Accumulating evidence suggests that neuroinflammation is one of the important etiologic factors of abusive and neuropsychiatric disorders. Platelet-activating factor (PAF) is potent proinflammatory lipid mediat1or and plays a pivotal role in neuroinflammatory disorders through the specific PAF receptor (PAF-R). Phencyclidine (PCP) induces a psychotomimetic state that closely resembles schizophrenia. Here, we investigated the role of PAF-R in the abnormal behaviors induced by PCP in mice. Repeated treatment with PCP resulted in a significant increase in PAF-R gene expression in the prefrontal cortex (PFC) and in the hippocampus. This increase was more pronounced in the PFC than hippocampus. Treatment with PCP resulted in a significant increase in nuclear translocation of the nuclear factor kappa beta (NF-κB) p65 and DNA binding activity, indicating that the proinflammatory molecule NF-κB was increased through up-regulation of PAF-R. Consistently, NF-κB activation was significantly protected by the PAF-R antagonist, ginkgolide B (Gink B), in PAF-R knockout mice and by the NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC). In addition, PCP-induced abnormal behaviors (i.e., reduced sociability, depression, cognitive impairment, and behavioral sensitization) were significantly attenuated by Gink B, in PAF-R knockout mice, and by PDTC. Importantly, PDTC did not significantly alter the attenuations observed in Gink B-treated mice or PAF-R knockout mice, indicating that NF-κB is a critical target for neuropsychotoxic modulation of PAF-R. Therefore, the results suggest that PAF-R mediates PCP-induced neuropsychotoxicity via a NF-κB-dependent mechanism, and that up-regulation of PAF-R may be associated with schizophrenia-like behavior in animal models.

Previously we demonstrated that p53 mediates dopaminergic neurotoxicity via inducing mitochondrial burdens and proapoptotsis. However, little is known about the role of p53 in the excitotoxicity induced by psychostimulant, such as cocaine. Cocaine-induced kindling (convulsive) behaviors significantly increased p53 expression in the brain. Cocaine-induced p53 expression was more pronounced in hippocampus than in striatum or prefrontal cortex. Genetic depletion of p53 significantly attenuated cocaine-induced convulsive behaviors, followed by c-Fos immunoreactivity, and oxidative burdens in the hippocampus of mice. The antioxidant potentials mediated by genetic depletion of p53 were more pronounced in the mitochondrial-than cytosolic-fraction. Depletion of p53 significantly attenuated the changes in mitochondrial transmembrane potential, intramitochondrial Ca2+ level, and mitochondrial oxidative burdens induced by cocaine. Consistently, depletion of p53 significantly inhibited mitochondrial p53 translocation, and cleaved-PKCδ induced by cocaine. In addition, depletion of p53 protected from cytosolic cytochrome c release, and pro-apoptotic changes induced by cocaine. Importantly, the protective/anticonvulsant potentials by genetic depletion of p53 were comparable to those by pifithrin-μ (PFT), a p53 inhibitor. Our results suggest that depletion of p53 offers anticonvulsive and neuroprotective potentials mainly via attenuating mitochondrial oxidative burdens, mitochondrial dysfunction, and pro-apoptotic signalings against cocaine-induced convulsive neurotoxicity.

Converging evidence has demonstrated that oxidative burdens are associated with drug dependence induced by psychostimulants. Here, we investigated whether oxidative stress directly mediates conditioned place preference and behavioral sensitization (drug dependence) induced by cocaine and whether glutathione peroxidase-1 (GPx-1), a major GPx, modulates cocaine-induced psychotoxic changes in mice. Cocaine-induced drug dependence was followed by increases in c-Fos-immunoreactivity (c-Fos-IR) in the nucleus accumbens. Simultaneously, cocaine significantly increased oxidative parameters and nuclear factor κB (NFκB) activity (i.e. nuclear translocation and DNA binding activity) in the striatum (including nucleus accumbens). Genetic depletion of GPx-1 made mice susceptible to drug dependence induced by cocaine in mice, while genetic overexpression of GPx-1 protected the mice from drug dependence. Pyrrolidine dithiocarbamate (PDTC), a NFκB inhibitor, significantly attenuated the sensitivity induced by the genetic depletion of GPx-1 in mice. However, PDTC did not exhibit any additive effects against the protection afforded by the genetic overexpression of GPx-1. Our results suggest that drug dependence induced by cocaine requires oxidative stress and NFκB activation, and that the GPx-1 gene is a potential protective factor against cocaine-induced drug dependence through positive modulation of NFκB.

We have previously demonstrated that repeated treatment with methamphetamine (MA) results in a recognition memory impairment via upregulation of protein kinase C (PKC) δ and downregulation of the glutathione peroxidase-1 (GPx-1)-dependent antioxidant system. We also demonstrated that far-infrared ray (FIR) attenuates acute restraint stress via induction of the GPx-1 gene. Herein, we investigated whether exposure to FIR modulates MA-induced recognition memory impairment in male mice, and whether cognitive potentials mediated by FIR require modulation of the PKCδ gene, extracellular signal-regulated kinase (ERK) 1/2, and glutathione-dependent system. Repeated treatment with MA significantly increased PKCδ expression and its phosphorylation out of PKC isoenzymes (i.e., PKCα, PKCβI, PKCβII, PKCζ, and PKCδ expression) in the prefrontal cortex of mice. Exposure to FIR significantly attenuated MA-induced increase in phospho-PKCδ and decrease in phospho-ERK 1/2. In addition, FIR further facilitated the nuclear factor E2-related factor 2 (Nrf2)-dependent glutathione synthetic system. Moreover, L-buthionine-(S, R)-sulfoximine, an inhibitor of glutathione synthesis, counteracted the FIR-mediated phospho-ERK 1/2 induction and memory-enhancing activity against MA insult. More important, positive effects of FIR are comparable to those of genetic depletion of PKCδ or the antipsychotic clozapine. Our results indicate that FIR protects against MA-induced memory impairment via activations of the Nrf2-dependent glutathione synthetic system, and ERK 1/2 signaling by inhibition of the PKCδ gene.