Endogenous κ-Opioid Receptor Systems Regulate Mesoaccumbal Dopamine Dynamics and Vulnerability to Cocaine

Abstract

Genetic and pharmacological approaches were used to examine -opioid receptor (KOR-1) regulation of dopamine (DA) dynamics in the nucleus accumbens and vulnerability to cocaine. Microdialysis revealed that basal DA release and DA extraction fraction (E d ), an indirect measure of DA uptake, are enhanced in KOR-1 knock-out mice. Analysis of DA uptake revealed a decreased K m but unchanged V max in knock-outs. Knock-out mice exhibited an augmented locomotor response to cocaine, which did not differ from that of wild-types administered a behavioral sensitizing cocaine treatment. The ability of cocaine to increase DA was enhanced in knock-outs, whereas c-fos induction was decreased. Although repeated cocaine administration to wild types produced behavioral sensitization, knock-outs exhibited no additional enhancement of behavior. Administration of the long-acting KOR antagonist nor-binaltorphimine to wild-type mice increased DA dynamics. However, the effects varied with the duration of KOR-1 blockade. Basal DA release was increased whereas E d was unaltered after 1 h blockade. After 24 h, release and E d were increased. The behavioral and neurochemical effects of cocaine were enhanced at both time points.These data demonstrate the existence of an endogenous KOR-1 system that tonically inhibits mesoaccumbal DA neurotransmission. Its loss induces neuroadaptations characteristic of "cocaine-sensitized" animals, indicating a critical role of KOR-1 in attenuating responsiveness to cocaine. The increased DA uptake after pharmacological inactivation or gene deletion highlights the plasticity of mesoaccumbal DA neurons and suggests that loss of KOR-1 and the resultant disinhibition of DA neurons trigger short-and long-term DA transporter adaptations that maintain normal DA levels, despite enhanced release.

Ablation of Kappa-Opioid Receptors from Brain Dopamine Neurons has Anxiolytic-Like Effects and Enhances Cocaine-Induced Plasticity

“…Here we describe initial characterization of these mice in molecular assays to confirm the efficacy of the mutation, as well as in a battery of behavioral tests that quantify effects of the mutations on metrics including hearing, vision, weight, locomotor activity in an open field and anxiety. We also examined the effects of acute and repeated cocaine on behavior in these mice, for comparison with findings from previous reports (Chefer et al, 2005). This early work provides a basis for future studies of KOR function in these mice.…”

“…No differences were detected in open arm time or open arm entries in the EPM (Figures 8c and d). Previous results suggest that KOR À / À mice fail to exhibit cocaine-induced behavioral sensitization, but appear presensitized to the locomotor-activating effects following the first injection of cocaine (Chefer et al, 2005). To determine whether our lines of mice-which differ from these previous lines because they were generated by loxP recombination-exhibit a similar behavioral phenotype, mice were tested in a cocaine-induced behavioral sensitization paradigm.…”

“…The methods were based on those previously described (Chefer et al, 2005) to enable direct comparisons between our mutant lines and published data. Briefly, at the same time each day mice were subjected to a 3 h test, which included a 1 h habituation session (0-60 min), a 1 h postsaline (10 ml/kg, IP) test session (60-120 min), and a final 1 h postcocaine (15 mg/kg, IP) test session (120-180 min).…”

“…We generated a line of mice in which exon 3 of the KOR gene (opioid receptor, kappa 1 (Oprk1)) was targeted for deletion by flanking it with Cre-lox (loxP) recombination sites, thereby enabling conditional (region-specific) KOR deletion and allowing the design of new studies that complement work conducted in previously reported lines (Chefer et al, 2005). 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 À / À ) and conditional knockouts that lack KORs in DA-containing neurons (DAT-KOR lox/lox ).…”

Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system

“…Briefly, increased activation of the nucleus accumbens results in a cAMP-response-element-binding-protein-mediated increase in dynorphin release that acts on inhibitory kappa receptors on the terminals and cell body of dopaminergic ventral tegmental area neurons. Kappa agonists have been shown to decrease mesolimbic DA release and activity (Di Chiara and Imperato 1988;Chefer et al 2005). Co-administration of kappa receptor agonists with cocaine has been shown to attenuate the rewarding and behavioral effects of cocaine.…”