key: cord-0334922-71cuzyl3 authors: Liu, Clarissa M.; Hsu, Ted M.; Suarez, Andrea N.; Subramanian, Keshav S.; Fatemi, Ryan A.; Cortella, Alyssa M.; Noble, Emily E.; Roitman, Mitchell F.; Kanoski, Scott E. title: Central oxytocin signaling inhibits food reward-motivated behaviors and VTA dopamine responses to food-predictive cues in male rats date: 2020-07-24 journal: bioRxiv DOI: 10.1101/2020.06.24.169540 sha: 8437a9ef2e0c04555ae48bcb7e1ea3efed139ba9 doc_id: 334922 cord_uid: 71cuzyl3 Oxytocin potently reduces food intake and is a potential target system for obesity treatment. A better understanding of the behavioral and neurobiological mechanisms mediating oxytocin’s anorexigenic effects may guide more effective obesity pharmacotherapy development. The present study examined the effects of central (lateral intracerebroventricular [ICV]) administration of oxytocin in rats on motivated responding for palatable food. Various conditioning procedures were employed to measure distinct appetitive behavioral domains, including food seeking in the absence of consumption (conditioned place preference expression), impulsive responding for food (differential reinforcement of low rates of responding), effort-based appetitive decision making (high-effort palatable vs. low-effort bland food), and postingestive reward value encoding (incentive learning). Results reveal that ICV oxytocin potently reduces food-seeking behavior, impulsivity, and effort-based palatable food choice, yet does not influence encoding of postingestive reward value in the incentive learning task. To investigate a potential neurobiological mechanism mediating these behavioral outcomes, we utilized in vivo fiber photometry in ventral tegmental area (VTA) dopamine neurons to examine oxytocin’s effect on phasic dopamine neuron responses to sucrose-predictive Pavlovian cues. Results reveal that ICV oxytocin significantly reduced food cue-evoked dopamine neuron activity. Collectively, these data reveal that central oxytocin signaling inhibits various obesity-relevant conditioned appetitive behaviors, potentially via reductions in food cue-driven phasic dopamine neural responses in the VTA. Highlights Central oxytocin inhibits motivated responding for palatable food reinforcement Central oxytocin does not play a role in encoding postingestive reward value Central oxytocin blunts VTA dopamine neuron activity in response to food cues Pavlovian cues as a potential mechanism contributing to oxytocin's anorexigenic effects. jeweler's screws and dental cement (Liu et al., 2020) . Following one week of recovery, 145 cannula placement was evaluated via measurement of cytoglucopenia-induced 146 sympathoadrenal-mediated glycemic effect that occurs from 210 µg (in 2 µl) of 5-thio-D-147 glucose (5TG) (Slusser and Ritter, 1980 Brunswick, NJ, USA) was placed on the chamber floor, and no food was presented 182 during non-food-paired sessions. All rats consumed the entire 5 g of food during each 183 food-paired session. CPP testing occurred 2 days after the last training session using a between-185 subjects design, and groups were matched for baseline context preference. Immediately 186 before the testing session, rats received either lateral ICV 1 µg/1µl oxytocin (Bachem, were on a DRL0 schedule, where each active lever press was reinforced with a 0 sec time 208 delay. They were then switched to a DRL5 schedule for five days, where rats had to 209 withhold presses on the active lever for at least a 5 sec interval for each active lever press 210 to be reinforced. Active lever presses that occurred before the 5 sec had elapsed were not 211 reinforced and the timer was restarted. They were then switched to 5 days of DRL10 (10 212 sec withholding period) and 10 days of DRL20 (20 sec withholding period). Efficiency in 213 DRL was calculated as the number of pellets earned divided by the number of active 214 lever presses. The DRL test was conducted using a within-subjects design and no training Rats were initially trained to lever press on a FR1 schedule (one active lever press for 231 one sucrose pellet) for 5 days, and then shifted to a PROG schedule for 10 days. During concurrently available in addition to the PROG sessions for 5 days. Active lever presses, 236 inactive lever presses, pellets earned, highest PROG ratio achieved, and chow intake 237 (including spill) were recorded throughout training. Testing in the PROG/Chow feeding choice task was conducted using a within-239 subjects design, and treatments were separated by 72 h. Drug treatment order was In addition to the PROG/Chow feeding choice task, the effect of ICV oxytocin on 245 preference between consumption of free chow and free sucrose concurrently available in 246 the apparatus was also examined (n=10, within-subjects design). Rats were maintained 247 at 85% of their free-feeding body weight and tested at the onset of the dark cycle. Rats were next trained in the reward-delivery chain phase ( Fig 4A) . Initially, only 268 the left (seeking) lever was retracted. One left lever press was rewarded by presentation 269 of the right (taking) lever, and one right lever press was rewarded with delivery of one 270 45 mg sucrose pellet. This reward-delivery chain lasted until 20 pellets were earned or 271 30 min elapsed. The seeking lever was continuously rewarded with the taking lever for 272 four sessions, then the reinforcement schedule was increased to random ratio (RR)-2 for 273 four sessions, and then to RR-4 until stable lever pressing was obtained (approximately 274 three to five sessions). The taking lever was always continuously rewarded (FR-1) and 275 retracted after sucrose delivery. Rats that did not earn 20 sucrose pellets on a RR-4 276 schedule were pulled out from the experiment. within-subjects) were tested under ad lib feeding conditions 1 hr after the onset of the 294 dark cycle. Rats received 1 µg/µl oxytocin or vehicle ICV injections immediately prior to 295 the test, where they were allowed to freely explore the arena for 10 min. The apparatus 296 was cleaned with 10% ethanol after each rat was tested. ). Interestingly, ICV oxytocin had no effect on chow intake ( Fig 3H) . Thus, oxytocin 405 significantly reduced the ratio of sucrose intake relative to chow intake (t[9] = 2.37, p = 0 406 0.042; effect size d = -1.412, Fig 3I) . where rats are allowed to freely move in a novel chamber devoid of food or food-related 423 cues. Results reveal that ICV oxytocin did not significantly affect the distance traveled 424 (Fig 5A) , nor did it affect time spent in the center zone ( Fig 5B) . 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