43, P > 0.05), however 24 h following conditioning, the METH+MK801 group (n = 5), but not the Ringer’s (n = 6) and or the METH-treated check details groups (n = 5), showed positive CPP toward the drug-paired chambers (P < 0.001). In addition, METH+MK801 rats showed a statistically greater increase in time deviation toward the drug-paired chambers compared to the controls (P < 0.001). One week following conditioning, only the previously METH-treated rats showed positive bias toward Ringer's-paired

chambers compared to both the METH+MK801 groups (P < 0.001) and the Ringer's groups (P < 0.05) (Fig. 6D and 6E). Our observation overall indicated that blocking the NMDA receptors reversed the diminished place learning Inhibitors,research,lifescience,medical following intra-VHC-METH. Inhibitors,research,lifescience,medical This attenuation in place learning could therefore be an NMDA receptor activation-mediated process. The observation could also be METH-induced place aversion. Alternatively, because the initial place preference was negative relative to the positively conditioned side of the apparatus, the finding could be a block of CPP and that the data may reflect a block of learning rather than an aversion. Figure 6 The top-down pathway of the Inhibitors,research,lifescience,medical hippocampus-VTA loop attenuates place preference learning following conditioning the VHC, which was

reversed by inhibiting NMDA receptors using MK801. (A) Baseline place preference as defined by the amount of time per session … In rats that were previously conditioned with intra-VHC-METH, intra-VTA-METH produced place Inhibitors,research,lifescience,medical aversion which was reversed by NMDA receptor blockade After we completed

conditioning the VHC, we continued conditioning the same rats from “Intra-VHC-METH diminished place reinforcement learning which was reversed by NMDA receptor blockade”, this time by applying METH intra-VTA (Fig. 1C). Twenty-four hours postintra-VTA conditioning, the METH-treated rats, but not the other two groups, showed increased time deviation toward the Ringer’s-paired chambers (potentially aversion), (P < 0.05), whereas METH+MK801 Inhibitors,research,lifescience,medical group, but nearly not the other two groups, showed a significant place preference toward drug-paired chambers (P < 0.05) a week following conditioning. Moreover, compared to METH+MK801 groups, the METH-treated rats showed significantly decreased time deviations away from the METH-paired chambers (P < 0.01) (Fig. 7A–D). The combination group (METH+MK801) preferred drug-paired chambers compared to the other two groups suggests that the METH induced place aversion that is potentially due to the activation of NMDA receptors. Overall, unlike the effect of METH on the induction of positive CPP that we observed following conditioning the bottom-up pathway of the hippocampus-VTA loop, METH in the top-down order of conditioning had place aversion effects even postconditioning the VTA (Fig. 7C and 7D).