SignificanceA central tenet of economics is that as the price of a commodity increases, its demand goes down because individuals choose to buy less. Mounting evidence supports a role for the neuromodulator dopamine in representing subjective value. We investigated the role of dopamine in valuation by presenting rats with a reward across a range of prices. We showed that dopamine concentration decreased with price and increasing release using optogenetic manipulations-altered price sensitivity. Increasing release prior to reward delivery made animals more sensitive to price, whereas increasing release at reward delivery made animals less sensitive to price. These data extend the notion that dopamine release events encode subjective value and further demonstrate that increasing dopamine release causally modifies price sensitivity.

Benzodiazepines are commonly prescribed anxiolytics that pose abuse liability in susceptible individuals. Although it is well established that all drugs of abuse increase brain dopamine levels, and benzodiazepines are allosteric modulators of the GABA receptor, it remains unclear how they alter dopamine release. Using in vivo fast-scan cyclic voltammetry, we measured diazepam-induced changes in the frequency and amplitude of transient dopamine release events. We found that diazepam concurrently increases the frequency and decreases the amplitude of transient dopamine release events in the awake and freely moving rat. The time course during which diazepam altered the frequency and amplitude of dopamine release events diverged, with the decreased amplitude effect being shorter lived than the increase in frequency, but both showing similar rates of onset. We conclude that diazepam increases the frequency of accumbal dopamine release events by disinhibiting dopamine neurons, but also decreases their amplitude. We speculate that the modest abuse liability of benzodiazepines is due to their ability to decrease the amplitude of dopamine release events in addition to increasing their frequency.

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While an extensive literature supports the notion that mesocorticolimbic dopamine plays a role in negative reinforcement, recent evidence suggests that dopamine exclusively encodes the value of positive reinforcement. In the present study, we employed a behavioral economics approach to investigate whether dopamine plays a role in the valuation of negative reinforcement. Using rats as subjects, we first applied fast-scan cyclic voltammetry (FSCV) to determine that dopamine concentration decreases with the number of lever presses required to avoid electrical footshock (i.e., the economic price of avoidance). Analysis of the rate of decay of avoidance demand curves, which depict an inverse relationship between avoidance and increasing price, allows for inference of the worth an animal places on avoidance outcomes. Rapidly decaying demand curves indicate increased price sensitivity, or low worth placed on avoidance outcomes, while slow rates of decay indicate reduced price sensitivity, or greater worth placed on avoidance outcomes. We therefore used optogenetics to assess how inducing dopamine release causally modifies the demand to avoid electrical footshock in an economic setting. Increasing release at an avoidance predictive cue made animals more sensitive to price, consistent with a negative reward prediction error (i.e., the animal perceives they received a worse outcome than expected). Increasing release at avoidance made animals less sensitive to price, consistent with a positive reward prediction error (i.e., the animal perceives they received a better outcome than expected). These data demonstrate that transient dopamine release events represent the value of avoidance outcomes and can predictably modify the demand to avoid.

Differential rodent responses to the sex of human experimenters could have far reaching consequences in preclinical studies. Here, we show that the sex of human experimenters affects mouse behaviours and responses to the rapid-acting antidepressant ketamine and its bioactive metabolite (2R,6R)-hydroxynorketamine. We found that mice manifest aversion to human male odours, preference to female odours, and increased susceptibility to stress when handled by male experimenters. This male induced aversion and stress susceptibility is mediated by the activation of brain corticotropin-releasing factor (CRF) neurons projecting from the entorhinal cortrex to hippocampal area CA1. We further establish that exposure to male scent prior to ketamine administration activates CRF neurons projecting from the entorhinal cortex to hippocampus, and that CRF is necessary and sufficient for the in vivo and in vitro actions of ketamine. Further understanding of the specific and quantitative contributions of the sex of human experimenters to different experimental outcomes in rodents may lead not only to reduced heterogeneity between studies, but also increased capability to uncover novel biological mechanisms.

In susceptible populations, stress is a major risk factor for the development of mental disorders, including depression. Estradiol, often considered a female hormone, is distributed in the male brain via aromatization of testosterone. The role of estrogen receptors (ERs) in male stress susceptibility and depression is not well understood. We found that absence of ERβ is associated with susceptibility to stress in male mice and that activity of ERβ-projecting neurons from the basolateral amygdala to nucleus accumbens is reduced in hypogonadal mice subjected to stress, while activation of this circuit reverses stress-induced maladaptive behaviors. We identified that absence of estradiol, but not testosterone per se, underlies stress susceptibility and that brain-selective delivery of estradiol prevents the development of depression-related behaviors. Our findings provide evidence for an estrogen-based mechanism underlying stress susceptibility and offer an unexpected therapeutic strategy for treating depression in males.

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The centers for disease control and prevention reports that heroin abuse has doubled for Americans aged 18–25. Drugs of abuse, such as heroin, are commonly thought to increase the concentration of dopamine (DA) in the nucleus accumbens core (NAcc), although their effects on phasic DA release events remains to be fully characterized. In contrast, when an addicted subject is withdrawn from a substance such as heroin, there is a clear suppression of phasic DA activity in the NAcc. Heroin withdrawal presents characteristic symptoms, most predominately increased craving for the drug, which contributes to further abuse. While withdrawal symptoms have been shown to be conditioned to previously neutral stimuli through classical conditioning, there is a lack of electrochemical evidence of conditioned withdrawal and its effects on non‐drug related stimuli. Here, we sought to explore how conditioned withdrawal in heroin addicted rats affects DA. We provided rats 23 hour access to IV heroin over 28 days. The 28 days are split into four blocks of increasing doses ranging from 0.06 mg/kg to 6 mg/kg to more accurately simulate the progression of heroin addiction. During the 28 day history, circadian changes in heroin, food, and water intake were altered and overall consumption of heroin increased. We then, investigated how conditioned withdrawal affects cue‐evoked dopamine release in the NAcc using fast scan cyclic voltammetry (FSCV) during conditioned suppression of food maintained responding. Here, animals were first trained to respond for food under an FR1 schedule for 3 consecutive days where food availability was predicted by a cue‐light placed above the lever. This was followed by 3 consecutive days of conditioned withdrawal training where a tone was conditioned to naloxone‐precipitated withdrawal. On test day, animals responded for food under normal conditions, but the withdrawal associated tone was presented concurrently with cue‐light onset during 50% of trials. By simultaneously presenting the withdrawal paired tone with the food predictive cue light we observed a substantial suppression of DA concentration at the cue light relative to non‐paired trials. These data demonstrated that conditioned suppression of food maintained responding induced by conditioned heroin withdrawal is accompanied by a transient suppression in dopamine concentrationSupport or Funding InformationFunding for the project was provided by NSF grant IOS‐1557755, NIH grant R03DA038734, Boettcher Young Investigator Award and NARSAD Young Investigator Award to EBO and an institutional UROP to KJP.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.