Behavioral deficits and recovery following transient focal cerebral ischemia in rats: glutamatergic and GABAergic receptor densities.

The neurobiologic mechanisms underlying the recovery process following stroke are poorly understood. The present study investigated glutamatergic and gamma-amino butyric acid (GABA)-ergic receptor densities following experimental stroke in rats exposed to different environmental housing or pharmacologic interventions. About 2 days after transient (120 min) middle cerebral artery (MCA) occlusion, the rats were singly housed in standard cages or were moved to an enriched environment and treated for 10 days with either 0.9% NaCl or with the alpha(2)-adrenoceptor antagonist, atipamezole (1.0 mg/kg, s.c.). The limb-placing, foot-slip, and water-maze tests were used to assess behavioral deficits and recovery following ischemia. The rats were decapitated on day 25 after the operation and their brains were processed for [3H]MK-801, [3H]D,L,-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), [3H]kainate, and [3H]muscimol autoradiography. Receptor binding site densities were different between sham-operated rats and ischemic rats only in the lesion core and lateral ventroposterior thalamic nucleus. Ischemic rats housed in an enriched environment and treated with atipamezole had better performance in the limb-placing test. The deficit in the water-maze test was most pronounced in ischemic rats housed in standard cages. There were a number of correlations between the behavioral data and receptor binding densities in ischemic rats. For example, recovery in the limb-placing test correlated with [3H]AMPA receptor binding sites in the contralateral frontal cortex (r=0.616, P<0.05), hindlimb cortex (r=0.649, P<0.05), and parietal cortex (r=0.674, P<0.05) in ischemic rats housed in an enriched environment. There were similar correlations between limb-placing recovery and [3H]kainate binding sites in the contralateral cortices in ischemic rats housed in standard cages. In addition, there were particularly strong clustered correlations between swimming speed in the water-maze test and [3H]AMPA receptor binding sites in the hippocampal subregions in the ischemic rats housed in an enriched environment. The present results suggest that transient focal cerebral ischemia does not induce significant long-term changes in glutamatergic and GABAergic receptors in areas remote from the infarct area. The correlational data, however, suggest an important role for the contralateral cortex in the behavioral outcome and maintenance of the recovered state of ischemic rats, depending on housing conditions. In addition, attenuation of spatial learning deficits observed in ischemic rats housed in an enriched environment might be due to an increase in the swimming speed through hippocampal AMPA receptor-mediated mechanisms.