Mechanisms of the initial treatment phenomenon to diazepam in the rat

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Abstract
The initial treatment phenomenon (ITP) to diazepam was investigated using a conditioned suppression of drinking (CSD) paradigm. Female Sprague-Dawley rats were trained to a stable baseline of punished and unpunished responses in the CSD paradigm. In Experiment 1, a control group (1) received vehicle after the CSD session on each of seven drug test days, while group 2 was treated with 3.0 mg/kg diazepam IP after each of these sessions. On drug test days 8–12, diazepam was administered to both groups before the CSD session. Drug test days were separated by 2–3 days when the animals were untreated but performed in the CSD. Prior exposure to diazepam in group 2 after sessions 1–7 conditioned the animals so that a greater release in punished behavior was seen during sessions 8–12 than in the control group (1). In Experiment 2, one group (3) of rats was administered diazepam vehicle after the CSD session for 4 drug test days and another group (4) was injected with 5.6 mg/kg diazepam after the CSD session on these same days. On the next 4 drug test days both groups received diazepam before they performed in the CSD. An ITP was observed in both the control (3) and the drug-conditioned (4) group, although the ITP was less obvious in the conditioned group. After a 28-day period of CSD exposure without vehicle or drug treatments, 5.6 mg/kg diazepam was administered to both groups before the CSD session for an additional 8 drug test days. During this last period both groups exhibited an ITP with no essential differences. These experiments demonstrate that the initial treatment phenomenon is complex, involving several components that include a behavioral tolerance to the disruptive effect of diazepam.