Frustrative Nonreward: Behavior, Circuits, Neurochemistry, and Disorders

Abstract

The surprising omission or reduction of vital resources (food, fluid, social partners) can induce an aversive emotion known as frustrative nonreward (FNR), which can influence subsequent behavior and physiology. FNR is an integral mediator of irritability/aggression, motivation (substance use disorders, depression), anxiety/fear/threat, learning/conditioning, and social behavior. Despite substantial progress in the study of FNR during the twentieth century, research lagged in the later part of the century and into the early twenty-first century until the National Institute of Mental Health's Research Domain Criteria initiative included FNR and loss as components of the negative valence domain. This led to a renaissance of new research and paradigms relevant to basic and clinical science alike. The COVID-19 pandemic's extensive individual and social restrictions were correlated with increased drug and alcohol use, social conflict, irritability, and suicide, all potential consequences of FNR. This article highlights animal models related to these psychiatric disorders and symptoms and presents recent advances in identifying the brain regions and neurotransmitters implicated.

Keywords: consummatory successive negative contrast; dopamine; drug use disorder; frustrated nonreward; irritability.

Figure 1.

Representative rolling average plots during FNR. A, Within-session extinction showing the transition from fixed-ratio 1 to extinction (FR1, EXT). B, Progressive ratio. C, Relief from frustration showing the transition from extinction to FR1. Lines represent rolling averages of 10 bar presses.

Figure 2.

Experimental schedule for cSNC. cSNC involves reward downshift (32 to 2% sucrose) compared with unshifted controls (32 to 32% and 2 to 2% sucrose). Consummatory behavior is suppressed on Session 11, but it recovers in subsequent postshift sessions. cSNC is used to map neural activation in a large set of brain regions in male and female rats.

Figure 3.

Head-restrained rats pursued a probabilistic reward (water) by repeating a sequence of actions (push/pull a lever) without any choice options. This task enabled a quantification of the ability to switch toward a new opportunity to obtain a probabilistic reward after a nonreward (from Ishino et al., 2023, reproduced with permission from Science Advances).

Figure 4.

The APRO paradigm with mice. A, Apparatus. B, Schedule and behavioral testing following APRO. Upward arrow, elevated levels of activity (open field) and aggressive behavior (resident intruder test). Dash lines, no effects.