Our brain’s reward system processes and reinforces pleasurable experiences, motivating us to seek out and engage in rewarding activities ranging from eating to social interactions to recreational drug use. Dopamine plays an important role in this process, mediated by the D2 dopamine receptor (D2R). New research published today in Nature Neuroscience finds that the same mechanism that causes drug addiction (desensitization of D2R) also controls the natural devaluation of repeated behaviors (e.g. seeking out the same thrill of going on a rollercoaster for the first time). This is the first natural use found for this mechanism.
Researchers from Boston Children’s Hospital used male fruit flies to study behavior fatigue. They found that during mating, dopamine signaled through the D2R to promote resilience in the face of threats that might otherwise cause the male to switch behaviors. However, after multiple matings, the receptors became desensitized, making dopamine less effective and subsequent matings more likely to be abandoned when challenged.
“Our findings suggest that this type of repetition-induced devaluation may underlie many types of commonly experienced mental and motivational fatigue (e.g., loss of interest),” said Michael Crickmore, PhD, from the F.M. Kirby Neurobiology Center at Boston Children’s Hospital and principal investigator of the study. “Drug addiction causes desensitization throughout the brain and, as a result, devalues all innately rewarding behaviors. Our findings suggest that localized dopamine release desensitizes local circuitry, causing the brain to devalue a specific behavior.”
Clinicians and researchers have long known that the desensitization of the D2R is the reason why it takes more and more drug to achieve the same effect within the context of addiction. However, up to now there was no evidence that this mechanism influences natural motivational behaviors.
“The demonstration of D2R desensitization in response to naturally released dopamine links this pathological mechanism to the natural ebb and flow of our individual drives. Better understanding of this mechanism could lead to new hypotheses for motivational control and how it becomes corrupted in addiction,” added Crickmore.
Nature Neuroscience
Behavioral devaluation by local resistance to dopamine
20-Nov-2025