Withdrawal from the chronic administration of nicotine has previously been shown to lead to an enhanced auditory startle response in rats. In order to explore the neuropharmacology and neurophysiology underlying this phenomenon, we examined the effects of various 5-hydroxytryptamine (5-HT)-1A antagonists and agonists on the nicotine-withdrawal-enhanced auditory startle response in male rats. Animals were treated with nicotine (6 mg/kg/day nicotine base, via subcutaneously implanted osmotic minipumps) for 12 days. After 12 days the pumps were removed and the animals allowed to undergo spontaneous withdrawal for several days. In agreement with previous results, nicotine withdrawal led to a significant elevation of the auditory startle response. Pretreatment with the 5-HT-1A agonists (+)8-OH-DPAT (0.001-0.1 mg/kg) and LY274600 (0.3-3.0 mg/kg) either had no affect or exacerbated the nicotine-withdrawal-enhanced startle response. Pretreatment with the 5-HT-1A antagonists NAN-190 (1-3 mg/kg), LY206130 (1-10 mg/kg), or WAY-100635 (0.1-1.0 mg/kg) blocked the increase in the startle response caused by nicotine withdrawal at doses that had no effect on baseline startle responses. These data indicate that 5-HT-1A receptors play a role in the neurophysiology of nicotine withdrawal. In addition, 5-HT-1A antagonists may be able to relieve some nicotine withdrawal symptoms in man and may represent a novel pharmacotherapy for smoking cessation.