Optical suppression of drug-evoked phasic dopamine release

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.

Transplantation of human retinal pigment epithelial cells in the nucleus accumbens of cocaine self-administering rats provides protection from seeking

“…In view of recent studies that show the critical role of synaptic and dendritic pathobiology (Villalba and Smith, 2013) seen in cocaine reinstatement studies (Shen et al, 2014), such studies may be of use in future transplantation experiments to evaluate whether VTA neuronal preservation will provide reversal of dendritic changes in post-synaptic NAc neurons. Our study also provides support to the growing consensus that the VTA-NAc pathway has a significant role in reinstatement of drug-seeking behavior and, as such, adds an additional line of evidence to recent related optogenetic studies in the VTA-NAc pathway (Adrover et al, 2014; Bocklisch et al, 2013; Chandra et al, 2013; McCutcheon et al, 2014; Stefanik et al, 2013). …”

Dopamine uptake dynamics are preserved under isoflurane anesthesia

“…FSCV experiments using urethane anesthesia have often been used to investigate DA changes in response to cocaine [2, 3, 14, 18], but the extent to which urethane itself alters cocaine’s effect on DAT remains unknown [8]. Here we demonstrate that neither urethane nor isoflurane alters cocaine’s effects ex vivo.…”

Dopamine Prediction Errors in Reward Learning and Addiction: From Theory to Neural Circuitry

“…To address these points, measurements of the activity of identified DA neurons using electrophysiology, deep brain calcium imaging, and FSCV can be made to determine when these neurons are activated and when DA is released relative to behavioral and drug events during learning, and temporally-specific inhibition of DA neuron activity can be conducted to counter the drug-induced putative DA-RPE to test causality. The feasibility of this latter approach was recently demonstrated in Th::Cre rats in which the light-sensitive inhibitory channel, halorhodopsin (NpHR), was expressed in DA neurons and NpHR-mediated inhibition of VTA DA somata was found to greatly reduce cocaine-induced phasic DA release in the NAc (McCutcheon et al, 2014). …”