in humans is not supported by the literature. In addition to anecdotal reports of hallucinations following overdoses of proprietary cough medicines containing dextromethorphan, sporadic cases of dextromethorphan abuse in which patients reported dysphoric symptoms have been documented* and Jasinski et al. reported ‘defiiiiie subjective effects of a psychotomimetic nature’ (see references in Ref. 3). Behavioural similarities are also evident in animal studies, where dextromethorphan shares disc~minative effects with other PCP receptor Iigands’ at doses related closely to those that reduce NMDA receptor-mediated neuronal excitations in uivo5. Rather __._~
than being a possible ‘psychotomimetic antagonist’ (Ref. l), dextromethorphan therefore appears to share the adverse dysphoric effects of other PCP-like NMDA receptor antagonists’. Secondly, the authors ascribe a functionally important role to high affinity dextromethorphan and/or o-binding sites in the behavioural pharmacology of dextromethorphan. However, in the absence of a selective antagonist for the dextromethorphan (or a-) site, the establishment of a clear rank order potency for binding to these sites is necessary before one can infer, even indirectly, the possibility of a causal relationship between an action at either site and behavioural effects. Indeed, binding and behavioural data are available for only a limited series of o- OT dextromethorphan receptor ligands. Similarly, it would appear unwise to attempt to differentiate between the binding properties and the pharmacology in viva of dextromethorphan and a-si.te ligands on the basis of data
Hejhai, L. (1977) World 1. Szrrg.1,515 9 Brindley. G. S. (1984) Lmtcef ii, 220-221 10 Lansky, M. R. and Seizer, J. (1984) J. Clir~. Psyclriafry 45, 232-233 11 Aloi, J. A., Insel, T. R., Mueller, E. A. and Murphy, D. L. (1984) Life Sci. 34, 1325-1331 12 Burke, 8. J,, Smith, P. J. B., Scott, G. L. and Wakerley, 6. R. (1983) ~osfgrad. Med. f. 59,332-333 13 Markwardt, F. and Landmann, H. (1971) Hn,rdb. Exp. Pharmncol. 27, 76-142 14 Wallis, R. B. (1988) Trends Phnrmncol. Sci. 9, 425-427 15 Markwardt, F. et al. (198s) Pharnrazie43, 202-207 16 Nutt, E. rf ~1. (1988) J. Biol. Ckenr. 263, 1016%10167 17 Max, B. (1987) Trends Phnmmcol. Sci. 8, 290-292 18 Davies, R. (1989) The Lyre of Orphees, Viking 19 Webb, E. C., ed. (1984) Enzyme Nonlencfafure 1984, Academic Press
obtained with a small number of non-selective compounds. For example, as well as having affinity for the high affinity u site (Ref. I), (+)-SKF10047 [together with the (+)-isomers of other benzomorphans including pentazocine and cyclazocine] has affinity for the PCP receptor; all these drugs act as PCP-like interoceptive cues in animal studies; and all reduce neuronal excitations evoked by NMDA with a rank order of potency that by and large parallels their known behavioural effects5,‘. To use the observation that (+)SKF10047 is a more potent anticonvulsant but has less affinity for the o-site than (+)-pentazocine, to infer differences in the functional roles of high affinity dextromethorphan or u-sites may lead to misunderstandings. An equally tenable explanation is that (+)-SKF10047 is a more potent NMDA antagonist than (+)-pentazocine5. Thirdly, I cannot agree with mentioned the ‘inconsistencies’ regarding the role of NMDA antagonism in the pharmacology of dextromethorphan. The finding that NMDA receptor ligands fail to compete with the dextromethorphan site, for example, would only assume importance if this site mediated the NMDA antagonist effects of dextromethorphan. Similarly, that dextrorphan does not eompete for the high affinity dextromethorphan site whilst being anticonvulsant should cast doubt on the functional relevance of this site in
TiPS - April 1990 [Vol. 1 l] anticonvulsant modulating activity rather than being thought of as an inconsistency in its proposed pharmacological role. Finally, the finding that dextromethorphan receptor ligands are able to reduce the K+-stimulated efflux of “Rb+ in rat cortical synaptosomes’, an effect not shared consistently by PCP or NMDA receptor ligands, again only assumes significance if this action is important to the behavioural effects of the drugs. Blockade of voltage-regulated K+ channels would be expected to promote epileptiform activity: the fact that dextromethorphan receptor ligands block a K+ conductance and yet are anticonvulsant suggests that this effect, which might be mediated by the dextromethorphan receptor, is unlikely to make a major contribution to their established behavioural actions’. I agree with Tortella et nl. that NMDA receptor antagonism aione is unlikely to be able to account fully for : 11of the pharmacological effects of dextromethorphan given its low potency both in vi& and in vitro? in this respect. However, this does not mean that NMDA receptor antagonism is not relevant at least to some of its actions, particularly given the established importance of NMDA receptormediated events in the pathophysiology of convulsive and neurodegenerative phenomena, and it should not allow a functional role for dextromethorphan or o-binding sites in the central pharmacology of dextromethorphan to be established by default. JOHN CHURCH
References 1 Tortella, F. 2 3 4 5
6 7 8
C., Pellicano, M. and Bowery, N. C. (1989) Trmds Phmmol. Sci. 10, 501-507 Degwitz, R. (1964) Ncrrrcm~rzf 35,412-414 Witkin, J. M. and Tortella, F. C. (1989) Drug Dcu. Rcs. 18, 57-65 Holtzman, S. G. (1982) Psyrho~hnnttncolopy 77, 295-300 I odge, D. cf nl. (1988) in Ercitnfor!y Amino Acids iu Hcnlth RIIII Disrnsc (Lodge, D., ed.), pp. 237-259, John Wiley and Sons Church, J. et RI. (1989) Gnu. /. Plr!ysio/. Plznrsrncof. 67, 561-567 Aram, ). A. ct nl. (1989) 1. Pknrtvnrol. Exp. T/w. 248, 320-328 Fletcher, E. 1. cl nl. (1989) Neuropknrmcolopy 28, 661-666
PCP: phencyclidine SKF10047: (+)-N-allylnormetazocine
147
Tortella and Bowery reply: We wouid like to make the following brief points in reply to the above letter. @ It is our contention that at present the small amount of preclinical and clinical evidence supporting psychotomimetic actions of dextromethorphan is not at all convincing. Thus, as reported by Degwitz’ and Frase?, the primary subjective responses associated with 1200-1500 mg doses of dextromethorphan are symptoms of drunkenness, con&fusion, slurred speech and a general dysphoria. The only instance of actual psychotomimesis, i.e. hallucinogenic/ delusional behavior, associated with these high doses of dextromethorphan occurred in a single ‘morphine-abstinent’ patient. To keep this in perspective, one must recognize that in these studies the doses of dexiromethorphan were approximately 100 times the recommended antitussive dose! How this relates to the anticonvulsant dose in humans remains to be determined. o The statement by Church that dextromethorphan ‘shnres discrin~inative effects with oth:*r FCP receptor Iigands’ also fails to depict the reported literature accurately. While it is true Holtzman3 showed ?CP-like discrimination for dextromethorphan in the squirrei monkey, he earlier reported” that it failed to discriminate to PCP in the rat. In citing this earlier study, Holtzman3 concluded that ‘dextromethorphan had only zoeak activity as a PCP-like discriminative stimuhs in the monkey, and almost no activity irz the rat’. o It may be too soon to ascribe unequivocally a functional role to the dextromethorphan-o-receptor, but surely it is appropriate to attempt a correlation of the rank order of selectivity for these sites relative to the PCP-NMDA site with their in-vivo CNS pharmacology. The explanation offered by Church to explain the anticonvulsant actions of (+)-SKFlOU47 is not unlike that proposed in our review. We ascribe this effect to the PCP,-NMDA-linked receptor complex since (+)-SKF10047 has been shown to have relatively high affinity for this site.
* We are surprised that Church does not agree with the inconsistencies in NMDA antagonism since, as he points out, dextromethorphan exhibits extremely low activity irl viva and irr vitro as an NMDA antagonist, and others have shown that the dextromethorphan-site ligands caramiphen and carbetapentane (also anticonvulsants) are completely inactive at NMDA receptorss. Furthermore, to suggest that the fact that dextrorphan (the metabolite of dextromethorphan) does not compete for the dextromethorphan binding site ‘should cnst doubt on the functional relevance of the site’ is irrelevant. This would be equivalent to assuming that dopamine and its metabolite noradrenaline act at the same site. 0 The observations concerning K+-stimulated Rb+ efflux may or may not be important in the actions of dextromethorphan (ditto for Ca”) but they cannot be excluded simply by stating that blockade of voltage-sensitive K+ channels would produce epileptiform activity rather than anticonvulsanl activity. K’ channel blockade with compounds such as TEA does not necessarily produce epileptiform activity’. Whether any of these observed effects of dexlromethorphan on ion channels, permeability, etc. bears directly on its anticonvulsant/ mechanism of neuroprotective action awaits further study. HOWever, we would like to think that rather than reflecting ‘inconsistencies’ the possibilities raised by our original comments concerning ion channels and non-synaptic alterrepresent mechanisms natives to established dogma. FRANK AND
NORMAN
References 1 Degwitz,R (1964)
C. G.
TORTELLA BOWERY*
Neroonmt35.412~14 2 Fraser, H. F. t-t nl. (I%13 /. Phnrmml. Erp. T/w. 133, 371-387 3 Holtzman, S. G. (1982) Psyc~ioylfnr~t10colqyjy 77, 295-300 4 Holtzman, ‘3. G. (1980) /. Pknmmcol. Exp. Ther. 214, 614-619 5 Aram, J, pt ~1. (1989) /. f’knnt117~0/.Exp. Thrr. 248, 320-328 6 Storm, J. (1987) /. Pkysiol. 385, 733-759
146 The most impressive and extensive group of secondary metabelites resulting from decarboxyl-
ation are the alkaloids. Most of this disparate group probably serve as plant defenses, their formation consti~ting one of the mechanisms whereby the highly successful angiosperms evolved in the face of predation by large bacterial viral, animals and and fungal onslaughts. The mammalian pharmacology of alkaloids is extensive; it is difficult to think of an alkaloid lacking in activity (Table III). Carboxylation and decarboxylation - these two processes, so simple in principle, have shaped and determined the respective
disc:plines
and
of biochemistry
pharmacology. 8.
MAX
References 1 winter, c. c. (1981) j. L&of. 125,212 2 Wasmer, 1. MM.,Carrion, H. M., Mekras, G. and Po&ano, V. A. (1981) J. UroI. 125, 204-207 3 Bafios, J. E., Bosch, F. and Far& M. (1989) Med. Toxicol. Adverse Dru.q Exper. 4,464 4 Starmers, A. and Colin-Jones, D. (1984) Latxrf ii, 978 5 Brindiey, G. S. (1983) Br. J. Ps~c;~iat~ 143,332-337 6 Krane, R. J., Goldstein, I. and Saenz de Tejada. I. (1989) N. Eql. I. Med. 321, 1648-1659 7 Ne!!ans, R. E., ELIis, L. R. and KramerLevien, D. (1987) J. Ural. 138, 52-54 8 Michal. V., Kramer, R., F’opischai,J. and
_ETTERS Dextromethoxphan, dysphoria and NMDA receptors
Neuromodulatoryeffects of dextromethorphan: role of NMDA receptors in responses I read with interest the recent article by Tortella and colleagues (Tips, December 1989)’ conceming the central actions of dextromethorphan. I agree with many of their points, but others require comment. Firstly, the authors’ statement that dextromethorphan is not psychotomimetic in humans is not supported by the literature. In addition to anecdotal reports of hallucinations following overdoses of proprietary cough medicines containing dextromethorphan, sporadic cases of dextromethorphan abuse in which patients reported dysphoric symptoms have been documented* and Jasinski et al. reported ‘defiiiiie subjective effects of a psychotomimetic nature’ (see references in Ref. 3). Behavioural similarities are also evident in animal studies, where dextromethorphan shares disc~minative effects with other PCP receptor Iigands’ at doses related closely to those that reduce NMDA receptor-mediated neuronal excitations in uivo5. Rather __._~
than being a possible ‘psychotomimetic antagonist’ (Ref. l), dextromethorphan therefore appears to share the adverse dysphoric effects of other PCP-like NMDA receptor antagonists’. Secondly, the authors ascribe a functionally important role to high affinity dextromethorphan and/or o-binding sites in the behavioural pharmacology of dextromethorphan. However, in the absence of a selective antagonist for the dextromethorphan (or a-) site, the establishment of a clear rank order potency for binding to these sites is necessary before one can infer, even indirectly, the possibility of a causal relationship between an action at either site and behavioural effects. Indeed, binding and behavioural data are available for only a limited series of o- OT dextromethorphan receptor ligands. Similarly, it would appear unwise to attempt to differentiate between the binding properties and the pharmacology in viva of dextromethorphan and a-si.te ligands on the basis of data
Hejhai, L. (1977) World 1. Szrrg.1,515 9 Brindley. G. S. (1984) Lmtcef ii, 220-221 10 Lansky, M. R. and Seizer, J. (1984) J. Clir~. Psyclriafry 45, 232-233 11 Aloi, J. A., Insel, T. R., Mueller, E. A. and Murphy, D. L. (1984) Life Sci. 34, 1325-1331 12 Burke, 8. J,, Smith, P. J. B., Scott, G. L. and Wakerley, 6. R. (1983) ~osfgrad. Med. f. 59,332-333 13 Markwardt, F. and Landmann, H. (1971) Hn,rdb. Exp. Pharmncol. 27, 76-142 14 Wallis, R. B. (1988) Trends Phnrmncol. Sci. 9, 425-427 15 Markwardt, F. et al. (198s) Pharnrazie43, 202-207 16 Nutt, E. rf ~1. (1988) J. Biol. Ckenr. 263, 1016%10167 17 Max, B. (1987) Trends Phnmmcol. Sci. 8, 290-292 18 Davies, R. (1989) The Lyre of Orphees, Viking 19 Webb, E. C., ed. (1984) Enzyme Nonlencfafure 1984, Academic Press
obtained with a small number of non-selective compounds. For example, as well as having affinity for the high affinity u site (Ref. I), (+)-SKF10047 [together with the (+)-isomers of other benzomorphans including pentazocine and cyclazocine] has affinity for the PCP receptor; all these drugs act as PCP-like interoceptive cues in animal studies; and all reduce neuronal excitations evoked by NMDA with a rank order of potency that by and large parallels their known behavioural effects5,‘. To use the observation that (+)SKF10047 is a more potent anticonvulsant but has less affinity for the o-site than (+)-pentazocine, to infer differences in the functional roles of high affinity dextromethorphan or u-sites may lead to misunderstandings. An equally tenable explanation is that (+)-SKF10047 is a more potent NMDA antagonist than (+)-pentazocine5. Thirdly, I cannot agree with mentioned the ‘inconsistencies’ regarding the role of NMDA antagonism in the pharmacology of dextromethorphan. The finding that NMDA receptor ligands fail to compete with the dextromethorphan site, for example, would only assume importance if this site mediated the NMDA antagonist effects of dextromethorphan. Similarly, that dextrorphan does not eompete for the high affinity dextromethorphan site whilst being anticonvulsant should cast doubt on the functional relevance of this site in
TiPS - April 1990 [Vol. 1 l] anticonvulsant modulating activity rather than being thought of as an inconsistency in its proposed pharmacological role. Finally, the finding that dextromethorphan receptor ligands are able to reduce the K+-stimulated efflux of “Rb+ in rat cortical synaptosomes’, an effect not shared consistently by PCP or NMDA receptor ligands, again only assumes significance if this action is important to the behavioural effects of the drugs. Blockade of voltage-regulated K+ channels would be expected to promote epileptiform activity: the fact that dextromethorphan receptor ligands block a K+ conductance and yet are anticonvulsant suggests that this effect, which might be mediated by the dextromethorphan receptor, is unlikely to make a major contribution to their established behavioural actions’. I agree with Tortella et nl. that NMDA receptor antagonism aione is unlikely to be able to account fully for : 11of the pharmacological effects of dextromethorphan given its low potency both in vi& and in vitro? in this respect. However, this does not mean that NMDA receptor antagonism is not relevant at least to some of its actions, particularly given the established importance of NMDA receptormediated events in the pathophysiology of convulsive and neurodegenerative phenomena, and it should not allow a functional role for dextromethorphan or o-binding sites in the central pharmacology of dextromethorphan to be established by default. JOHN CHURCH
References 1 Tortella, F. 2 3 4 5
6 7 8
C., Pellicano, M. and Bowery, N. C. (1989) Trmds Phmmol. Sci. 10, 501-507 Degwitz, R. (1964) Ncrrrcm~rzf 35,412-414 Witkin, J. M. and Tortella, F. C. (1989) Drug Dcu. Rcs. 18, 57-65 Holtzman, S. G. (1982) Psyrho~hnnttncolopy 77, 295-300 I odge, D. cf nl. (1988) in Ercitnfor!y Amino Acids iu Hcnlth RIIII Disrnsc (Lodge, D., ed.), pp. 237-259, John Wiley and Sons Church, J. et RI. (1989) Gnu. /. Plr!ysio/. Plznrsrncof. 67, 561-567 Aram, ). A. ct nl. (1989) 1. Pknrtvnrol. Exp. T/w. 248, 320-328 Fletcher, E. 1. cl nl. (1989) Neuropknrmcolopy 28, 661-666
PCP: phencyclidine SKF10047: (+)-N-allylnormetazocine
147
Tortella and Bowery reply: We wouid like to make the following brief points in reply to the above letter. @ It is our contention that at present the small amount of preclinical and clinical evidence supporting psychotomimetic actions of dextromethorphan is not at all convincing. Thus, as reported by Degwitz’ and Frase?, the primary subjective responses associated with 1200-1500 mg doses of dextromethorphan are symptoms of drunkenness, con&fusion, slurred speech and a general dysphoria. The only instance of actual psychotomimesis, i.e. hallucinogenic/ delusional behavior, associated with these high doses of dextromethorphan occurred in a single ‘morphine-abstinent’ patient. To keep this in perspective, one must recognize that in these studies the doses of dexiromethorphan were approximately 100 times the recommended antitussive dose! How this relates to the anticonvulsant dose in humans remains to be determined. o The statement by Church that dextromethorphan ‘shnres discrin~inative effects with oth:*r FCP receptor Iigands’ also fails to depict the reported literature accurately. While it is true Holtzman3 showed ?CP-like discrimination for dextromethorphan in the squirrei monkey, he earlier reported” that it failed to discriminate to PCP in the rat. In citing this earlier study, Holtzman3 concluded that ‘dextromethorphan had only zoeak activity as a PCP-like discriminative stimuhs in the monkey, and almost no activity irz the rat’. o It may be too soon to ascribe unequivocally a functional role to the dextromethorphan-o-receptor, but surely it is appropriate to attempt a correlation of the rank order of selectivity for these sites relative to the PCP-NMDA site with their in-vivo CNS pharmacology. The explanation offered by Church to explain the anticonvulsant actions of (+)-SKFlOU47 is not unlike that proposed in our review. We ascribe this effect to the PCP,-NMDA-linked receptor complex since (+)-SKF10047 has been shown to have relatively high affinity for this site.
* We are surprised that Church does not agree with the inconsistencies in NMDA antagonism since, as he points out, dextromethorphan exhibits extremely low activity irl viva and irr vitro as an NMDA antagonist, and others have shown that the dextromethorphan-site ligands caramiphen and carbetapentane (also anticonvulsants) are completely inactive at NMDA receptorss. Furthermore, to suggest that the fact that dextrorphan (the metabolite of dextromethorphan) does not compete for the dextromethorphan binding site ‘should cnst doubt on the functional relevance of the site’ is irrelevant. This would be equivalent to assuming that dopamine and its metabolite noradrenaline act at the same site. 0 The observations concerning K+-stimulated Rb+ efflux may or may not be important in the actions of dextromethorphan (ditto for Ca”) but they cannot be excluded simply by stating that blockade of voltage-sensitive K+ channels would produce epileptiform activity rather than anticonvulsanl activity. K’ channel blockade with compounds such as TEA does not necessarily produce epileptiform activity’. Whether any of these observed effects of dexlromethorphan on ion channels, permeability, etc. bears directly on its anticonvulsant/ mechanism of neuroprotective action awaits further study. HOWever, we would like to think that rather than reflecting ‘inconsistencies’ the possibilities raised by our original comments concerning ion channels and non-synaptic alterrepresent mechanisms natives to established dogma. FRANK AND
NORMAN
References 1 Degwitz,R (1964)
C. G.
TORTELLA BOWERY*
Neroonmt35.412~14 2 Fraser, H. F. t-t nl. (I%13 /. Phnrmml. Erp. T/w. 133, 371-387 3 Holtzman, S. G. (1982) Psyc~ioylfnr~t10colqyjy 77, 295-300 4 Holtzman, ‘3. G. (1980) /. Pknmmcol. Exp. Ther. 214, 614-619 5 Aram, J, pt ~1. (1989) /. f’knnt117~0/.Exp. Thrr. 248, 320-328 6 Storm, J. (1987) /. Pkysiol. 385, 733-759