This study investigates the roles of hippocampal N-methyl-D-aspartate (NMDA) glutamate receptors and CaMKII (calcium/calmodulin-dependent protein kinase II) in amphetamine-produced conditioned place preference (AMPH-CPP) in rats. An earlier report showed that AMPH-CPP resulted in the enhancement of hippocampal CaMKII activity. In this study, AMPH-CPP significantly increased hippocampal GluR1 receptors, though AMPH-CPP was impaired by either blockade of NMDA receptors (AP5) or inhibition of CaMKII (KN-93) during conditioning. These treatments also impaired CPP if administered before testing, but CPP recovered during the next testing session. Therefore, these treatments had no effect on the extinction of CPP. If the conditioned rats were, however, reexposed to AMPH-CPP after a hippocampal-infusion of AP5 or KN-93, the extinction of the original CPP was greater than that seen in the controls. The hippocampal-infusion of D-cycloserine before CPP testing enhanced the extinction of CPP. These results, taken together, indicate that NMDA receptor activation and CaMKII activity are essential for the AMPH-CPP. AMPH-CPP reexposure is similar to the memory reconsolidation process, being disrupted by either a blockade of the NMDA receptor or an inhibition of CaMKII. Furthermore, the extinction of CPP resembles new learning, which is an active process and is facilitated by a partial NMDA agonist.

Administration of haloperidol for 2 weeks causes an increase within the caudate nucleus of asymmetrical synapses associated with a discontinuous or perforated, postsynaptic density (PSD) [Meshul et al. (1992), Psychopharmacology, 106:45-52; Meshul et al. (1992), Neuropsychopharmacology, 7:285-293]. Coadministration of the N-methyl-D-aspartate noncompetitive antagonist, MK-801, with haloperidol blocked the increase in striatal synapses containing a perforated PSD [Meshul et al. (1994), Brain Res., 648:181-195]. Examination of the caudate using immuno-gold electron microscopy revealed the vast majority (90%) of asymmetrical synapses were labelled with a glutamate antibody [Meshul et al. (1994), Brain Res., 648:181-195]. The purpose of this study was to determine if there were any changes in the density of glutamate immunoreactivity within presynaptic terminals of asymmetric synapses within the striatum following treatment with haloperidol for 1 month that would correlate with the previously observed increase in synapses with perforated PSDs. We also determined the activity of striatal calcium/calmodulin kinase II (CaMK II), an enzyme known to be localized within the synaptic region, after administration of haloperidol. We report here that haloperidol causes an increase in the activity of CaMK II and a decrease in the density of immuno-gold labelling for glutamate within the nerve terminals of asymmetrical synapses containing a perforated or nonperforated PSD. These results are consistent with the hypothesis that the haloperidol-induced increase in activity of CaMK II and the increase in glutamate release, as suggested by the decrease in presynaptic glutamate immunoreactivity, may ultimately lead to an increase in the number of synapses displaying a perforated PSD. These results support the speculation that the haloperidol-induced increase in synapses containing a perforated PSD may be associated with enhanced activity at excitatory synapses.

N-methyl-D-aspartate (NMDA) receptor/channel antagonists have previously been shown to impair spatial working memory and hippocampal long-term potentiation. The present experiment investigated the effects of a variety of doses of NMDA antagonists on a working memory task in rats involving an auditory delayed conditional discrimination. Signal detection analysis and an exponential memory decay model were used to extract independent measures of stimulus discriminability and rate of forgetting. A competitive NMDA antagonist, (CPP, 0.33, 1.0, 10.0 mg/kg, IP) produced a reduction in discriminability which was linearly related to log dose, but which was only clear at the 10 mg/kg dose. Rate of forgetting was not increased by any dose. Similar results were obtained with a non-competitive antagonist (MK-801, 0.1, 0.33 mg/kg, IP). These data suggest that doses of NMDA receptor channel antagonists sufficient to disrupt hippocampal long-term potentiation and radial arm maze performance will also disrupt delayed conditional discrimination. The effect on delayed conditional discrimination is due to a disruption of stimulus discriminability and not to an increased rate of forgetting. The extent to which these effects relate to the reported changes in hippocampal long-term potentiation and radial arm maze performance remains to be determined.

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