A pharmacological MRI assessment of dizocilpine (MK-801) in the 3-nitroproprionic acid-lesioned rat

The NMDA-antagonist dizocilpine (MK-801) is known to have dissociative, neurotoxic and neuroprotective properties. Although its neuroprotective properties are well documented, at present only ex vivo autoradiography has demonstrated its activity in lesioned brains. We report here the use of pharmacological magnetic resonance imaging (phMRI) to visualise the neural substrates of MK-801 in normal control rats and in animals that received systemic 3-nitroproprionic acid (3-NPA) 2 weeks earlier. In control animals, this NMDA-antagonist resulted in activity in the hippocampus, retrospinal (RS) cortex, anterior cingulate and the medial prefrontal cortex (MPFC). Activity in the MPFC has been associated with the dissociative properties of this agent and has been suggested to be the neurological substrate of positive psychotic symptoms, whereas RS and hippocampus have been the main sites of neurotoxic actions of MK-801. In contrast, in animals with 3-NPA-lesions affecting the striatum, no activity in the MPFC was observed, but a positive BOLD signal in the striatum was apparent. Lesioned animals injected with saline did not show this pattern of activity indicating that it is not merely an artefact of the ongoing neurodegeneration. This striatal activity could therefore be a site of MK-801-mediated neuroprotection. phMRI therefore sheds further light on the in vivo activity of MK-801 which, in turn, may allow us to more fully understand the different actions of NMDA-antagonists.