Previous studies have focused on gastric dysmotility and delayed emptying in diabetes mellitus. There is little information about the effects of hyperglycemia on colonic motility and secretion. 5-HT was reported to mediate contractile activity by activating receptors on both enteric neurons and smooth muscle cells. The aim of this study was to investigate and compare the effects of 5-HT on circular contractile activity coordinated with secretion in streptozocin-induced diabetic and non-diabetic rats. Sonomicrometry and voltage clamping techniques were used to measure motility and secretion simultaneously in isolated whole thickness colonic sheets. Male Sprague Dawley rats were injected with streptozocin (65 mg/kg body weight) in 0.1 M sodium citrate buffer, into the tail veins. Glucose levels of 300-400 mg/dl and above were achieved. The control rats were injected with the same volumes of vehicle (0.1 M sodium citrate buffer). Animals were sacrificed 10-12 days following the induction of hyperglycemia. Flat sheets of colon were mounted serosal side up in Ussing chambers. 1 mm piezocrystals were glued to the serosal surface 4-5 mm apart to measure circular contractions as decrease in inter-crystal distances (ICD). Voltage-clamping the tissues at 0 mV was used ix to measure short circuit current (Isc), indicative of chloride secretion. In diabetic rats 50 gM 5-HT caused mean amplitude of contractions of 174 ± 26 gm (n=4), which was significantly reduced as compared to the response in non-diabetic rats of 970 + 243 gm (n=4; p<0.05). The secretory response in diabetic rats paralleled the reduction in ICD (diabetic: 23 +1 gA/cm2, controls: 57 + 18 gA/cm2). Neural blockade with 0.1 gM TTX revealed a decreased myogenic contractile activity in diabetic rats. The mean amplitude of contractions after TTX in diabetic rats was 162 ± 45 gm verses controls of 612 ± 86 gm. These results suggest that the reduction of the 5-HT contractile response in diabetic rats may be a composite of direct effects on the smooth muscle as well as indirect effects on the neurons. / Department of Physiology and Health Science