Major coexpression of κ‐opioid receptors and the dopamine transporter in nucleus accumbens axonal profiles

Abstract

The behavioral effects of psychostimulants, which are produced at least in part through inhibition of the dopamine transporter (DAT), are modulated by kappa-opioid receptors (KOR) in the nucleus accumbens (Acb). Using electron microscopic immunocytochemistry, we reveal that in the Acb KOR labeling is mainly, and DAT immunoreactivity is exclusively, presynaptic. From 400 KOR-labeled presynaptic structures, including axon terminals, intervaricosities, and small axons, 51% expressed DAT and 29% contacted another population of terminals exclusively labeled for DAT. Within axonal profiles that contained both antigens, DAT and KOR were prominently localized to plasma membrane segments that showed overlapping distributions of the respective immunogold-silver and immunoperoxidase markers. KOR labeling was also localized to membranes of small synaptic vesicles in terminals with or without DAT immunoreactivity. In addition, from 24 KOR-immunoreactive dendritic spines 42% received convergent input from DAT-containing varicosities and unlabeled terminals forming asymmetric, excitatory-type synapses. Our results provide the first ultrastructural evidence that in the Acb, KOR is localized to strategic sites for involvement in the direct presynaptic release and/or reuptake of dopamine. These data also suggest a role for KOR in the presynaptic modulation of other neurotransmitters and in the postsynaptic excitatory responses of single spiny neurons in the Acb. Dual actions on dopamine terminals and their targets in the Acb may account for KOR-mediated attenuation of drug reinforcement and sensitization.

κ-Opioid receptor modulation of accumbal dopamine concentration during operant ethanol self-administration

“…Chefer et al (2005)has suggested that dopamine release is in fact enhanced after long-term kappa blockade with NOR-BNI, but that basal dopamine concentration remains unchanged due to an increase in dopamine uptake. Thus, the KOPr system may interact with the dopamine transporter to regulate basal dopamine levels, a possibility supported by their anatomical localization (Svingos et al, 2001). How this interaction may affect dopamine dynamics during ethanol self-administration, however, is unknown at present.…”

The role of the dynorphin/κ opioid receptor system in anxiety

“…κ Opioid receptors are located on both the cell bodies and terminals of mosocorticolimbic DA neurons [72,73] . Activation of κ opioid receptors leads to the inhibition of DA neurons in the VTA [74] and decreases DA release in regions that receive VTA input [75,76] .…”

Kappa-Opioid Agonist U69593 Potentiates Locomotor Sensitization to the D2/D3 Agonist Quinpirole: Pre- and Postsynaptic Mechanisms

“…Indeed, already upon an acute injection of the kappa agonist with QNP, the depressive effects of QNP turned into locomotor excitation (Figure 2a) and the total amount of locomotion was equivalent to what could be observed after 5-6 injections of QNP alone (Figure 1). Considering that, like D2 autoreceptors, the kappa receptors regulating dopamine release are located on presynaptic dopamine terminals (Svingos et al, 2001) (as are presumably the tyrosine hydroxylase regulating kappa receptors), the coadministration of the kappa agonist probably facilitates sensitization to QNP by a presynaptic mode of action that enhances not only the blockade of dopamine release but also the reduction in basal levels of extracellular dopamine.…”