Long-term abecarnil administration produces tolerance and withdrawal signs in the rat

Abecarnil is a non-benzodiazepine that possesses anxiolytic and anticonvulsant properties. Conflicting reports of tolerance and withdrawal signs following chronic abecarnil administration have emerged from animal studies using different species and different models of tolerance and dependence. This study used a radiotelemetric method to examine any emergence of tolerance and abstinence signs in the rat following long-term abecarnil administration. Hooded Wistar rats, n=6 per group, were administered either abecarnil (8 mg/kg/bidaily, i.p.) or vehicle for 24 days. Locomotor activity, body temperature and electromyographic (EMG) activity were measured daily immediately following abecarnil administration. Tolerance to the abecarnil-induced muscle relaxant effects and decreased locomotor activity developed within 21 days. Administration of the benzodiazepine antagonist flumazenil (25 mg/kg), 18 h after abecarnil cessation, precipitated abstinence signs that included decreases in body temperature, and large increases in locomotor activity and muscle tone. Moreover, continuous recording of these measures over the 4 days after flumazenil administration indicated a prolonged increase in daytime locomotor activity, suggestive of spontaneous withdrawal. These data support earlier findings that reported signs of tolerance during administration of abecarnil and abstinence signs following abecarnil cessation.