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Kappa‐opioid receptors (KOR) control dopamine (DA) levels in the striatum and contribute significantly to the progression of drug addiction. Repeated exposure to psychostimulants has been associated with up‐regulated KOR activity and increased DA levels in dorsal striatum. However, it has not been tested if both processes are linked. In this work, we studied if a mechanism mediated by KOR is contributing to the increase in DA levels in the dorsolateral striatum (DLS) after amphetamine (AMPH) sensitization. The AMPH sensitization was assessed after single or repeated once‐a‐day AMPH injections (1 mg/kg). Only repeated AMPH exposure produced a significant locomotor sensitization. No‐net flux microdialysis was used to assess basal DA dialysate, DA extracellular concentration (Cext), and DA uptake in DLS of anesthetized rats. The role of KOR on DA dynamics in DLS was evaluated by local perfusion (250 μM) and systemic administration (10 mg/kg) of the KOR antagonist nor‐binaltorphimine. A significant decrease in DA Cext is observed in the DLS after an AMPH challenge in rats exposed to a single dose of AMPH. The decrease in DA Cext was associated with both a decreased basal DA dialysate and an increased DA uptake. Conversely, the expression of AMPH sensitization was accompanied by a significant increase in DA Cext associated with an increased basal DA dialysate and an attenuation in DA uptake. Both local and systemic administration of nor‐binaltorphimine reversed changes in DLS after AMPH pre‐treatment. These findings indicate that endogenous KOR system tunes DLS DA dynamics during the progression to AMPH sensitization. We proposed that dynorphin contributes to dopamine (DA) dynamics during progression to amphetamine (AMPH) sensitization modifying DA transporter activity. A significant decrease in DA extracellular levels is observed in the dorsolateral striatum (DLS) after a single dose of AMPH. The decrease in DA extracellular is associated with an increased DA uptake. Conversely, the expression of AMPH sensitization is accompanied by a significant increase in DA extracellular levels associated with attenuation in DA uptake. The administration of nor‐BNI reverses the changes in DLS after AMPH pre‐treatment tending to normalize DA extracellular levels modifying DA uptake activity. [ABSTRACT FROM AUTHOR]

Acute activation of κ-opioid receptors (KOR) decreases dopamine (DA) extracellular levels in both the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc). Also, the acute activation of KOR prevents alterations in behavior and neurochemistry occurring after repeated use of psychostimulants. Opposing to the acute effects, repeated administration of the KOR agonist, U-6593, potentiates both high-potassium and amphetamine induced DA release in the NAc, suggesting that repeated activation of KOR sensitizes mesolimbic dopaminergic neurotransmission. This study investigated the effect of repeated treatment with U-69593 on basal and stimulated DA and serotonin (5HT) extracellular levels in the rat mPFC. Rats were injected once daily with U-69593 (0.16-0.32 mg/kg) or vehicle for 4 days. One day after the last injection, microdialysis experiments assessing DA and 5HT extracellular levels in mPFC were conduced. The repeated treatment with U-69593 significantly augmented potassium-stimulated DA extracellular levels, without affecting potassium-stimulated 5HT extracellular levels, suggesting an increase in DA releasability. Synapse 64:898-904, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]