Effects of repeated yohimbine administration on reinstatement of palatable food seeking: involvement of dopamine D₁-like receptors and food-associated cues

Abstract

Acute exposure to the pharmacological stressor yohimbine induces relapse to both food and drug seeking in a rat model. However, no systematic studies on the effects of chronic stress on relapse have been conducted. Because chronic stress causes changes in dopamine D1-like receptor-mediated transmission in prefrontal cortex (a relapse node), we tested the hypothesis that chronic exposure to stress increases vulnerability to relapse via dopamine-mediated mechanisms. Additionally, to determine the role of food-conditioned cues in reinstatement of food seeking, we made discrete food-paired cues either available (CS Present) or not available (CS Absent) during extinction and reinstatement testing. Rats responded for palatable food reinforcers in daily 3-hr sessions, and the behavior was extinguished. To model chronic stress, rats were injected daily with yohimbine (0.0, 2.5, or 5.0 mg/kg; i.p.) during the first 7 days of extinction. Injections were combined with SCH-23390 (0.0, 5.0, or 10.0 μg/kg; i.p.), a D1-like receptor antagonist. Rats were then tested for reinstatement of food seeking triggered by acute yohimbine (0.0, 1.0, or 2.0 mg/kg; i.p.) and pellet priming. Rats treated previously with chronic yohimbine displayed increased responding following acute yohimbine priming relative to non-chronically stressed rats, but in the CS Absent condition only. Conversely, the lower dose of chronic yohimbine caused an increase in pellet-primed reinstatement, but this effect was more pronounced in the CS Present condition. Importantly, SCH-23390 combined with repeated yohimbine injections attenuated these effects. Thus, chronic stress may increase vulnerability to relapse under specific circumstances via a dopamine D1-like receptor mediated mechanism.

Chronic restraint stress causes a delayed increase in responding for palatable food cues during forced abstinence via a dopamine D1-like receptor-mediated mechanism

“…These results support and extend our previous findings with the pharmacological stressor yohimbine [9, 10] by showing that a non-pharmacological stressor, restraint, also produces lasting increases in palatable food-seeking behavior. We hypothesize that this is due to engagement of a common pathway involved in food seeking.…”

“…The release of dopamine in PFC and the activation of D 1 Rs in general appear to be critical mechanisms underlying food-seeking behavior [16, 17, 19]. Results showing that SCH-23390 combined with yohimbine [9, 10] and restraint stress (present study) blocked the effects of both stressors on food seeking provide further support for a shared mechanism.…”

“…Chronic stress, moreover, has been shown to cause changes in mesocortical dopamine transmission [24] and D 1 R signaling [25, 26]. Particularly relevant to the present study, we found that SCH-23390, when combined with chronic yohimbine injections, reversed or attenuated all effects of yohimbine on later food seeking after extinction [10]. Thus, in the present study, we tested the possibility that blockade of D 1 Rs with SCH-23390 during repeated restraint stress would attenuate any effects of this treatment on later food seeking after abstinence.…”

“…), a D 1 R antagonist, immediately prior to placement in restrainers. SCH-23390 was dissolved in physiological saline at a concentration of 10.0 μg/ml, and the dose is based on previous research [9, 10, 16, 18]. Unstressed rats were injected daily with SCH-23390 or vehicle and then returned to their home cages.…”

“…The prototype α-2 adrenoceptor antagonist yohimbine has been the stressor of choice in contemporary reinstatement studies because of its robust and reliable effects on reinstatement of food seeking when administered acutely [8]. Moreover, we recently showed that rats with a history of chronic yohimbine exposure showed greater acute yohimbine- and food-priming-induced reinstatement of food seeking several days after the cessation of chronic yohimbine treatment [9, 10]. …”