The Pharmacological Stressor Yohimbine, but Not U50,488, Increases Responding for Conditioned Reinforcers Paired with Ethanol or Sucrose

Rationale: Environmental stimuli paired with alcohol can function as conditioned reinforcers (CRfs) and trigger relapse to alcohol-seeking. In animal models, pharmacological stressors can enhance alcohol consumption and reinstate alcohol-seeking, but it is unknown whether stress can potentiate the conditioned reinforcing properties of alcohol-paired stimuli.

Objectives: We examined whether the pharmacological stressors, the α-2 adrenoreceptor antagonist yohimbine (vehicle, 1.25, 2.5 mg/kg; IP) and the K-opioid receptor agonist U50,488 (vehicle, 1.25, 2.5 mg/kg; SC), increase responding for conditioned reinforcement, and if their effects interact with the nature of the reward (alcohol vs. sucrose). We subsequently examined the effects of yohimbine (vehicle, 1.25, 2.5 mg/kg; IP) on responding for sensory reinforcement.

Methods: Male Long-Evans underwent Pavlovian conditioning, wherein a tone-light conditioned stimulus (CS) was repeatedly paired with 12% EtOH or 21.7% sucrose. Next, tests of responding for a CRf were conducted. Responding on the CRf lever delivered the CS, whereas responding on the other lever had no consequences. In a separate cohort of rats, the effects of yohimbine on responding just for the sensory reinforcer were examined.

Results: Both doses of yohimbine, but not U50,488, increased responding for conditioned reinforcement. This enhancement occurred independently of the nature of the reward used during Pavlovian conditioning. Yohimbine-enhanced responding for a CRf was reproducible and stable over five tests; it even persisted when the CS was omitted. Both doses of yohimbine also increased responding for sensory reinforcement.

Conclusions: Yohimbine increases operant responding for a variety of sensory and conditioned reinforcers. This enhancement may be independent of its stress-like effects.