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Chronic intermittent sucrose solution access has been shown to increase opioid and dopamine functioning in rats. Rats given intermittent sucrose access experience increases in mu-opioid receptor binding in the limbic system and especially the nucleus accumbens. Subjects under this condition experience increased mu-opioid binding in the nucleus accumbens shell, cingulate cortex, hippocampus, locus coeruleus. Mu-opioid binding decreased in the substantia nigra pars reticulata. Similar changesin rodent models when subjects without access are injected with opioid agonists or psychostimulants (Colantuoni et al. 2001).
Levels of mu-opioid receptor mRNA decrease in the striatum of rats that have chronic intermittent sucrose access.These changes in gene expression are similar those that occur in morphine-dependent rats (Spangler et al. 2004). Behavioral studies have also indicated a relationship between sucrose consumption and increases in opioid function. A study by Jewett, Grace, and Levine (2005) found that chronic sucrose consumption reduced the dose of nalbuphine (mu-opioid agonist) required to produce its discriminative stimulus effects in a two-choice operant procedure. Taken together, these molecular and behavioral studies support the idea that chronic sucrose consumption causes a change in mu-opioid function.
Our laboratory has previously demonstrated that chronic intermittent sucrose access, which facilitates an increase in endorphin function, allows rats to discriminate naltrexone (NTX) from saline in an operant choice procedure. NTX is a non-selective opioid antagonist at the mu-, kappa-, and delta-opioid receptors. We wondered if the NTX discriminative stimulus that the rats attend to is mediated by the antagonism of a specific opioid-receptor subtype or a mixture of subtypes. To test the kappa-opioid receptors we introduced the kappa-opioid agonist U69,593 to the NTX discrimination testing in an attempt to disrupt the discriminative stimulus, which could be evident by a change in subjects responding.
U69,593 is an opioid agonist that selectively activates kappa-opioid receptors (France, Medzihradsky, and Woods, 1994). We wondered if activation of kappa opioid receptors would alter the discriminative stimulus effects of naltrexone.If kappa-opioid receptors have a role in the NTX discriminative stimulus, activation of the kappa-opioid receptor should reduce the ability of naltrexone to produce its discriminative stimulus effects, and consequently require an increased dose of NTX to produce its discriminative stimulus.
In some studies with NTX and opioid agonists, such as morphine, subjects acquired sensitivity, or an increase in potency, to the discriminative stimulus effects of NTX (France and Woods 1985a).
France’s and Woods’s 1985b pigeons chronic administration of morphine and trained the subjects to discriminate between NTX, morphine, and saline in a three-choice, operant paradigm. The pigeons developed a tolerance to morphine, which was evident with a rightward shift in the morphine discrimination dose-effect curve.
In another study, France and Woods (1985b) investigated combinations of morphine and NTX in pigeons in an operant paradigm. Small doses of naltrexone were administered before morphine in tests to create a morphine dose-effect curve. This pretreatment caused a shift in the morphine dose-effects curve to the right indicating that NTX antagonized morphine and decreased morphine’s potency. Larger doses of NTX blocked the discriminative stimulus effects of morphine and the subjects responded as if they were under NTX conditions. [That is true. How does this relate to our study? A statement or sentence at the beginning of this paragraph may be helpful. I stopped reading the introduction here.]
Subjects gained sensitivity to NTX after chronic morphine treatment (France and Woods, 1985a). Prior to the treatment, the rate of responding under morphine conditions, was suppressed with a dose of 100.0 mg/kg NTX. After the chronic morphine treatment, the rate of responding was suppressed with 0.1 mg/kg NTX. NTX’s potency to suppress the rate of responding increased by 1000-fold after chronic morphine treatment. The subjects that were chronically treated with morphine developed tolerance to morphine and sensitivity to NTX.
France and Woods (1985b) also used pretreatments of morphine before creating NTX dose-effect curve. France and Woods found that smaller morphine pretreatment doses shifted the NTX dose-effect curve to the left, indicating that the subjects were more sensitive to NTX and with larger doses of morphine, subjects identified the condition as morphine. The NTX discriminative stimulus is changed by small morphine doses and can be reversed by large doses of morphine. MOVE/CONDENSE
Many studies LIST THE STUDIES have found that sensitivity to NTX can occur with the chronic use of morphine, which is an opioid agonist, and chronic NTX treatment. Potentially chronic intermittent sucrose access could facilitate sensitivity to NTX due to increases opioid functioning.
We found that rats with chronic intermittent sucrose access can discriminate NTX from saline in an operant choice procedure. NTX antagonizes the mu-, kappa-, and delta-opioid receptors. U69 is kappa agonist. Sensitivity to NTX.
We aim to test the effect of U69,593 in rats trained to discriminate NTX from saline in an operant choice procedure. We also observed subjects for NTX sensitivity.
Materials and Methods
Seven male Sprague Dawley rats were housed in separate polycarbonate cages under 12-hour light and 12-hour dark conditions. The University of Wisconsin-Eau Claire Institutional Animal Care and Use Committee approved this study.
Subjects had access to only a 25% sucrose solution for 12 hours a day beginning in the lights off cycle. Subjects began sucrose access at 6 pm and trained or tested at 7 pm. After testing subjects returned to their home cages and continued sucrose access. During the light cycle, 6 am – 6 pm subjects only had access to water.
Before discrimination training began subjects had chronic intermittent sucrose access for two weeks. After two weeks access continued, and discrimination training began.
MedPC (Med Associates) operant chambers and program were used for operant training. Operant chambers consisted of two levers, a house light, and a pellet dispenser. Reinforcers were 45 mg sugar pellets. Background white noise was present during all training and testing sessions to minimize the influence of extraneous sounds.
NTX (0.001 – 10.0 mg/kg) and U69,593 (0.001 – 0.1 mg/kg) were dissolved in saline. All drugs and saline were administered subcutaneously (s.c.). Saline was injected at body weight-appropriate volumes (1.0 mL/kg).
Discrimination Training Procedure
Subjects were food restricted to 80% of their free-feeding weight. Subjects were trained to lever press by reinforcing any lever presses until the subject would reliably lever press to earn a reinforcer. Then subjects would be reinforced to the right or left lever until the subject learned to reliably lever press in all conditions. Subjects’ lever pressing was reinforced on a fixed ratio schedule of reinforcement. Training conditions were presented quasi-randomly.
In discrimination training, a session was either a saline or NTX condition. Under NTX (1.0 mg/kg, s.c.) conditions, left lever presses were reinforced, and in sessions with saline (1.0 mL/kg, s.c.) conditions, the right lever responses were reinforced. Responses to the inappropriate lever in either condition were punished with 8 seconds of darkness.
Discrimination criteria determined if subjects acquired the discrimination between NTX and saline. One part of the criteria is, subjects’ responding must be at least 80% to the condition appropriate lever before the first consequence. Another part of the criteria is, at least 80% of responses to the must be to the condition appropriate lever for overall responses during the session. Finally, the previous criteria must occur 8 of 10days and when all criteria are met testing can begin.
Once discrimination criteria are met, subjects can undergo dose generalization testing using cumulative dosing. Subjects are tested beginning with 0.1 mg/kg NTX through the training dose of 1.0 mg/kg NTX. These data were used to create subjects’ dose-effect curves with NTX.
After NTX dose-effect curves were established U69,593 was injected before NTX in following tests. In anticipation of a dose-effect curve shift, the doses of NTX tested began at 0.32 mg/kg and up to 10.0 mg/kg. Various doses to U69,593 were tested (0.001 – 0.1 mg/kg).
NTX was administered before U69,593 in reversal tests. The training dose of NTX was administered and the NTX discriminative stimulus was established. Next subjects were injected with U69,593 (0.001 – 0.1 mg/kg, s.c.) and tested at least every 30 minutes over a 120-minute period. Control tests were conducted by administrating U69,593 in place of saline.
The seven subjects were able to acquire the discrimination in a mean of 91.9 sessions (SD = 40.2).
Generalization tests yielded limited results. With most doses of U69,593 in some subjects, it appears that the potency of NTX was decreased by U69,593 (Figure 1). Two subjects that developed sensitivity to NTX exhibited a leftward shift of their dose-effect curve (Figure 2). Initially, both subject recognized 0.32 mg/kg NTX as the discriminative stimulus but three months later recognized 0.001 mg/kg NTX. The dose of U69,593 which produced a shift in the NTX dose-effect curve was inconsistent between subjects. One other subject tested to create NTX cumulative dose curves with U69,593 but displayed a lack of stimulus control and minimal test data was collected.
Responses to reversal testing are presented in Figure 4. Subjects did not report a change the discriminate stimulus effects of NTX after U69,593 was injected or after 120 minutes from the session start. Six subjects were tested at differing doses of U69,593 ranging from 0.001 – 0.1 mg/kg and responding was consistent.
Rats that gained sensitivity to NTX appeared to have a rightward shift in their NTX dose-effect curve with U69,593. Only two subjects tested reliably and consistently with U69,593 and NTX. Other subjects acquired the discrimination, but lack of stimulus control prevented testing so limited test data is available for the other subjects. Many of the other subjects tested largely with reversal testing.
Sensitivity to NTX appeared in two subjects and the subjects reported a ~1000-fold (0.001 – 0.32 mg/kg) difference in the dose of NTX that is discriminable over three months of testing. This increase in NTX sensitivity matches the sensitivity found by France and Woods (1985a) in subjects that had chronic morphine treatment.
The reversal tests that attempted to disrupt the established discriminative stimulus effects of NTX yielded no change in the subjects’ ability to discriminate NTX over 120 minutes. This test was discontinued as many test sessions with different doses of U69,593 had consistent results without significant differences.
- Colantuoni, C. Schwenker, J., McCarthy, J., Rada, P., Ladenheim, B., Cadet, J. L., Schwartz, G. J., Moran, T. H., & Hoebel, B. G. (2001). Excessive sugar intake alters binding to dopamine and mu-opioid receptors in the brain. NeuroReport, 12(16), 3549-3552. doi:10.1097/00001756-200111160-00035
- France, C. P., Medzihradsky, F., Woods, J. H. (1994). Comparison of kappa opioids in Rhesus monkeys: Behavioral effects and receptor binding affinities.Journal of Pharmacology and Experimental Therapeutics, 268(1), 47-58.
- France, C. P., & Woods, J. H. (1985a -MARCH-). Effects of morphine, naltrexone, and dextrorphan in untreated and morphine-treated pigeons. Psychopharmacology, 85, 377-382.
- France, C. P., & Woods, J. H. (1985b -AUGUST-). Opiate agonist-antagonist interactions: Application of a three-key drug discrimination procedure. Journal of Pharmacology and Experimental Therapeutics, 234(1), 81-89.
- Jewett, D. C., Grace, M. K., & Levine, A. S. (2005). Chronic sucrose ingestion enhances mu-opioid discriminative stimulus effects. Brain Research, 1050(1-2), 48-52. doi:10.1016/j.brainres.2005.05.012
- Spangler, R., Wittkowski, K. M., Goddard, N. L., Avena, N. M., Hoebel, B. G., & Leibowitz, S. F. (2004). Opiate-like effects of sugar on gene expression in reward areas of the rat brain. Molecular Brain Research, 124, 134-142. doi: 10.1016/j.molbrainres.2004.02.013
Figure 1 present data from two subjects that gained a sensitivity to NTX and had a rightward shift in their NTX and U69,593 dose-effect curve. Both subjects had similar NTX dose effect curve before sensitivity and after. Different doses of U69,593 shifted the dose-effect curve for each subject.
*****Need to make symbols consistent
Figure 2. These graphs display NTX cumulative dose-effect curves from subjects that displayed NTX sensitivity. [The figure caption should explain the figure (axes and data). This would be similar to the words one would use when talking about the figure during a poster presentation.]
EXPLAIN AS IF TO A NEW PERSON COMING INTO LAB
Figure 3 shows NTX appropriate responding of subjects during reversal testing. . [Please see the comments for Figure 3.]
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