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Amphetamine increases timing variability by degrading prefrontal temporal encoding
Journal article   Peer reviewed

Amphetamine increases timing variability by degrading prefrontal temporal encoding

Matthew A. Weber, Kartik Sivakumar, Braedon Q. Kirkpatrick, Hannah R. Stutt, Ervina E. Tabakovic, Alexandra S. Bova, Young-cho Kim and Nandakumar S. Narayanan
Neuropharmacology, Vol.275, 110486
09/01/2025
DOI: 10.1016/j.neuropharm.2025.110486
PMCID: PMC12261982
PMID: 40324651

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Abstract

Amphetamine is a commonly abused psychostimulant that increases synaptic catecholamine levels and impairs executive functions. However, it is unknown how acute amphetamine affects brain areas involved in executive control, such as the prefrontal cortex. We studied this problem in mice using interval timing, which requires participants to estimate an interval of several seconds with a motor response. Rodent prefrontal cortex ensembles are required for interval timing. We tested the hypothesis that amphetamine disrupts interval timing by degrading prefrontal cortex temporal encoding. We first quantified the effects of amphetamine on interval timing performance by conducting a meta-analysis of 15 prior rodent studies. We also implanted multielectrode recording arrays in the dorsomedial prefrontal cortex of 7 mice and then examined the effects of 1.5 mg/kg D-amphetamine injected intraperitoneally on interval timing behavior and prefrontal neuronal ensemble activity. A meta-analysis of previous literature revealed that amphetamine produces a large effect size on interval timing variability across studies but only a medium effect size on central tendencies of interval timing. We found a similar effect on interval timing variability in our task, which was accompanied by greater trial-to-trial variability in prefrontal ramping, attenuated interactions between pairs of ramping neurons, and dampened low-frequency oscillations. These findings suggest that amphetamine alters prefrontal temporal processing by increasing the variability of prefrontal temporal encoding. Our work provides insight into how amphetamine affects prefrontal activity, which may be useful in developing new neurophysiological markers for amphetamine use and novel treatments targeting the prefrontal cortex. [Display omitted] •Acute amphetamine increased response time variability in an interval timing task•Amphetamine degraded temporal processing in prefrontal cortex ensembles•Amphetamine dampened low-frequency cortical rhythms related to interval timing
 Dopamine Electrophysiology amphetamine cognition interval timing prefrontal cortex

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