Cognition-Enhancing Doses of Methylphenidate Preferentially Increase Prefrontal Cortex Neuronal Responsiveness

Abstract

Despite widespread use of low-dose psychostimulants for the treatment of attention-deficit/hyperactivity disorder (ADHD), the neural basis for the therapeutic actions of these drugs are not well understood. We recently demonstrated that low-dose methylphenidate (MPH) increases catecholamine efflux preferentially within the prefrontal cortex (PFC), suggesting that the PFC is a principal site of action in the behavioral-calming and cognition-enhancing effects of low-dose psychostimulants. To understand better the neural mechanisms involved in the behavioral actions of low-dose stimulants, this study examined the effects of low-dose MPH on the discharge properties of individual and ensembles of PFC neurons. Extracellular activity of multiple individual PFC neurons was recorded in freely moving rats using multichannel recording techniques. Behavioral studies identified optimal, working memory-enhancing doses of intraperitoneal MPH. The effects of these low-doses of MPH on PFC neuronal discharge properties were compared with 1) the effects of high-dose MPH on PFC neuronal discharge and 2) the effects of low-dose MPH on neuronal discharge within the somatosensory cortex. Only working memory-enhancing doses of MPH increased the responsivity of individual PFC neurons and altered neuronal ensemble responses within the PFC. These effects were not observed outside the PFC (i.e., within somatosensory cortex). In contrast, high-dose MPH profoundly suppressed evoked discharge of PFC neurons. These observations suggest that preferential enhancement of signal processing within the PFC, including alterations in the discharge properties of individual PFC neurons and PFC neuronal ensembles, underlie the behavioral/cognitive actions of low-dose psychostimulants.