Date of Award
Ph.D. in Psychology
Karen E. Sabol
John P. Bentley
Impaired attention is common in many neurological disorders. Normal attention promotes the selective processing of important sensory information. This selective processing relies on neurotransmitters, like glutamate, and neuromodulators, like norepinephrine, acting in frontal, parietal, and visual cortices. We tested treatments targeting the glutamatergic and noradrenergic systems using a rat model of attentional lapses.Rats were trained to respond quickly to stimuli in a two-choice reaction time task (2CRTT). Response times were split into initiation time (IT) and movement time (MT). Performance measures were derived from IT and MT distributions. IT mode represents sensorimotor processing speed when rats are attentive. IT deviation from mode (devmode) measures distribution skew which is thought to reflect attentional lapses. Altered MT mode or trials completed could reflect drug-induced side-effects. We tested the NMDA receptor co-agonist, D-serine, in a group of rats. We then tested a combination treatment of D-serine and the norepinephrine reuptake inhibitor, atomoxetine (ATX). New rats were used in a follow-up test. Data were analyzed using linear mixed models or repeated measures ANOVA. We did not find an effect of D-serine on IT mode; however, the highest dose (300 mg/kg) reduced IT devmode. The initial test of the combination treatment (100 mg/kg D-serine with 0.5 mg/kg ATX) did not reveal an effect on IT mode; however, the combination treatment reduced IT devmode with no effect following either drug alone. The follow-up test (125 mg/kg D-serine with 0.3 mg/kg ATX) did not reveal an effect on IT mode; however, IT devmode was reduced following ATX or the combination treatment. Importantly, the combination treatment reduced IT devmode more than either drug alone. Furthermore, the combination treatment did not increase MT mode or trials completed compared to ATX alone. Activating NMDA receptors with D-serine appears to reduce attentional lapses without affecting sensorimotor processing speed. The present findings also support the efficacy of a combination treatment comprising D-serine and ATX. This combination treatment does not appear to increase unwanted side-effects associated with ATX. Taken together, these findings suggest that simultaneously targeting glutamate and NE systems could be a safe and effective strategy for treating impaired attention.
Redding, Zach V., "Pharmacological manipulation of NMDA receptor activation and synaptic norepinephrine levels: Effects on sustained attention in male rats" (2021). Electronic Theses and Dissertations. 2048.