κ opioids selectively control dopaminergic neurons projecting to the prefrontal cortex

Abstract

Dopaminergic afferents arising from the ventral tegmental area (VTA) are crucial elements in the neural circuits that mediate arousal, motivation, and reinforcement. Two major targets of these afferents are the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc). Whereas dopamine (DA) in the mPFC has been implicated in working memory and attentional processes, DA in the NAc is required for responding to reward predictive cues. These distinct functions suggest a role for independent firing patterns of dopaminergic neurons projecting to these brain regions. In fact, DA release in mPFC and NAc can be differentially modulated. However, to date, electrophysiological studies have largely overlooked heterogeneity among VTA neurons. Here, we provide direct evidence for differential neurotransmitter control of DA neural activity and corresponding DA release based on projection target. opioid receptor agonists inhibit VTA DA neurons that project to the mPFC but not those that project to the NAc. Moreover, DA levels in the mPFC, but not the NAc, are reduced after local infusion of opioid receptor agonists into the VTA. These findings demonstrate that DA release in specific brain regions can be independently regulated by opioid targeting of a subpopulation of VTA DA neurons. Selective control of VTA DA neurons projecting to the mPFC has important implications for understanding addiction, attention disorders, and schizophrenia, all of which are associated with DA dysfunction in the mPFC.GABA ͉ reward ͉ motivation ͉ nucleus accumbens ͉ ventral tegmental area T he dopaminergic neurons of the ventral tegmental area (VTA) play a critical role in motivation and reinforcement (1-3). Two major projection targets of VTA dopamine (DA) neurons are the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc). DA plays different roles in these two projection targets, contributing to working memory processes in the mPFC (4, 5) and motivated responding in the NAc (6). Despite evidence that DA levels in the mPFC and NAc are differentially modulated during various behavioral conditions (7,8), electrophysiological studies have focused on the functional similarities among the VTA neurons.The VTA is an important site for opioid control of goaldirected behaviors (9). We previously showed that opioid receptor (KOP-R) agonists directly inhibit a subset of DA neurons in the VTA through activation of a G-protein-coupled, inwardly rectifying potassium channel (10). This finding, in conjunction with previous reports that limbic and cortical projections arise from largely separate populations of VTA neurons (11, 12), led us to hypothesize that postsynaptic KOP-R agonist effects on VTA neurons segregate on the basis of projection target. To address this question, we made whole-cell, patchclamp recordings in VTA neurons that were retrogradely labeled from the NAc or the mPFC and tested their postsynaptic sensitivity to KOP-R agonists. Neurons were filled with biocytin, and, after recording, brain slices were fixed and immunohistochemi...

Endogenous Opioid Blockade and Impulsive Responding in Alcoholics and Healthy Controls

“…This is consistent with studies demonstrating opioid regulation of DA neurons (eg, Ostrowski et al, 1982;Sesack and Pickel, 1992;Oswald and Wand, 2004;Berthele et al, 2005), including those projecting to prefrontal cortex (Margolis et al, 2006). Given that NTX acts at both m-and k-opioid receptors, which exert opposing effects on forebrain DA release (Spanagel et al, 1992;Herz and Spangel, 1995;Margolis et al, 2006), differential effects of NTX on DA levels could be due to differences in relative m-and k-mediated effects of NTX, as depicted in Figure 6.…”

“…This is consistent with studies demonstrating opioid regulation of DA neurons (eg, Ostrowski et al, 1982;Sesack and Pickel, 1992;Oswald and Wand, 2004;Berthele et al, 2005), including those projecting to prefrontal cortex (Margolis et al, 2006). Given that NTX acts at both m-and k-opioid receptors, which exert opposing effects on forebrain DA release (Spanagel et al, 1992;Herz and Spangel, 1995;Margolis et al, 2006), differential effects of NTX on DA levels could be due to differences in relative m-and k-mediated effects of NTX, as depicted in Figure 6. Relative m-receptor to k-receptor blockade effects would be expected to differ in subjects with low circulating levels of endogenous m-receptor ligands, as is the case with alcoholics and their offspring (Govoni et al, 1983;Vescovi et al, 1992;del Arbol et al, 1995;Dai et al, 2005), or in subjects with low levels of m-receptor expression, as is found in subjects with low frontal DA levels (Berthele et al, 2005) owing to their catechol-O-methyltransferase genotype (Meyer-Lindenberg et al, 2005), and in subjects with the A118G polymorphism of the m-receptor (Zhang et al, 2005).…”

Acute Amphetamine Exposure Selectively Desensitizes κ-Opioid Receptors in the Nucleus Accumbens

“…In the rat VTA, KOPs inhibit mesocortical, but not mesolimbic, DA neurons (Margolis et al, 2006). Acute amphetamine exposure does not alter KOP receptor function in the VTA.…”

“…For example, KOP receptor agonists injected into either the VTA or the NAc produce conditioned place aversion (Bals-Kubik et al, 1993). In the rat VTA, KOP receptors directly hyperpolarize a subset of dopamine (DA) neurons (Margolis et al, 2003), specifically those that project to the prefrontal cortex (Margolis et al, 2006). Within the NAc, KOP receptor agonists inhibit the release of glutamate (Yuan et al, 1992;Hjelmstad andFields, 2001, 2003).…”

The Effects of Pharmacological Opioid Blockade on Neural Measures of Drug Cue-Reactivity in Humans

“…interaction with VTA κ-opioid receptors (Margolis et al, 2006), and by decreasing inhibition of excitatory output from the PFC to the dorsal striatum, which would, in turn, appear as enhanced functional connectivity between the VTA, PFC, and dorsal striatum. Given that inputs from the PFC to the dorsal striatum regulate the expression of reward-driven decision-making (Delgado et al, 2004;Haber et al, 2006), and that increased fronto-striatal connectivity is associated with greater frontal regulation over subcortical signals reflecting heightened reward sensitivity (Heatherton and Wagner, 2011), these results suggest greater frontal regulation of salience attribution was occurring during methamphetamine cue processing under opioid blockade (Goldstein and Volkow, 2011;Hare et al, 2009).…”