Individual Differences in Stimulus Control in Rats with Chronic‐Intermittent Sucrose Access Trained to Discriminate Between Naltrexone and Saline

Abstract

Drug discrimination has been a useful behavioral approach for understanding the neuropharmacological mechanisms of drug‐induced stimuli. Naltrexone (NTX) is an opioid antagonist with known binding affinities for mu‐, kappa‐, and delta‐opioid receptors. Our present study investigates the receptor‐mediated discriminative stimulus effects of NTX, as well as differences in stimulus control maintenance. We previously reported that rats given chronic, intermittent sucrose access can be trained to discriminate NTX (0.1 – 3.2 mg/kg) from saline (SAL). In the present study, nine male Sprague‐Dawley rats were housed in a 12‐hour light, 12‐hour dark cycle. During the dark cycle, subjects were given access to 25% sucrose solution and were trained to discriminate NTX from SAL. Discrimination criteria were defined as 80% or greater condition‐appropriate responding before the first reinforcer delivery and total session for 8 out of 10 consecutive sessions. After these criteria were met, generalization testing was conducted. Generalization tests included an injection of SAL followed by a dose of NTX differing from the training dose. Between test sessions, subjects followed a single alternation training procedure to ensure maintenance of NTX/SAL discrimination. Our single alternation procedure required two consecutive sessions of criteria‐appropriate responding. We observed variations in accuracy during training sessions conducted after acquisition criteria were completed. During post‐acquisition training sessions, subjects averaged 82.05% condition‐appropriate responding when given SAL and averaged 68.15% when given NTX. Means were significantly different from each other and chance performance. SAL‐appropriate responding was not significantly different from our criteria of 80%, while NTX‐appropriate responding did differ. Rapid improvement in NTX‐appropriate accuracy was observed leading up to discrimination acquisition. Stimulus control was maintained for an average of 25 sessions before accuracy of NTX‐appropriate responding began to decrease. In some subjects, accuracy of SAL‐appropriate responding was maintained while accuracy of NTX‐appropriate responding fluctuated over time. The inverse was true for other subjects. A third subset of subjects showed varying accuracy in response to both conditions. Rate suppression occurred in several subjects following NTX administration and was attenuated by reducing the NTX dose. Doses as small as 0.0001 mg/kg NTX generalized to the training dose in some subjects, indicating sensitivity development. A single dose of the kappa‐opioid agonist U69,593 (0.01 mg/kg – 0.1 mg/kg, s.c.) was administered 30 minutes prior to NTX (0.0001 mg/kg – 1.0 mg/kg, s.c.). U69,593 eliminated NTX‐appropriate responding in some, but not all, subjects. Our data show that while NTX has the ability to produce discriminative stimulus effects in rats given chronic, intermittent sucrose access, there are individual differences in post‐acquisition stimulus control.Support or Funding InformationUW‐EC ORSP Grant