Aberrant glutamatergic systems underlying impulsive behaviors: Insights from clinical and preclinical research

Abstract

Impulsivity is a broad construct that often refers to one of several distinct behaviors and can be measured with self-report questionnaires and behavioral paradigms. Several psychiatric conditions are characterized by one or more forms of impulsive behavior, most notably the impulsive/hyperactive subtype of attention-deficit/hyperactivity disorder (ADHD), mood disorders, and substance use disorders. Monoaminergic neurotransmitters are known to mediate impulsive behaviors and are implicated in various psychiatric conditions. However, growing evidence suggests that glutamate, the major excitatory neurotransmitter of the mammalian brain, regulates important functions that become dysregulated in conditions like ADHD. The purpose of the current review is to discuss clinical and preclinical evidence linking glutamate to separate aspects of impulsivity, specifically motor impulsivity, impulsive choice, and affective impulsivity. Hyperactive glutamatergic activity in the corticostriatal and the cerebro-cerebellar pathways are major determinants of motor impulsivity. Conversely, hypoactive glutamatergic activity in frontal cortical areas and hippocampus and hyperactive glutamatergic activity in anterior cingulate cortex and nucleus accumbens mediate impulsive choice. Affective impulsivity is controlled by similar glutamatergic dysfunction observed for motor impulsivity, except a hyperactive limbic system is also involved. Loss of glutamate homeostasis in prefrontal and nucleus accumbens may contribute to motor impulsivity/affective impulsivity and impulsive choice, respectively. These results are important as they can lead to novel treatments for those with a condition characterized by increased impulsivity that are resistant to conventional treatments.