Low-Dose Methylphenidate Actions on Tonic and Phasic Locus Coeruleus Discharge

Abstract

Methylphenidate (MPH) and other psychostimulants are highly effective in the treatment of attention deficit hyperactivity disorder (ADHD). Evidence indicates the therapeutic actions of stimulants in ADHD probably involve the locus coeruleus (LC)-norepinephrine system. LC neurons display different firing modes (tonic and phasic), each associated with distinct behavioral and cognitive processes. To date, the impact of low, clinically relevant doses of psychostimulants on LC discharge is unknown. The present study examined the effects of low-dose MPH on LC tonic and phasic discharge in the halothane-anesthetized rat. In these studies, MPH produced a dose-dependent suppression of tonic and phasic discharge that was relatively modest at the lower doses. Nonetheless, these lower doses of MPH suppressed the signal-to-noise ratio of excitatory phasic discharge and increased the signal-to-noise ratio of the inhibitory component of the phasic response. Largely comparable effects were observed with oral and intraperitoneal administration of MPH. Combined, these observations indicate relatively modest suppression of LC neuronal discharge activity by low-dose MPH and that evoked discharge may be more sensitive than tonic activity to the lowest doses of MPH. It is posited that the behavioral-calming and cognition-enhancing effects of low-dose psychostimulants probably involve modest alterations in LC discharge combined with increased catecholamine efflux within select forebrain regions (i.e., the prefrontal cortex).