Elsevier

Biological Psychiatry

Volume 72, Issue 3, 1 August 2012, Pages 221-227
Biological Psychiatry

Archival Report
Psychostimulants Act Within the Prefrontal Cortex to Improve Cognitive Function

https://doi.org/10.1016/j.biopsych.2011.12.002Get rights and content

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.

Section snippets

Animals

Male Sprague-Dawley rats (260–280 grams; Charles River, Wilmington, Massachusetts) were pair-housed in clear polycarbonate cages on a 13/11-hour light/dark cycle (lights on 0600 hours). Animals were fed ad libitum for the first 7 days and subsequently restricted to 15 to 17 grams of food per day following training/testing. Training/testing was conducted between 0900 and 1600 hours (typically 6 days/week). Rats were weighed twice weekly to confirm animals did not lose weight and were assigned a

Cognitive Effects of Intra-PFC MPH Infusion

Given the likely involvement of rat dAcg in working memory performance (21), we avoided placement of guide cannulae directly into this dorsal-most region of the rat mPFC and utilized small gauge (33-gauge) infusion needles. As shown in Figure 1, this approach resulted in minimal damage to the mPFC. Vehicle infusions had minimal, nonsignificant effects on working memory performance (.75% ± 2.37% change from baseline, n = 13; Figure 1). In contrast, direct infusion of MPH (500 nL) into the dmPFC

Discussion

Despite the widespread use of psychostimulants as cognitive enhancers, surprisingly little is known about the neural circuitry involved in their cognitive/therapeutic actions. Although systemic administration of low-dose psychostimulants improves frontostriatal function, whether this reflects direct or indirect actions in the PFC or striatum is unclear. The current studies provide unambiguous evidence that psychostimulant action within the PFC/frontal cortex is sufficient to promote higher

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