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Brain kappa-opioid receptors (KORs) are implicated in states of motivation and emotion. Activation of KORs negatively regulates mesolimbic dopamine (DA) neurons, and KOR agonists produce depressive-like behavioral effects. To further evaluate how KOR function affects behavior, we developed mutant mice in which exon 3 of the KOR gene (Oprk1) was flanked with Cre-lox recombination (loxP) sites. By breeding these mice with lines that express Cre-recombinase (Cre) in early embryogenesis (EIIa-Cre) or only in DA neurons (dopamine transporter (DAT)-Cre), we developed constitutive KOR knockouts (KOR−/−) and conditional knockouts that lack KORs in DA-containing neurons (DAT-KOR lox/lox). Autoradiography demonstrated complete ablation of KOR binding in the KOR−/− mutants, and reduced binding in the DAT-KOR lox/lox mutants. Quantitative reverse transcription PCR (qPCR) studies confirmed that …