Faculty Bibliography

In prior studies, systemic opioid receptor antagonism with naltrexone (NTX) failed to block flavor preference conditioning by the sweet taste or post-oral actions of sugar despite reducing overall flavored saccharin intake. Further, NTX microinjections into the nucleus accumbens (NAc) shell or core failed to alter the expression of preferences conditioned by the sweet taste or post-oral actions of sugars. In contrast, fructose-conditioned flavor preferences (CFP) were reduced or eliminated by systemic or intracerebral administration of dopamine (DA) D1 or D2 antagonists in the NAc, medial prefrontal cortex (mPFC), amygdala (AMY) or lateral hypothalamus (LH). The present study examined whether NTX microinjections into the mPFC, AMY or LH would alter expression of fructose-CFP and total flavored saccharin intake. Food-restricted rats with bilateral cannulae aimed at the mPFC, AMY or LH were trained to drink a fructose (8%)+saccharin (0.2%) solution mixed with one flavor (CS+, e.g., cherry) and a 0.2% saccharin solution mixed with another flavor (CS-, e.g., grape) during 10 one-bottle sessions. Two-bottle tests with the cherry and grape flavors in 0.2% saccharin solutions occurred 10min following total bilateral NTX doses of 0, 1, 25 and 50mug administered into the mPFC, AMY or LH. Rats preferred the CS+ over CS- flavor following vehicle and all NTX doses administered into either the mPFC or LH. CS+ intake was significantly greater than CS- intake following vehicle and the low NTX dose in the AMY; however, at the 25 and 50mug AMY NTX doses, CS+ intakes did not significantly exceed CS- intakes. Total flavored saccharin intake was significantly reduced by all three LH NTX doses (20-35%), by the 25 (14%) and 50 (22%)mug AMY NTX doses, but not by mPFC NTX. Thus, opioid antagonism in the AMY, but not the mPFC or LH attenuated, but did not block the expression of fructose-CFP, and LH and AMY, but not mPFC, NTX significantly reduced total saccharin intake. Therefore, whereas opioid antagonism in the LH and AMY reduces sweet intake, they appear less effective in altering fructose-CFP.

The attraction to sugar-rich foods is influenced by conditioned flavor preferences (CFP) produced by the sweet taste of sugar (flavor-flavor learning) and the sugar's post-oral actions (flavor-nutrient) learning. Brain dopamine (DA) circuits are involved in both types of flavor learning, but to different degrees. This study investigated the role of DA receptors in the lateral hypothalamus (LH) on the flavor-flavor learning produced the sweet taste of fructose. In an acquisition study, food-restricted rats received bilateral LH injections of a DA D1 receptor antagonist (SCH23390), a D2 antagonist (RAC, raclopride) or vehicle prior to 1-bottle training sessions with a flavored 8% fructose+0.2% saccharin solution (CS+/F) and a less-preferred flavored 0.2% saccharin solution (CS-). Drug-free 2-bottle tests were then conducted with the CS+ and CS- flavors presented in saccharin. The fructose-CFP did not differ among groups given vehicle (76%), 12 nmol SCH (78%), 24 nmol (82%) or 24 nmol RAC (90%) during training. In an expression study with rats trained drug-free, LH injections of 12 or 24 nmol SCH or 12-48 nmol RAC prior to 2-bottle tests did not alter CS+ preferences (77-90%) relative to vehicle injection (86%). Only a 48 nmol SCH dose suppressed the CS+ preference (61%). The minimal effect of LH DA receptor antagonism upon fructose flavor-flavor conditioning differs with the ability of LH SCH injections to block the acquisition of glucose flavor-nutrient learning.

In our prior studies, systemic administration of the opioid receptor antagonist naltrexone (NTX) did not block flavor preference conditioning by the sweet taste or post-oral actions of sugar despite reducing intake. Because opioid signaling in the nucleus accumbens (NAc) is implicated in food reward, this study determined if NTX administered into the NAc would block the expression of sugar-conditioned preferences. In Experiment 1, food-restricted rats with bilateral NAc shell or core cannulae were trained to drink a fructose (8%)+saccharin (0.2%) solution mixed with one flavor (CS+) and a less-preferred 0.2% saccharin solution mixed with another flavor (CS-) during one-bottle sessions. Two-bottle tests with the two flavors mixed in saccharin solutions occurred 10 min following total bilateral NAc shell or core doses of 0, 1, 25 and 50 microg of NTX. The rats preferred the CS+ over CS- following vehicle (80%) and all NTX doses in the shell and core. The CS+ preference was reduced to 64% and 72% by 50 microg NTX in the shell and core, although only the core effect was significant. In Experiment 2, food-restricted rats were trained to drink one flavored saccharin solution (CS+) paired with an intragastic (IG) glucose (8%) infusion and a second flavored saccharin solution (CS-) paired with an IG water infusion. In subsequent two-bottle tests, the rats displayed significant preferences for the CS+ (81-91%) that were unaltered by any NTX dose in the shell or core. CS+ intake, however, was reduced by NTX in the shell, but not the core. These data indicate that accumbal opioid antagonism slightly attenuated, but did not block the expression of sugar-conditioned flavor preferences. Therefore, while opioid drugs can have potent effects on sugar intake they appear less effective in altering sugar-conditioned flavor preferences.

Systemic administration of dopamine D1-like (SCH23390) and, to a lesser degree D2-like (raclopride), receptor antagonists significantly reduce the acquisition and expression of fructose-conditioned flavor preferences (CFP) in rats. Given the role of dopamine in the amygdala (AMY) in the processing and learning of food reward, the present study examined whether dopamine D1-like or D2-like antagonists in this site altered acquisition and/or expression of a fructose-CFP. In Experiment 1, food-restricted rats with bilateral AMY cannulae were trained to drink a fructose (8%)+saccharin (0.2%) solution mixed with one flavor (e.g., grape, CS+/Fs) and a less-preferred 0.2% saccharin solution mixed with another flavor (e.g., cherry, CS-/s) during one-bottle (16 ml) sessions. Two-bottle tests with the two flavors mixed in saccharin solutions (CS+/s, CS-/s) occurred 10 min following total bilateral AMY doses of 0, 12, 24 and 48 nmol of SCH23390 or raclopride. Preference for CS+/s over CS-/s was significantly reduced relative to vehicle baseline by the 48 nmol doses of SCH23390 and raclopride (from 77% to 66% and 68%), but not lower doses. In Experiment 2, rats received bilateral AMY injections (12 nmol) of SCH23390 (D1 group) or raclopride (D2 group) 10 min prior to one-bottle training sessions with CS+/Fs and CS-/s. Yoked Control rats received vehicle and were limited to the CS intakes of the D1 and D2 groups; untreated controls were not injected or limited to drug group intakes during training. Subsequent two-bottle tests revealed initial preferences of CS+/s over CS-/s in all groups that remained stable in untreated and Yoked Controls, but were lost over the 6 tests sessions in the D1 group, but not in the D2 group. These data indicate that dopamine D1-like and D2-like antagonists significantly attenuated the expression of the previously acquired fructose-CFP, and did not block acquisition of the fructose-CFP. D1-like antagonism during training hastened extinction of the fructose-CFP. The results are similar to those produced by dopamine D1-like and D2-like antagonist injections into the nucleus accumbens shell which suggests that flavor conditioning involves a regionally distributed brain network.

Systemic administration of dopamine D1 (SCH23390) and less so D2 (raclopride) receptor antagonists significantly reduce acquisition and expression of fructose-conditioned flavor preferences (CFP). Because dopamine in the nucleus accumbens shell (NAcS) is implicated in food reward, the present study examined whether NAcS D1 or D2 antagonists altered acquisition and/or expression of fructose-CFP. In Experiment 1, food-restricted rats with bilateral NAcS cannulae were trained to drink a fructose (8%)+saccharin (0.2%) solution mixed with one flavor (CS+/Fs) and a less-preferred 0.2% saccharin solution with mixed another flavor (CS-/s). Unlimited two-bottle tests with the two flavors in saccharin (0.2%: CS+/s, CS-/s) occurred 10 min following total bilateral NAcS doses of 0, 12, 24 or 48 nmol of SCH23390 or raclopride. Preference for CS+/s over CS-/s following vehicle treatment (76%) was significantly reduced by SCH23390 (48 nmol, 62%) and raclopride (24 nmol, 63%). In Experiment 2, rats received bilateral NAcS injections (12 nmol) of SCH23390 or raclopride on one-bottle training (16 ml) days. Yoked control rats received vehicle and were limited to the CS intakes of the D1 and D2 groups, whereas untreated controls without injections received their CS ration during training. Subsequent unlimited two-bottle tests revealed initial preferences of CS+/s over CS-/s in all groups that remained stable in untreated and yoked controls, but were lost over the six tests sessions in D1 and D2 groups. These data indicate that NAcS D1 and D2 antagonists significantly attenuated the expression of the fructose-CFP and did not block acquisition, but hastened extinction of fructose-CFP.

Male rodents display greater systemic morphine antinociception than females which show their most marked effects during late diestrus or proestrus. Morphine (1-2.5 mug) antinociception on the tail-flick test elicited from the ventrolateral periaqueductal gray was examined across estrus phases in female relative to male rats. Morphine antinociception was greatest in magnitude and potency in males followed by females tested during the proestrus phases relative to estrus and met-diestrus. These data confirm morphine's systemic effects, implicate the ventrolateral periaqueductal gray in estrus phase-mediated effects, and underscore the control of the phase of the estrus cycle in examining sex differences in opioid antinociception.