Schedule-induced polydipsia (SIP) poses a general buffering property to reduce the heightened arousal produced by a schedule of intermittent feeding. It thus provides a unique opportunity to study CNS integration in stress-coping reactions. In the present study, we examined the role of the locus coeruleus (LC) and the pharmacological actions of serotonergic (5-HT2) analogs on SIP. Water intake, licking, and bar presses per minute in rats were recorded as indices of SIP activity after they had been subjected to 1-h performance of a fixed-interval 1-min operant pellet conditioning. Our results showed that SIP was progressively decreased after lesions were placed bilaterally in the LC areas and then followed by further lesioning in the bilateral ventral tegmental area. Neurotoxin DSP-4 also had an inhibitory action on the SIP potency. In addition, SIP was attenuated by 2,5-dimethoxy-4-iodoamphetamine (0.1, 0.5, or 1.0 mg/kg, IP), a 5-HT2 agonist, and activated by ritanserin (2.5 mg/kg, IP), a 5-HT2 agonist. After bilateral LC lesions, SIP was attenuated and the activating effect of RIT was abolished. Our data suggest that the LC is involved in the central integration of SIP and that the modulating effects of 5-HT2 receptors on SIP depend upon the integrity of LC function.