Moving beyond shock: Rich–lean transition procedures as a modern approach to anxiolytic screening

Anxiety disorders remain among the most prevalent psychiatric conditions worldwide,¹ yet preclinical models for evaluating anxiolytic compounds have changed little over the past several decades.² Many contemporary approaches rely on assays of unconditioned behavior (eg, elevated plus maze), which are poorly suited to within-subject longitudinal designs that require repeated testing across multiple doses.3, 4, 5 Conditioned conflict procedures, including punishment contingencies, also have important limitations, most notably, their reliance on aversive stimuli such as foot shock. For example, in the Geller–Seifter procedure,⁶ lever pressing maintained by food is assessed in alternating components that are signaled by distinct discriminative stimuli. In 1 component, responses are reinforced with food delivery; in the other, food-maintained responding is punished, typically by pairing food delivery with electric shock. Anxiolytic compounds are evaluated based on whether they selectively increase response rates in the reinforcement+ punishment component while leaving responding in the reinforcement-only component unchanged.² Although this procedure has strong predictive validity,7, 8, 9 the use of shock raises welfare concerns and practical challenges, particularly in nonhuman primates.

As behavioral pharmacology places greater emphasis on reducing reliance on aversive procedures, new approaches are needed that preserve the behavioral specificity and predictive validity of established preclinical assays for anxiolytic compounds, especially in translationally relevant nonhuman primate models. The manuscript by Toegel et al¹⁰ offers a promising novel alternative: the use of rich–lean transitions as an operant procedure that produces reliable behavioral disruption following a shift from a favorable to an unfavorable reinforcement condition. In that study, 4 female and 5 male rhesus monkeys were trained on a multiple-schedule of food presentations with rich and lean components. In the rich component, completion of a fixed-ratio requirement resulted in the delivery of four food pellets, whereas in the lean component, completion of the same response requirement produced only 1 food pellet. Each session consisted of several components arranged in a semirandom sequence so that transition types could be assessed across lean–lean, lean–rich, rich–lean, and rich–rich conditions. The primary dependent variable was pausing following each transition type. Rich–lean transitions consistently produced longer pauses than all other transitions, indicating disruption of behavior similar to that observed in the Geller–Seifter procedure when reinforcement is combined with punishment.

To validate this procedure as a tool for assessing anxiolytic compounds, Toegel et al¹⁰ conducted acute dose–response evaluations of 5 drugs and examined their effects on pausing after each transition type. They tested midazolam and alprazolam (nonselective full-efficacy benzodiazepines), TPA-023B (partial efficacy GABA_A-positive allosteric modulator), morphine (mu-opioid receptor agonist), and d-amphetamine (psychomotor stimulant). As would be expected for compounds with anxiolytic properties, midazolam, alprazolam, and TPA-023B decreased pauses during rich–lean transitions across subjects without affecting pausing after other transition types. In contrast, morphine and d-amphetamine increased the duration of pausing during rich–lean transitions, suggesting potential anxiogenic effects. Together, these findings demonstrated that the rich–lean transition procedure was a sensitive assay for putative anxiolytic medications. By establishing its feasibility in rhesus monkeys and its pharmacological specificity across multiple drug classes, the authors position the rich–lean transition model as a modern, humane, and practical tool for preclinical anxiolytic drug evaluation.

The work by Toegel et al¹⁰ demonstrated several notable strengths. First, it provides the initial demonstration of rich–lean transition effects in nonhuman primates using a nondrug reinforcer, extending prior pigeon and rodent work into a species with high translational value for anxiolytic drug development. Beyond this species extension, the study showed that rich–lean transitions could serve as a practical assay for evaluating novel anxiolytic compounds in nonhuman primates. The experimental design preserved robust responding while selectively disrupting behavior during rich–lean transitions, allowing clear detection of both anxiolytic and anxiogenic drug effects. Pharmacologically, the combination of a within-subject dosing strategy and rigorous baseline criteria produced generally orderly dose–response functions and reduced interindividual variability, supporting the reliability of the procedure. Finally, sessions were conducted in the monkeys’ home-cage, including animals fitted with jacket-and-tether systems for chronic intravenous catheters, demonstrating that the procedure is compatible with ongoing self-administration studies.

At the same time, the present work highlights several important questions that define a clear agenda for future research using the rich–lean transition model. Although extended pausing in rich–lean transitions functions as a sensitive behavioral endpoint, its precise psychological and neurobiological determinants remain to be specified. It is still unclear whether reduced pausing after treatment with putative anxiolytic compounds reflects a true reduction in anxiety, or instead changes in other, non–anxiety-related processes such as sensitivity to changes in reinforcement contingencies.^11,12 Linking this behavioral endpoint to neurobiological markers of anxiety that have been identified in human subjects will be essential for refining its construct validity. Although the present pharmacological sample encompassed benzodiazepines, a GABA_A-positive allosteric modulator, a mu-opioid agonist, and a psychomotor stimulant, expanding to additional drug classes will be crucial. In particular, serotonin-targeting compounds commonly used in the clinic for the treatment of anxiety (eg, buspirone) and agents that reliably induce anxiogenesis (eg, kappa-opioid agonists) could help further establish the model’s predictive validity.

Although challenging, larger sample sizes will also be important for gauging generalizability and for testing whether individual-difference variables, such as sex, baseline behavioral inhibition, or prior drug history, moderate drug effects in this procedure. However, it is important to acknowledge that increasing sample size in nonhuman primate studies is often constrained by cost. Moreover, because the task is inherently compatible with home-cage testing in tethered monkeys with chronic intravenous catheters, future studies can embed rich–lean sessions within ongoing drug self-administration experiments. This approach would permit within-subject assessment of how acute and chronic exposure to self-administered drugs alters pausing during rich–lean transitions, as well as how sensitivity to anxiolytic drugs changes with drug use. Such work is a particularly important future direction given the high comorbidity between anxiety disorders and substance use disorders in humans.¹³

In sum, Toegel et al¹⁰ advance the field by demonstrating that rich–lean transitions can be implemented in monkeys as a practical and pharmacologically selective platform for screening anxiolytic compounds. The pattern of results across benzodiazepines, a subtype-selective GABA_A modulator, an opioid agonist, and a psychomotor stimulant illustrates that this procedure can differentiate compounds with anxiolytic potential from those that are ineffective or anxiogenic, without relying on shock-based behavioral paradigms. As this work is extended to additional drug classes and integrated with self-administration and neurobiological measures, the rich–lean model is well positioned to complement and, in some contexts, replace traditional assays. Clinically, the development of a humane, nonhuman primate–based assay for evaluating anxiolytic compounds is especially valuable for guiding future treatments for patients with anxiety, including those with co-occurring substance use disorders.

Conflict of interest

Mia I. Rough reports financial support was provided by National Institute on Drug Abuse Division of Neuroscience and Behavior. Mia I. Rough reports financial support was provided by National Institute on Alcohol Abuse and Alcoholism. Julia L. Kratzenberg declares no conflicts of interest.