Effect of yohimbine on reinstatement of operant responding in rats is dependent on cue contingency but not food reward history

Abstract

Yohimbine is an alpha-2 adrenoceptor antagonist that has been used in numerous studies as a pharmacological stressor in rodents, monkeys, and humans. Recently, yohimbine has become the most common stress manipulation in studies on reinstatement of drug and food seeking. However, the wide range of conditions under which yohimbine promotes reward seeking is significantly greater than that of stressors like intermittent footshock. Here we addressed two fundamental questions regarding yohimbine’s effect on reinstatement of reward seeking: (1) whether the drug’s effect on operant responding is dependent on previous reward history or cue contingency, and (2) whether yohimbine is aversive or rewarding under conditions typically used in reinstatement studies. We also used in vivo microdialysis to determine yohimbine’s effect on dopamine levels in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). We found that the magnitude of yohimbine-induced (0.5, 1.0, 2.0 mg/kg) operant responding during the reinstatement tests was critically dependent on the contingency between lever-pressing and discrete tone-light cue delivery but not the previous history with food reward during training. We also found that yohimbine (2 mg/kg) did not cause conditioned place aversion. Finally, we found that yohimbine modestly increased dopamine levels in mPFC but not NAc. Results suggest that yohimbine’s effects on operant responding in reinstatement studies are likely independent of the history of contingent self-administration of food or drug rewards and may not be related to the commonly assumed stress-like effects of yohimbine.

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

“…Given that yohimbine-induced reinstatement of food seeking requires activation of D 1 Rs in mPFC (Nair et al, 2011) and that acute stressors, including yohimbine (Chen et al, 2014; Tanda et al, 1996), selectively increase dopamine in the mPFC—an effect that is sensitized in chronically stressed animals (Di Chiara et al, 1999; Gresch et al, 1994)—we speculate that the enhanced yohimbine-induced responding observed in saline + yohimbine rats in Experiment 1 was due to augmented D 1 R activation in mPFC relative to controls. Blockade of D 1 Rs during yohimbine stress may have attenuated the stress-induced changes in dopaminergic transmission in mPFC.…”

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

“…Moreover, recent evidence suggests that some of the effects of yohimbine on operant responding may not be related to stress-like effects and may be independent of the history of contingent self-administration of food [12]. Therefore, a main goal of the present study was to extend our previous findings by determining whether the effects of chronic yohimbine on palatable food seeking generalize to a non-pharmacological stressor.…”

“…We hypothesize that this is due to engagement of a common pathway involved in food seeking. Indeed, both yohimbine and non-pharmacological stressors strongly activate [29, 30] and selectively increase dopamine release [12, 31] in PFC. 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].…”

The Nociceptin/Orphanin FQ receptor agonist SR-8993 as a candidate therapeutic for alcohol use disorders: Validation in rat models

“…However, it should be noted that recent data suggest the actions of yohimbine on operant responding not to be primarily due to its stress-like effects on motivation for drug seeking. Chen et al (2015) presented data showing that the dose commonly used for stress-induced reinstatement for alcohol and other drugs of abuse does not induced conditioned place aversion on its own (Chen et al 2015). Furthermore, they show reinstatement to be due to increased cue-reactivity and/or arousal, since increased responding following extinction and yohimbine-induced reinstatement was seen in a group of animals trained using a cue only (and no reward present).…”