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Organic cation transporter-3 (OCT3) is expressed in several tissues including the brain. We have previously demonstrated that rats with behavioral sensitization to methamphetamine (METH) increased the brain penetration of METH with decreased expression of OCT3 in brain. Considering the earlier in vitro studies demonstrating that 1) OCT3 could transport dopamine (DA) and 2) the specific transport via OCT3 could be inhibited by METH, these results suggest that decreased OCT3 might decrease the efflux of METH and/or DA from brain, subsequently causing the development of behavioral sensitization. Thus, in the present study, behavioral task related to DA and pharmacokinetic experiment were performed using rats treated with antisense against OCT3 (OCT3-AS) since no specific ligands for OCT3 are still available. The continuous infusion of OCT3-AS into the third ventricle significantly decreased the expression of OCT3 in choroid plexus (CP) epithelial cells. Both METH-induced hyperlocomotion and METH-induced extracellular DA levels in nucleus accumbens and prefrontal cortex were significantly increased in OCT3-AS-treated rats. Moreover, the concentrations of METH were significantly increased in cerebrospinal fluid as well as extracellular areas at the nucleus accumbens in OCT3-AS-treated rats. These results suggested that decreased OCT3 elevated the concentration of METH and/or DA in brain, subsequently enhancing dopaminergic neuronal transmission and increasing METH-induced hyperlocomotion. In summary, OCT3 at the CP could regulate the effect of METH by controlling the levels of METH and/or DA in brain. Thus, these results suggest that OCT3 may be a new molecular target to treat METH-related disorders such as drug abuse and schizophrenia.

In the amygdala (AMG) slices obtained from both the young (4-7 months old) and aged (17-20 months old) groups of Senescence-Accelerated Mouse (SAM) P10, spontaneous bursts were recorded in the medial, central and basolateral nuclei. The spontaneous bursts were also observed in the slices from the young group of SAMR1, whereas the mean frequency was significantly lower than that from the young group of SAMP10. The spontaneous burst was barely detectable in slices from the aged group of SAMR1 during perfusing with the standard solution, while bicuculline methiodide (10 microM), a GABAA receptor antagonist, or Mg2+-free solution induced a similar bursting activity observed in the young group. The burst response was also evoked in the medial, central and basolateral AMG following stimulation of the stria terminalis (ST). Both spontaneous and evoked bursts were completely suppressed by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 4 microM), an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptor antagonist, but not by (+)-5-methyl-10, 11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine hydrogen maleate (MK-801, 30 microM), an N-methyl-d-aspartate receptor antagonist. The hyperexcitability of the AMG neurons was further substantiated by optical recordings. Following stimulation of the ST, the optical signals reflected postsynaptic responses spread into the medial and central AMG areas at 2-5 ms and faded out at 20-30 ms after stimulation. The intensity of the optical signal recorded in the slice from the young SAMP10 was significantly higher than that from SAMR1 or ddY mice. These observations indicate that bursts mediated by AMPA/kainate receptors were transiently generated in the AMG of SAMR1 at the young age, while the bursts with higher frequency were continuously generated in the AMG of SAMP10. The chronic neuronal hyperactivity in the AMG may be partially responsible for the age-related deterioration of memory and learning abilities observed in SAMP10.