Background: Many antidepressants are effective in alleviating ethanol withdrawal symptoms. However, most
of them suppress rapid eye movement (REM) sleep. Thus, development of antidepressants without undesirable
side effects would be preferable. Previously, crude alkaloid extract from Mitragyna speciosa (MS) Korth
was found to produce antidepressant activities. It was hypothesized that the alkaloid extract from MS may
attenuate ethanol withdrawal without REM sleep disturbance.
Methods: Adult male Wistar rats implanted with electrodes over the frontal and parietal cortices were used
for two separated studies. For an acute study, 10 mg/kg fluoxetine or 60 mg/kg alkaloid extract from MS were
administered intragastrically. Electroencephalographic (EEG) signals were recorded for 3 h to examine sleep
profiles and EEG fingerprints. Another set of animal was used for an ethanol withdrawal study. They were
rendered dependent on ethanol via a modified liquid diet (MLD) containing ethanol ad libitum for 28 days.
On day 29, fluoxetine (10 mg/kg) or alkaloid extract from MS (60 mg/kg) were administered 15 min before
the ethanol-containing MLD was replaced with an isocaloric ethanol-free MLD to induced ethanol withdrawal
symptoms.
Results: The sleep analysis revealed that alkaloid extract from MS did not change any REM parameters which
included average duration of each REM episode, total REM time, number of REM episode and REM latency
whereas fluoxetine significantly suppressed all REM parameters and delayed REM latency. However, power
spectral analysis revealed similar fingerprints for fluoxetine and alkaloid extract from MS characterized by
decreasing powers in the slow frequency range in frontal and parietal cortical EEG. Neither treatment affected
spontaneous motor activity. Finally, both alkaloid extract from MS and fluoxetine were found to significantly
attenuate ethanol withdrawal-induced hyperexcitability (increases gamma activity) in both cortices and to
reduce locomotor activity.
Conclusion: The present study demonstrated that the alkaloid extract from MS alleviates ethanol withdrawal
severity with no side effect on REM sleep. In addition, these data suggest that suppressive effects on slow
frequency powers but not REM sleep may be hallmarks of effective antidepressants for ethanol withdrawal
treatmen