Kappa opioids selectively control dopaminergic neurons projecting to the prefrontal cortex - PubMed (original) (raw)

Kappa opioids selectively control dopaminergic neurons projecting to the prefrontal cortex

Elyssa B Margolis et al. Proc Natl Acad Sci U S A. 2006.

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. Kappa 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 kappa 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.

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Conflict of interest statement

Conflict of interest statement: No conflicts declared.

Figures

Fig. 1.

Fig. 1.

VTA projections to the mPFC and NAc arise from different populations of neurons. (A and B) Sample coronal brain sections showing injection tracks (Left) and tracer deposits (Right) resulting from the bilateral injection of the retrograde tracer DiI into the mPFC (A) or the NAc (B). (Scale bars: 2 mm.) (C1) Horizontal brain slice. The white box in the magnified midbrain region identifies the VTA region where experiments were completed (modified from ref. 36). (C2 and C3) Sample horizontal slices of midbrain region showing transported DiI (white) 7 days after mPFC (C2) or NAc (C3) injections. (Scale bars: 1 mm.) (D) VTA section from a rat injected with FluoroGold (green) into the mPFC and DiI (red) into the NAc shows a minority of colabeled (yellow) neurons. Neurons examined throughout the VTA show a relatively small amount of colabeling in this protocol (n = 3 rats).

Fig. 2.

Fig. 2.

Dopaminergic and GABAergic VTA neurons project to the mPFC and NAc. (A) VTA slices containing retrogradely labeled neurons (red) were immunohistologically processed for TH or GAD67 immunoreactivity (green), and colabeling (yellow) was observed. (B) Quantified colabeling across animals (NAc/TH, n = 3; NAc/GAD67, n = 4; mPFC/TH, n = 6; mPFC/GAD67, n = 7).

Fig. 3.

Fig. 3.

VTA neurons with a larger _I_h project to the mPFC. (A and B) Sample action potentials (calibration: 20 mV and 1 ms) and _I_h curves (calibration: 100 pA and 50 ms) measured in mPFC-projecting (A) and NAc-projecting (B) VTA neurons. (C) Sample mPFC-projecting neuron lacking an _I_h. This neuron was retrogradely labeled by DiI injection into the mPFC (red), filled with biocytin during recording (green), and was TH(−) (blue). (D) Among _I_h(+) neurons, the _I_h activated by a voltage step from −60 mV to −90, −100, −110, and −120 mV was significantly larger in mPFC projections (n = 18) than in NAc projections (n = 20). (Inset) _I_h was measured as the difference between the initial and final current during a 200-ms voltage step. (E) _I_h activation during a voltage step to −120 mV was significantly larger in confirmed TH(+), mPFC-projecting neurons (n = 10) than in NAc-projecting, TH(+) neurons (n = 7). ∗, P < 0.05; ∗∗, P < 0.01.

Fig. 4.

Fig. 4.

DA neurons that project to the mPFC but not to the NAc are inhibited by KOP-R agonists. (A) Example of a neuron labeled with DiI after injection into the mPFC (red), filled with biocytin during recording (green), and immunohistochemically confirmed as TH(+) (blue). (B) This neuron expressed a prominent _I_h (Inset; scale bar: 100 pA and 50 ms) and was inhibited by the KOP-R agonist U69593 (1 μM). (C) Summary of U69593 effects in mPFC-projecting _I_h(+) neurons. The numbers of confirmed TH(+) neurons are in parentheses. (D) Example neuron labeled with DiI after injection into the NAc (red), filled with biocytin during recording (green), and immunohistochemically confirmed as TH(+) (blue). (E) This neuron expressed an _I_h (Inset; calibration: 100 pA and 50 ms) and was unaffected by U69593 (1 μM). (F) U69593 inhibited only one NAc-projecting _I_h(+) neuron. The numbers of confirmed TH(+) neurons are in parentheses. (G) In vivo measurement of DA in the mPFC using microdialysis shows that perfusion of 5 μM U69593 into the VTA significantly decreased mPFC DA levels (n = 7). This effect was blocked by administration of the KOP-R-selective antagonist nor-BNI at 1 μM (n = 3). (H) Intra-VTA U69593 did not change DA levels in the NAc (n = 6).

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