Sensitization to amphetamine, but not PCP, impairs attentional set shifting: reversal by a D1 receptor agonist injected into the medial prefrontal cortex

Psychopharmacology (Berl). 2005 Dec;183(2):190-200. doi: 10.1007/s00213-005-0157-6. Epub 2005 Nov 9.


Rationale: Repeated exposure to psychomotor stimulants can lead to sensitization to their effects, and sensitization has been implicated in the pathophysiology of schizophrenia and drug abuse. These disorders are characterized by cognitive deficits, particularly in prefrontally mediated executive function.

Objective: The present experiments were conducted to investigate the effects of sensitizing regimens of amphetamine and phencyclidine (PCP) on attentional set shifting.

Methods: Rats received injections of amphetamine, PCP or saline three times per week for 5 weeks. Four weeks later, rats were trained to dig for food in one of two bowls, each bowl having an odour and a texture. Only one dimension (odour or texture) correctly predicted which bowl was baited. Rats were then tested on a series of discriminations including those requiring an intra-dimensional shift (IDS), an extra-dimensional shift (EDS) or a reversal of previously relevant and irrelevant stimuli.

Results: Rats sensitized to amphetamine performed normally on the IDS, but were impaired on the EDS, as well as on reversal discriminations. PCP-sensitized rats were unaffected on any of the discriminations. In amphetamine-sensitized rats the deficit at the EDS stage was reversed by infusion of the D(1) receptor agonist SKF38393 into the medial prefrontal cortex (mPFC).

Conclusions: Results show that the amphetamine-sensitized state impairs prefrontally mediated attentional set shifting. This is consistent with cognitive deficits in schizophrenia and addiction, and with the evidence that amphetamine sensitization is accompanied by functional changes in the mPFC. These results further add to a growing literature showing that activating D(1) receptors in the mPFC improves aspects of cognition.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / administration & dosage*
  • Amphetamine / adverse effects*
  • Analysis of Variance
  • Animals
  • Attention Deficit Disorder with Hyperactivity / chemically induced*
  • Attention Deficit Disorder with Hyperactivity / drug therapy*
  • Behavior, Animal / drug effects
  • Conditioning, Operant / drug effects
  • Discrimination Learning / drug effects
  • Dopamine Uptake Inhibitors / adverse effects*
  • Drug Interactions
  • Excitatory Amino Acid Antagonists / adverse effects
  • Male
  • Motor Activity / drug effects
  • Phencyclidine / adverse effects
  • Prefrontal Cortex / drug effects*
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D1 / agonists*


  • Dopamine Uptake Inhibitors
  • Excitatory Amino Acid Antagonists
  • Receptors, Dopamine D1
  • 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
  • Amphetamine
  • Phencyclidine