The opioid antagonist naltrexone (NTX) decreases intake of preferred diets in rats at very low doses relative to doses needed to decrease intake of “bland” laboratory chow. In the absence of an opioid agonist, NTX is not discriminable using operant techniques. In the current study, we found that rats given intermittent access to a 25% sucrose solution learned to discriminate between various naltrexone doses and saline. None of the rats given only water learned to discriminate between naltrexone and saline. When access to the sucrose solution was discontinued for 14 days, the rats lost the ability to discriminate between NTX and saline. We also studied the changes of c-Fos IR in selected brain regions in rats treated with saline versus NTX that were drinking water or 25% sucrose. An injection of NTX or saline resulted in a significant drug, diet, and interaction effect in various brain regions associated with feeding behavior, particularly the amygdala, accumbens, and hypothalamic sites. Thus, we found that ingestion of a sucrose solution results in the ability of rats to reliably discriminate naltrexone administration. In addition, sucrose and naltrexone altered c-Fos IR in an interactive fashion in brain regions known to be involved in ingestion behavior.
Naltrexone (NTX) is a nonspecific opioid antagonist that binds to mu‐, kappa‐, and delta‐opioid receptors. Previous research has demonstrated that rats given chronic, intermittent sucrose access have increased endorphin function. We have shown that rats given chronic, intermittent sucrose can discriminate 1.0 mg/kg NTX from saline in a two‐lever, operant choice procedure. We wondered if NTX's discriminative stimulus effects were mediated by kappa‐opioid receptors. To examine this possibility, we tested the effects of the kappa‐opioid agonist U69,593 in our discrimination procedure. Male Sprague‐Dawley rats were given access to 12‐hour access to a 25% sucrose solution and trained to discriminate NTX (1.0 mg/kg) from saline. Once discrimination criteria (80% or greater condition‐appropriate responding for 8 of 10 consecutive sessions) were reached, generalization testing began. We used a cumulative dosing procedure to determine if U69,593 alters the ability of NTX to produce its discriminative stimulus effects. Subjects were pretreated with U69,593 (0.0001 mg/kg – 0.1 mg/kg, s.c.) followed by increasing doses of NTX (0.001 mg.kg – 10.0 mg/kg, s.c.). Fifteen to 30 minutes after the injection, a test session began. Injections continued until response rates were suppressed or 10.0 mg/kg NTX was administered. Reversal tests were also conducted. During these tests, the training dose of NTX was administered and a test session began 15 minutes later. Then a single dose of U69,593 (0.001 mg/kg – 0.1 mg/kg, s.c.) was administered, followed by test sessions 15 to 120 minutes after the injection. U69,593 did not significantly alter the discriminative stimulus effects of NTX. This suggests that kappa‐opioid receptor antagonism is not sufficient to produce NTX's discriminative stimulus effects in rats given chronic, intermittent sucrose access.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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 Information UW‐EC ORSP Grant
Chronic, intermittent sucrose access has been shown to induce neurochemical changes in the brain, including increasing the levels of dopamine and D3‐receptor mRNA, decreasing the levels of D2‐receptor mRNA, and increasing μ‐opioid receptor binding. We wondered if chronic, intermittent sucrose consumption would alter the ability of rats to discriminate drugs that affect endorphin and dopamine functioning. We successfully trained rats with chronic, intermittent sucrose access to discriminate various naltrexone training doses (ranging from 0.32 – 3.2 mg/kg) from saline. In the present series of studies, we sought to determine if chronic, intermittent sucrose consumption alters the ability of haloperidol to serve as a discriminative stimulus. Sprague‐Dawley rats were trained to discriminate between haloperidol [0.018–0.56 mg/kg, 30 min pretreatment (PT)] and vehicle in a two‐lever, operant choice procedure. Most subjects reached the discrimination criteria (80% or greater condition‐appropriate responding for 8 of 10 consecutive sessions). Among subjects that acquired the discrimination, there were no significant differences in acquisition between subjects with chronic, intermittent sucrose access and subjects with 24‐hr water access. Haloperidol (0.032 – 0.056 mg/kg) produced significant rate suppression. Increasing the PT to 60 minutes increased rates of lever pressing and reinforcers earned, but did not alter haloperidol generalization functions. Taken together, chronic sucrose consumption enhanced naltrexone's ability to function as a discriminative stimulus, but did not affect the discriminative stimulus effects of haloperidol.Support or Funding InformationUniversity of Wisconsin‐Eau Claire Office of Research and Sponsored ProgramsThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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