Effect of Sumatriptan on Cortical 5-ht1b Receptors in Rat Brain

Sumatriptan is a novel and highly effective drug against migraine and cluster headache attacks. The drug is known to exert its effect through the modulation of serotonin (5-HT)mediated neurotransmission. 5-HT1B receptors in rats and 5-HT1D receptors in humans have been thought to be likely targets of sumatriptan. In the present study the effect of varying dose and duration of sumatriptan on the density of 5-HT1B receptors in the rat cortex were studied to understand its mechanism of action. Sprague Dawley rats were administered with different doses of sumatriptan (0.2-16 mg /kg body wt, i.p.) for seven days and 2, 4 and 8 mg/kg of sumatriptan for 7, 14 and 21 days. The radioligand binding assays were performed in cortical membranes using [3H]5-HT. Treatment with different doses of sumatriptan for seven days showed a significant (p<0.0001) downregulation of 5-HT1B receptors in a dose dependent manner. A significant decrease in the density of 5-HT1B receptors was observed with 0.2 mg (45%), 0.5 mg (72%) and 1 mg (70%) of sumatriptan treatment, with a significant decrease (p<0.0001) in Kd values. No further decrease in either the density or in the Kd values was observed with increasing doses of sumatriptan from 2 to 16 mg/kg body wt. The magnitude of decrease in the receptor density was more significant with a lower dose (2 mg) of sumatriptan for a prolonged period of exposure (21 days). However, such change was not observed with higher doses (4 and 8 mg/kg). Furthermore, sumatriptan showed a higher affinity for 5-HT1B receptors with a Ki value of 9.4+0.9 nM, when compared to other agonists and antagonists. Taken together, these findings suggest that desensitization of 5-HT1B receptor is dose and time dependent, which may be an important factor underlying the mechanism of action of sumatriptan as an antimigraine drug.