Potentiated startle as a measure of the negative affective consequences of repeated exposure to nicotine in rats

Rationale: Elevated acoustic startle amplitude has been used to measure anxiety-like effects of drug withdrawal in humans and animals. Withdrawal from a single opiate administration has been shown to produce robust elevations in startle amplitude ("withdrawal-potentiated startle") that escalate in severity with repeated exposure. Although anxiety is a clinical symptom of nicotine dependence, it is currently unknown whether anxiety-like behavior is elicited during the early stages of nicotine dependence in rodents. Objective: The objective of this study is to examine whether, as is the case with opiates, single or repeated exposure to nicotine can produce withdrawal-potentiated startle. Methods: Rats received daily nicotine injections for 14 days, and startle amplitude was tested during spontaneous withdrawal on injection days 1, 7, and 14. Results: Elevated startle responding was observed during nicotine withdrawal on days 7 and 14 but not on day 1, was greater at higher nicotine doses, and was reduced by a nicotine replacement injection given during an additional test session on day 15. Additional experiments demonstrated that nicotine withdrawal-potentiated startle was reduced by the α₂- adrenergic agonist clonidine and that precipitated withdrawal-potentiated startle could not be induced by injection of the nicotinic acetylcholine receptor antagonist mecamylamine. Conclusions: These results suggest that nicotine withdrawal escalates in severity across days, similar to the previously reported escalation of opiate withdrawal-potentiated startle. Potentiated startle may be a reliable measure of withdrawal from different classes of abused drugs and may be useful in the study of the early stages of drug dependence.