Abstract
A dextromethorphan (3-methoxy-17-methylmorphinan) analog, dimemorfan (3-methyl-N-methylmorphinan) that is not metabolized to dextrorphan [3-hydroxy-17-methylmorphinan, which induces phencyclidine (PCP)-like behavioral effects], attenuates maximal electroshock seizures. However, the pharmacological mechanism of action of dimemorfan remains to be determined. In this study, we assessed the locomotor activity mediated by these morphinans. Circling behavior was pronounced in mice treated with PCP or dextrorphan, while animals treated with dextromethorphan exhibited moderate behaviors. Dimemorfan did not show any significant behavioral effects. We used BAY k-8644 (an L-type Ca 2+ channel agonist in the dihydropyridine class) to explore the effects of dextromethorphan and dimemorfan on the convulsant activity regulated by calcium channels. Intracerebroventricular injection of BAY k-8644 (37.5μg) significantly induced seizures in mice. As with dextromethorphan (6.25 or 12.5mg/kg), dimemorfan (6.25 or 12.5mg/kg) pretreatment significantly attenuated BAY k-8644-induced seizures in a dose-dependent manner. BAY k-8644-induced seizure activity paralleled increased expression of c-fos and c-jun, AP-1 DNA binding activity, and fos-related antigen immunoreactivity. Pretreatment with dextromethorphan or dimemorfan significantly attenuated the expression induced by BAY k-8644. Therefore, our results suggest that the anticonvulsant effects of dextromethorphan and dimemorfan are mediated, at least in part, via L-type calcium channel, and that dimemorfan is equipotent to dextromethorphan in preventing BAY k-8644-induced seizures, while it lacks behavioral side effects related to psychotomimetic reactions.
| Original language | English |
|---|---|
| Pages (from-to) | 267-276 |
| Number of pages | 10 |
| Journal | Behavioural Brain Research |
| Volume | 151 |
| Issue number | 1-2 |
| DOIs | |
| Publication status | Published - 2004 May 5 |
| Externally published | Yes |
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Keywords
- AP-1 DNA binding activity
- BAY k-8644
- c-fos
- c-jun
- Dextromethorphan
- Dimemorfan
- fos-related antigen
- Phencyclidine-like behavior
ASJC Scopus subject areas
- Behavioral Neuroscience
Cite this
Dimemorfan prevents seizures induced by the L-type calcium channel activator BAY k-8644 in mice. / Shin, Eun Joo; Nabeshima, Toshitaka; Lee, Phil Ho; Kim, Won-Ki; Ko, Kwang Ho; Jhoo, Jin Hyeong; Jhoo, Wang Kee; Cha, Joo Young; Kim, Hyoung Chun.
In: Behavioural Brain Research, Vol. 151, No. 1-2, 05.05.2004, p. 267-276.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Dimemorfan prevents seizures induced by the L-type calcium channel activator BAY k-8644 in mice
AU - Shin, Eun Joo
AU - Nabeshima, Toshitaka
AU - Lee, Phil Ho
AU - Kim, Won-Ki
AU - Ko, Kwang Ho
AU - Jhoo, Jin Hyeong
AU - Jhoo, Wang Kee
AU - Cha, Joo Young
AU - Kim, Hyoung Chun
PY - 2004/5/5
Y1 - 2004/5/5
N2 - A dextromethorphan (3-methoxy-17-methylmorphinan) analog, dimemorfan (3-methyl-N-methylmorphinan) that is not metabolized to dextrorphan [3-hydroxy-17-methylmorphinan, which induces phencyclidine (PCP)-like behavioral effects], attenuates maximal electroshock seizures. However, the pharmacological mechanism of action of dimemorfan remains to be determined. In this study, we assessed the locomotor activity mediated by these morphinans. Circling behavior was pronounced in mice treated with PCP or dextrorphan, while animals treated with dextromethorphan exhibited moderate behaviors. Dimemorfan did not show any significant behavioral effects. We used BAY k-8644 (an L-type Ca 2+ channel agonist in the dihydropyridine class) to explore the effects of dextromethorphan and dimemorfan on the convulsant activity regulated by calcium channels. Intracerebroventricular injection of BAY k-8644 (37.5μg) significantly induced seizures in mice. As with dextromethorphan (6.25 or 12.5mg/kg), dimemorfan (6.25 or 12.5mg/kg) pretreatment significantly attenuated BAY k-8644-induced seizures in a dose-dependent manner. BAY k-8644-induced seizure activity paralleled increased expression of c-fos and c-jun, AP-1 DNA binding activity, and fos-related antigen immunoreactivity. Pretreatment with dextromethorphan or dimemorfan significantly attenuated the expression induced by BAY k-8644. Therefore, our results suggest that the anticonvulsant effects of dextromethorphan and dimemorfan are mediated, at least in part, via L-type calcium channel, and that dimemorfan is equipotent to dextromethorphan in preventing BAY k-8644-induced seizures, while it lacks behavioral side effects related to psychotomimetic reactions.
AB - A dextromethorphan (3-methoxy-17-methylmorphinan) analog, dimemorfan (3-methyl-N-methylmorphinan) that is not metabolized to dextrorphan [3-hydroxy-17-methylmorphinan, which induces phencyclidine (PCP)-like behavioral effects], attenuates maximal electroshock seizures. However, the pharmacological mechanism of action of dimemorfan remains to be determined. In this study, we assessed the locomotor activity mediated by these morphinans. Circling behavior was pronounced in mice treated with PCP or dextrorphan, while animals treated with dextromethorphan exhibited moderate behaviors. Dimemorfan did not show any significant behavioral effects. We used BAY k-8644 (an L-type Ca 2+ channel agonist in the dihydropyridine class) to explore the effects of dextromethorphan and dimemorfan on the convulsant activity regulated by calcium channels. Intracerebroventricular injection of BAY k-8644 (37.5μg) significantly induced seizures in mice. As with dextromethorphan (6.25 or 12.5mg/kg), dimemorfan (6.25 or 12.5mg/kg) pretreatment significantly attenuated BAY k-8644-induced seizures in a dose-dependent manner. BAY k-8644-induced seizure activity paralleled increased expression of c-fos and c-jun, AP-1 DNA binding activity, and fos-related antigen immunoreactivity. Pretreatment with dextromethorphan or dimemorfan significantly attenuated the expression induced by BAY k-8644. Therefore, our results suggest that the anticonvulsant effects of dextromethorphan and dimemorfan are mediated, at least in part, via L-type calcium channel, and that dimemorfan is equipotent to dextromethorphan in preventing BAY k-8644-induced seizures, while it lacks behavioral side effects related to psychotomimetic reactions.
KW - AP-1 DNA binding activity
KW - BAY k-8644
KW - c-fos
KW - c-jun
KW - Dextromethorphan
KW - Dimemorfan
KW - fos-related antigen
KW - Phencyclidine-like behavior
UR - http://www.scopus.com/inward/record.url?scp=16544393829&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=16544393829&partnerID=8YFLogxK
U2 - 10.1016/j.bbr.2003.09.004
DO - 10.1016/j.bbr.2003.09.004
M3 - Article
VL - 151
SP - 267
EP - 276
JO - Behavioural Brain Research
JF - Behavioural Brain Research
SN - 0166-4328
IS - 1-2
ER -