Effects of clonidine on progressive ratio schedule performance in Fmr1 knockout mice

Fragile X syndrome (FXS), the most prevalent genetic form of intellectual disability, is characterized by intellectual impairment, impaired sociability, aggression, self-injury, hyperactivity, and attention deficits. A consequence of the hyperactivity and attention deficits is that individuals with FXS are frequently diagnosed with attention deficit hyperactivity disorder (ADHD) and treated with medications approved for ADHD (e.g., the α₂-agonist clonidine). The pharmacotherapy of FXS is often accompanied with behavioral therapies that rely on positive reinforcement and other operant principles. Despite the commonplace mixture of drug and behavioral therapy, little attention has been paid to the observation that clonidine or other psychotropic drugs may alter operant processes.

In the present progressive ratio study, we used a knockout mouse model to test the effects of the fragile X genotype, the α₂-agonist clonidine, and the fragile X genotype and clonidine together on operant processes in a positive reinforcement task.

We found that clonidine decreased the progressive ratio breakpoint, increased the length of post-reinforcement pauses, and slowed the run rate. None of these effects varied by genotype. The effect on breakpoint suggests that clonidine alters motivation, but analysis using mathematical principles of reinforcement (MPR) did not rule out motor parameters as a contributor.

Our findings show that clonidine alters operant behavior and serve as a caution for combining clonidine with behavioral therapies that rely on positive reinforcement. Further research using different murine behaviors (e.g., touchscreen tasks) or different animal models (e.g., knockout rats) is needed to explore the interaction between pharmaco- and behavioral therapy.