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, 2004). Intra-SN administration of the enkephalinase inhibitor thiorphan, which slows the degradation rate of endogenous enkephalin, potentiated the amphetamine-induced dopamine release in the striatum (Schad et al., 2002). Enkephalin acts as an endogenous agonist and has a high affinity for ��- and ��-ORs. Thus, it is possible that endogenous opioid peptides enhance dopamine release in the terminals through activation of ��-OR PTPRJ on GABA neurons and then disinhibition of dopamine neurons of the VTA and SN. The METH-produced enhancement of dopamine release and behavioral response should be attenuated in ��-OR knockout mice, as observed in the present study. In addition to dopamine release and reuptake, its metabolic enzymes are also affected by METH (Pereira et al., 2006). Dopamine is oxidized to 3,4-dihydroxyphenylacetic acid (DOPAC) by sequential action of monoamine oxidase (MAO) within cytosol after reuptake from the synaptic cleft. Catechol-O-methyltransferase (COMT) then oxidizes DOPAC to HVA. Alternatively, dopamine is methylated to 3-methoxytyramine by COMT, and then oxidized to HVA by MAO (Standaert and Galanter, 2008). METH inhibits the intraneuronal oxidative metabolism of dopamine through MAO inhibition (Fenton, 2002) and leads to a decrease in tissue concentration of DOPAC (Pereira et al., 2006). As a result, the cytosolic dopamine homeostasis click here would be disrupted. In a recent in vivo microdialysis study, we found that the basal values of DOPAC and HVA in striatal dialysates in wild-type mice was lower (P find more result of increased extracellular dopamine levels. Depletion of endogenous dopamine stores by pretreatment with reserpine fails to block and even enhances the amphetamine-induced behavioral responses (Callaway et al., 1989). Dopamine receptor supersensitivity following reserpine treatment is considered to be responsible for this phenomenon (Feldman et al., 1997). Multiple doses of METH have been reported to cause dopamine 2 (D2) receptor supersensitivity, which is related to the drug-induced locomotor hyperactivity and stereotyped behaviors (Ujike et al., 1990). In a previous study, we treated mice with different doses of METH for 7 consecutive days and sacrificed them on day 11 (4 days after the last injection) for neurochemical measurements. Quantitative autoradiographic analysis of striatum and NAc showed that METH treatment leads to a decrease in D1 receptor ligand binding in ��-OR knockout mice but not in wild-type mice.