Psychostimulants act within the prefrontal cortex to improve cognitive function

Abstract

Background: 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.

Methods: 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).

Results: 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.

Conclusions: 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.

Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

(A) Representative photomicrograph depicting an infusion site into dorsomedial prefrontal cortex (dmPFC). Note minimal damage to dorsal areas. (B) Infusion of MPH into the dmPFC improved working memory performance in an inverted-U dose-dependent manner, with 0.125 μg/hemisphere producing a maximal improvement. (C) Schematic diagram indicating all 0.125 μg infusion sites into the dmPFC. dAcg, dorsal anterior cingulate; PL, prelimbic; IL, infralimbic. Numbers represent AP level (52). *P < 0.05 relative to vehicle treatment.

Figure 2

(A) Representative photomicrograph indicating site of MPH infusion into the infralimbic subregion of the mPFC. (B) Schematic of 0.125μg MPH infralimbic infusion sites. (C) Infusion of MPH into the IL PFC had no significant effect on working memory performance measured as the percent change from baseline (mean ± SEM). mPFC, medial prefrontal cortex; dAcg, dorsal anterior cingulate; PL, prelimbic; IL, infralimbic. Numbers represent AP level (52).

Figure 3

(A) Fluorogold retrograde tracer infused into dmSTR (top panel) results in strong neuronal labeling of dorsomedial PFC (Top Panel, 40x; Bottom Panel, 200x; A+2.7). (B) Representative photomicrograph depicting muscimol/MPH dmSTR infusion sites. (C) Intra-dmSTR muscimol significant impaired working memory performance as measured by the percent change from baseline (mean ± SEM). The magnitude of this impairment is comparable to that seen with PFC inactivation, indicating a critical role of the dmSTR in working memory performance. (D) Intra-dmSTR infusion of MPH had no significant effect on working memory performance as measured by the percent change from baseline (mean ± SEM). dmSTR, dorsomedial striatum; dAcg, dorsal anterior cingulate; PL, prelimbic; IL, infralimbic. **P < 0.01 relative to vehicle (AECF) treatment.