Anxiogenic-like effects of opiate withdrawal seen in the fear-potentiated startle test, an interdisciplinary probe far drug-related motivational states

Rationale: Anxiety-like effects may be universal to withdrawal from drugs of abuse. The study of withdrawal would benefit from the acoustic startle response (ASR), a discrete, cross-species reflex which is increased by fear-related states. However, existing reports of opiate-related effects on baseline ASR have not validated ASR as a measure of drug-related motivation. Objective: The effects of opiate treatment and withdrawal were examined using fear-potentiated startle, a startle test more sensitive to fear than baseline changes. Methods: Fear-conditioned rats were treated with Alzet osmotic pumps delivering 0.25 mg/kg per day fentanyl or placebo pumps. Experiment 1 examined changes before and during opiate treatment on locomotor activity and baseline, prepulse inhibition, and fear-potentiated startle. Experiment 2 examined the same responses during withdrawal precipitated after 4-7 days of treatment using IV naloxone. Results: Experiment 1 revealed an attenuated fear-potentiated startle on the first test after the start of fentanyl treatment (4 h); this was not seen on subsequent tests and suggested tolerance to this acute effect, Experiment 2 found an enhancement of fear-potentiated startle precipitated in fentanyl-treated rats after injection of 0.025 and 0.16 mg/kg naloxone; this was not seen at 1 mg/kg naloxone, even though more physical withdrawal signs were most prevalent at this dose. In neither experiment did locomotor activity, baseline ASR, or prepulse inhibition of the ASR show any treatment effect. Conclusions: Fear-potentiated startle may provide a specific and valid measure of anxiety-like effects of drug withdrawal. Discussed were conditions needed to see this effect and the relevance of the findings for different mechanisms of withdrawal discomfort.