Orexin/hypocretin receptor 1 signaling mediates Pavlovian cue-food conditioning and extinction.

Learned food cues can drive feeding in the absence of hunger, and orexin/hypocretin signaling is necessary for this type of overeating. The current study examined whether orexin also mediates cue-food learning during the acquisition and extinction of these associations. In Experiment 1, rats underwent two sessions of Pavlovian appetitive conditioning, consisting of tone-food presentations. Prior to each session, rats received either the orexin 1 receptor antagonist SB-334867 (SB) or vehicle systemically. SB treatment did not affect conditioned responses during the first conditioning session, measured as food cup behavior during the tone and latency to approach the food cup after the tone onset, compared to the vehicle group. During the second conditioning session, SB treatment attenuated learning. All groups that received SB, prior to either the first or second conditioning session, displayed significantly less food cup behavior and had longer latencies to approach the food cup after tone onset compared to the vehicle group. These findings suggest orexin signaling at the 1 receptor mediates the consolidation and recall of cue-food acquisition. In Experiment 2, another group of rats underwent tone-food conditioning sessions (drug free), followed by two extinction sessions under either SB or vehicle treatment. Similar to Experiment 1, SB did not affect conditioned responses during the first session. During the second extinction session, the group that received SB prior to the first extinction session, but vehicle prior to the second, expressed conditioned food cup responses longer after tone offset, when the pellets were previously delivered during conditioning, and maintained shorter latencies to approach the food cup compared to the other groups. The persistence of these conditioned behaviors indicates impairment in extinction consolidation due to SB treatment during the first extinction session. Together, these results demonstrate an important role for orexin signaling during Pavlovian appetitive conditioning and extinction.

Keefer SE ，Cole S ，Petrovich GD 《-》

Orexin/hypocretin signaling at the orexin 1 receptor regulates cue-elicited cocaine-seeking.

Smith RJ ，See RE ，Aston-Jones G 《-》

Orexin/Hypocretin-1 Receptor Antagonism Selectively Reduces Cue-Induced Feeding in Sated Rats and Recruits Medial Prefrontal Cortex and Thalamus.

Cole S ，Mayer HS ，Petrovich GD 《Scientific Reports》

Renewal of conditioned responding to food cues in rats: Sex differences and relevance of estradiol.

Cues associated with food can stimulate food anticipation, procurement, and consumption, independently of hunger. These and other behaviors driven by learned cues are persistent and can reappear after extinction, because the original learned associations continue to exist. Renewal, or reinstatement, of extinguished conditioned behavior may explain the inability to change maladaptive eating habits driven by food cues, similar to the mechanisms of drug use relapse. Here, we investigated sex differences in context-induced renewal of responding to food cues, and the role of estradiol in females in a Pavlovian conditioning preparation. We compared adult male and female rats because there is evidence for sex differences in learning and memory and in the control of feeding. Context-induced renewal involves conditioning and extinction in different contexts and the renewal of conditioned behavior is induced by return to the conditioning context ("ABA renewal"; experimental groups). Control groups remain in the same context during conditioning, extinction, and test. In Experiment 1, male and female rats were trained to associate a tone with food pellets during acquisition, and after extinction with tone only presentations, were tested for renewal of responding to the tone. Learning was assessed through the expression of the conditioned response, which included approach and activity directed at food receptacle (food cup behavior). Males and females learned the acquisition and extinction of tone-food associations similarly, but there were sex differences during renewal of the conditioned responses to the food cue. Males showed robust renewal of responding, while renewal in intact females was inconsistent. Males in the experimental group had significantly higher food cup behavior compared to males in the control group, while females in both groups showed similar levels of food cup behavior during the tone. In Experiment 2, we examined a potential role of estradiol in renewal, by comparing intact females with ovariectomized females with, and without, estradiol replacement. Rats in all groups acquired and extinguished tone-food associations similarly. During the test for renewal, the ovariectomized rats with estradiol replacement in the experimental group showed renewal of responding, evidenced by significantly higher food cup behavior compared to the control group. Intact and ovariectomized rats in the experimental groups had similar rates of food cup behavior as their corresponding control groups. These results provide novel evidence for sex differences and relevance of estradiol in renewal of responding to food cues and more broadly in contextual processing and appetitive associative learning, potentially relevant to maladaptive eating habits and eating disorders.

Anderson LC ，Petrovich GD 《-》

Role of orexin/hypocretin in conditioned sucrose-seeking in female rats.

The orexin/hypocretin system has recently been implicated in reward-seeking, especially for highly salient food and drug rewards. Given that eating disorders affect women more than men, we reasoned that the orexin system may be strongly engaged in female rats, and during periods of food restriction as we recently reported in male rats. Therefore, the present study examined the involvement of the orexin system in operant responding for sucrose, and in cue-induced reinstatement of extinguished sucrose-seeking, in ad libitum fed vs. food-restricted female subjects. Female Sprague Dawley rats were trained to self-administer sucrose pellets, and we determined the effects of pretreatment with the OxR1 receptor antagonist SB 334867 (SB; 10-30 mg/kg) on fixed ratio (FR) sucrose self-administration, and on cue-induced reinstatement of extinguished sucrose-seeking. SB decreased sucrose self-administration in food-restricted but not in ad libitum-fed females. SB did not alter active lever responding during cue-induced reinstatement of sucrose-seeking in either feeding group. These results confirm our previous results in male rats that signaling at the OxR1 receptor is involved in the sucrose reinforcement and self-administration in food-restricted subjects. However, the finding that SB is ineffective at attenuating cue-induced reinstatement in females, but was effective in food-restricted males, leads us to conclude that food seeking induced by conditioned stimuli engages the orexin system differentially in males and females.

Cason AM ，Aston-Jones G 《-》