Unmasking Impulsivity as a Glutamatergic Dysfunction Phenomenon: Presynaptic and Postsynaptic Considerations

Loss of impulse control is a pervasive hallmark of many neuropsychiatric disorders, such as bipolar disorder, pathological gambling, schizophrenia, substance use disorders, obesity, etc. Characterized as action without thinking, impulsive behavior is recognized as a complex, behavioral endophenotype with multiple dimensions extending into motor activity, higher level cognition and executive functioning, reward/reinforcing attributes, and motivation. Motor impulsivity refers to the inability to withhold a response or delay gratification, and efforts to unmask its complex neurobiology constitutes ongoing areas of research. Indeed, impulsivity has been characterized as a phenomenon driven by the dopamine (DA) and serotonin (5-HT) systems, however the glutamate (Glu) system, localized throughout the central nervous system and responsible for most excitatory signaling, has largely been left untouched. This is striking because like impulsivity, Glu is heavily involved in many neuropsychiatric disorders, several of which overlap with impulsivity. Classically defined as a system that encodes learning and memory, the Glu system has extended roles in reward signaling and motivation. We conducted a series of preclinical studies that aimed to examine glutamatergic presynaptic and postsynaptic neural substrates in key brain regions underlying motor impulsivity. Impulsivity is thought to be a function of a cortical imbalance that results in excessive “go” signaling (i.e. loss of inhibitory control). We discovered that high trait impulsivity (relative to low trait impulsivity) is characterized by imbalances in N-methyl-D-aspartate receptor (NMDAR) expression and synaptic targeting and stabilization. To test the hypothesis that high motor impulsivity is driven by GluR dysfunction, we administered ketamine, a NMDAR channel blocker that induces synaptic plasticity (i.e. GluR strengthening) and the AMPAkine HJC0122, known for its neuroprotective and enhanced cognitive effects. We observed that ketamine and HJC0122, alone and in combination, reduced motor impulsivity, suggesting that indeed, impulsivity is driven partly by GluR dysfunction. We hypothesized that GluR dysfunction may extend to the nucleus accumbens, a limbic area that is largely known as one of the “reward centers” in the brain and involved in the some of the rewarding and motivational aspects of motor impulsivity. We identified the vesicular glutamate transporter 3 (VGLUT3) as a potential glutamatergic presynaptic target. VGLUT3 co-packages Glu and 5-HT into synaptic vesicle for release at the synapse and is localized to the NAc and other brain regions, such as the dorsal raphe nucleus (DRN). We observed that a loss of VGLUT3 tone attenuates impulsive responding in high trait impulsivity rats. Taken together, we implicate the Glu system, from a presynaptic and postsynaptic perspective, as a modulator of high motor impulsivity. These studies and others will inform future clinical decisions on managing neuropsychiatric disorders characterized by loss of impulse control.