Psychostimulants Act Within the Prefrontal Cortex to Improve Cognitive Function

Abstract

At low and clinically relevant doses, psychostimulants enhance cognitive and behavioral function dependent on the prefrontal cortex (PFC) and extended frontostriatal circuitry. These actions are observed in individuals with attention-deficit/hyperactivity disorder, as well as in normal human and animal subjects. Despite the widespread use of these drugs, the sites of action involved in their cognition-enhancing and therapeutic effects are poorly understood. Indirect and/or correlative evidence suggests the cognition-enhancing/therapeutic effects of psychostimulants may involve actions directly within the PFC or extended frontostriatal circuitry. The current studies examined the degree to which methylphenidate (MPH) (Ritalin) acts within distinct frontostriatal subfields to improve PFC-dependent cognition as measured in a delayed-response test of spatial working memory. Working memory performance was assessed following microinfusion of vehicle or varying doses of MPH (.03-8.0 μg/500 nL) directly into the dorsomedial PFC (dorsal prelimbic and dorsal anterior cingulate cortex), the ventromedial PFC (infralimbic), and the dorsomedial striatum of rats (n = 69). Methylphenidate infusion into the dorsomedial PFC, but not ventromedial PFC, elicited an inverted U-shaped facilitation of PFC-dependent cognition as measured in this task. The magnitude of this improvement was comparable with that seen with systemic administration. Additional studies demonstrated that although the dorsomedial striatum is necessary for accurate performance in this task, MPH infusion into this region did not affect working memory performance. These observations provide the first definitive evidence that the PFC is a site of action in the cognition-enhancing and presumably therapeutic actions of low-dose psychostimulants.