Optical suppression of drug-evoked phasic dopamine release - PubMed (original) (raw)

Optical suppression of drug-evoked phasic dopamine release

James E McCutcheon et al. Front Neural Circuits. 2014.

Abstract

Brief fluctuations in dopamine concentration (dopamine transients) play a key role in behavior towards rewards, including drugs of abuse. Drug-evoked dopamine transients may result from actions at both dopamine cell bodies and dopamine terminals. Inhibitory opsins can be targeted to dopamine neurons permitting their firing activity to be suppressed. However, as dopamine transients can become uncoupled from firing, it is unknown whether optogenetic hyperpolarization at the level of the soma is able to suppress dopamine transients. Here, we used in vivo fast-scan cyclic voltammetry to record transients evoked by cocaine and raclopride in nucleus accumbens (NAc) of urethane-anesthetized rats. We targeted halorhodopsin (NpHR) specifically to dopamine cells by injecting Cre-inducible virus into ventral tegmental area (VTA) of transgenic rats that expressed Cre recombinase under control of the tyrosine hydroxylase promoter (TH-Cre(+) rats). Consistent with previous work, co-administration of cocaine and raclopride led to the generation of dopamine transients in NAc shell. Illumination of VTA with laser strongly suppressed the frequency of transients in NpHR-expressing rats, but not in control rats. Laser did not have any effect on amplitude of transients. Thus, optogenetics can effectively reduce the occurrence of drug-evoked transients and is therefore a suitable approach for studying the functional role of such transients in drug-associated behavior.

Keywords: TH-Cre; dopamine transients; fast-scan cyclic voltammetry; nucleus accumbens; optogenetics; rat.

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Figures

Figure 1

Figure 1

Specific expression of Cre-dependent transgenes in midbrain dopamine neurons. TH-Cre+ rats infected with Cre-dependent eYFP show a high degree of colocalization between eYFP and TH immunoreactivity in VTA. Left-hand panel, eYFP expression (green); center panel, TH immunoreactivity (red); right-hand panel, merged image (yellow). Scale bar = 100 μm.

Figure 2

Figure 2

Neurons expressing Cre-dependent transgenes project to NAc. TH-Cre+ rats infected with Cre-dependent NpHR show expression of eYFP reporter in cell body regions (VTA, left-hand panel) and terminal regions (NAc, right-hand panel). Scale bar = 100 μm.

Figure 3

Figure 3

Representative data from a single rat showing optical suppression of drug-evoked dopamine transients. (A) Color plot from single trial after administration of cocaine and raclopride. Applied voltage is on _y_-axis, time is on _x_-axis, and current shown as pseudocolor. Purple features correspond to dopamine oxidation (~+0.6 V). Laser decreases the occurrence of dopamine transients. (B) 10 individual trials from the same rat showing that the laser consistently reduces occurrence of transients. (C) Average color plot produced from 10 trials in (B). Conventions are the same as in (A). (D) Dopamine concentration extracted from color plot using principal component analysis.

Figure 4

Figure 4

A steady-state pattern of dopamine release is unmasked by optical suppression. Recordings from a rat in which no transients or dopamine release were observed until laser was administered. Top color plot (conventions as in Figure 3A) shows a single trial in which laser was switched on (green bar) and bottom color plot shows single trial in which laser was not switched on. Bottom panels show dopamine concentration traces extracted from color plots. In this rat, steady state dopamine release was not evident until laser was used to activate NpHR.

Figure 5

Figure 5

Group data showing optical suppression of dopamine signaling. (A) In TH-Cre+ rats transfected with NpHR (n = 8), laser illumination of VTA strongly suppressed dopamine, relative to trials in which the laser was not turned on. (B) No effect of laser was seen in control rats (n = 5). (C) Quantification of data in (A) and (B). Circles are individual rats and bars are mean values. * p < 0.05 laser on vs. laser off.

Figure 6

Figure 6

Optical suppression of dopamine transients. (A) Single trial examples showing effect of laser on dopamine transients. Color plots and concentration traces (conventions as in Figure 3A) are shown from an NpHR-expressing rat (left-hand panel) and an eYFP-expressing control rat (right-hand panel). Asterices show detected transients. (B) Frequency of dopamine transients is reduced during laser illumination of VTA, relative to trials in which laser was not turned on, in TH-Cre+ rats expressing NpHR (n = 7), but not control rats (n = 4). * p < 0.05 laser on vs. laser off. (B) Amplitude of transients was not significantly affected by laser illumination in either group.

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