Prefrontal Cortical Kappa-Opioid Receptor Modulation of Local Neurotransmission and Conditioned Place Aversion

Abstract

Kappa-opioid receptors (KORs) are important for motivation and other medial prefrontal cortex (mPFC)-dependent behaviors. Although KORs are present in the mPFC, their role in regulating transmission in this brain region and their contribution to KOR-mediated aversion are not known. Using in vivo microdialysis in rats and mice, we demonstrate that intra-mPFC administration of the selective KOR agonist U69,593 decreased local dopamine (DA) overflow, while reverse dialysis of the KOR antagonist nor-Binaltorphimine (nor-BNI) enhanced mPFC DA overflow. Extracellular amino-acid levels were also affected by KORs, as U69,593 reduced glutamate and GABA levels driven by the glutamate reuptake blocker, l-trans-pyrrolidine-2,4-dicarboxylate. Whole-cell recordings from mPFC layer V pyramidal neurons revealed that U69,593 decreased the frequency, but not amplitude, of glutamatergic mini EPSPs. To determine whether KOR regulation of mPFC DA overflow was mediated by KOR on DA terminals, we utilized a Cre recombinase-driven mouse line lacking KOR in DA neurons. In these mice, basal DA release or uptake was unaltered relative to controls, but attenuation of mPFC DA overflow by local U69,593 was not observed, indicating KOR acts directly on mPFC DA terminals to locally inhibit DA levels. Conditioning procedures were then used to determine whether mPFC KOR signaling was necessary for KOR-mediated aversion. U69,593-mediated conditioned place aversion was blocked by intra-mPFC nor-BNI microinjection. These findings demonstrate that mPFC KORs negatively regulate DA and amino-acid neurotransmission, and are necessary for KOR-mediated aversion.

Prefrontal Cortical Kappa Opioid Receptors Attenuate Responses to Amygdala Inputs

“…Furthermore, KORs increase impulsive behavior (Walker and Kissler, 2013), which is inhibited by mPFC activation. As mPFC KOR signaling is sufficient to produce aversion and necessary for KOR-mediated aversion (BalsKubik et al, 1993;Tejeda et al, 2013), it is possible that heightened PFC KOR signaling contributes to a negative affective state during abstinence. This is of importance as negative affective states are powerful mediators of negative reinforcement processes that drive addiction.…”

“…KORs are present in limbic and cortical regions involved in these functions, such as the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA), and mPFC KORs may have a crucial role in anxiety and stress. Indeed, mPFC KOR signaling is necessary and sufficient for KOR-mediated aversion (Bals-Kubik et al, 1993;Tejeda et al, 2013). Furthermore, KOR antagonism in the BLA produces anxiolytic effects (Bruchas et al, 2009;Knoll et al, 2011).…”

A Role for p38 Mitogen-activated Protein Kinase-mediated Threonine 30-dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference

“…Nonspecific uptake was defined as uptake in the presence of 100 M desipramine and subtracted from total accumulation to yield specific NET-mediated NE uptake. DAT-mediated DA uptake by NAc synaptosomes was measured using 10 nM [ 3 H]DA (78 Ci/mmol [2,5,6,7,8-3 H]dihydroxyphenylethylamine, PerkinElmer Life Sciences) at 37°C for 5 min as described earlier (26,27). DA uptake was measured in the presence of 100 nM nisoxetine (a NET-specific blocker to isolate total DAT-mediated DA uptake).…”

Pain-Related Depression of the Mesolimbic Dopamine System in Rats: Expression, Blockade by Analgesics, and Role of Endogenous κ-opioids

“…Nevertheless, these data suggest that a visceral noxious stimulus that depresses ICSS may also trigger delayed but more sustained changes (eg, those in the PFC) that increase vulnerability to depressive-like behaviors at later time points (eg, days after the initial pain stimulus). For example, recent work shows that KOR activation in the PFC causes local reductions in DA levels and establishes conditioned place aversions (Tejeda et al, 2013), suggesting that elevated dynorphin function in this region can produce another hallmark sign of depressive illness (dysphoria). These data provide a rationale for future work in which vulnerability to depressive behavior is studied at time points far beyond the acute effects of a painful/stressful stimulus (Knoll and Carlezon, 2010).…”