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Oncologist well-being is critical to initiating and maintaining the physician-patient relationship, yet many oncologists suffer from symptoms of burnout. Burnout has been linked to poor physical and mental health, as well as increased medical errors, patient dissatisfaction, and workforce attrition. In this Call to Action article, we discuss causes of and interventions for burnout and moral distress in oncology, highlight existing interventions, and provide recommendations for addressing burnout and improving well-being at the individual and organizational levels to deliver ethical, quality cancer care.

Acute alcohol exposure alters the trafficking and function of many G-protein–coupled receptors (GPCRs) that are associated with aberrant behavioral responses to alcohol. However, the molecular mechanisms underlying alcohol-induced changes in GPCR function remain unclear. β-Arrestin is a key player involved in the regulation of GPCR internalization and thus controls the magnitude and duration of GPCR signaling. Although β-arrestin levels are influenced by various drugs of abuse, the effect of alcohol exposure on β-arrestin expression and β-arrestin–mediated GPCR trafficking is poorly understood. Here, we found that acute ethanol exposure increases β-arrestin2 degradation via its increased ubiquitination in neuroblastoma-2a (N2A) cells and rat prefrontal cortex (PFC). β-Arrestin2 ubiquitination was likely mediated by the E3 ligase MDM2 homolog (MDM2), indicated by an increased coupling between β-arrestin2 and MDM2 in response to acute ethanol exposure in both N2A cells and rat PFC homogenates. Importantly, ethanol-induced β-arrestin2 reduction was reversed by siRNA-mediated MDM2 knockdown or proteasome inhibition in N2A cells, suggesting β-arrestin2 degradation is mediated by MDM2 through the proteasomal pathway. Using serotonin 5-HT1A receptors (5-HT1ARs) as a model receptor system, we found that ethanol dose-dependently inhibits 5-HT1AR internalization and that MDM2 knockdown reverses this effect. Moreover, ethanol both reduced β-arrestin2 levels and delayed agonist-induced β-arrestin2 recruitment to the membrane. We conclude that β-arrestin2 dysregulation by ethanol impairs 5-HT1AR trafficking. Our findings reveal a critical molecular mechanism underlying ethanol-induced alterations in GPCR internalization and implicate β-arrestin as a potential player mediating behavioral responses to acute alcohol exposure.

INTRODUCTION: The COVID-19 pandemic is an unprecedented global crisis profoundly affecting oncology care delivery. PURPOSE: This study will describe the occupational and personal consequences of the COVID-19 pandemic on oncologist well-being and patient care. MATERIALS AND METHODS: Four virtual focus groups were conducted with US ASCO member oncologists (September-November 2020). Inquiry and subsequent discussions centered on self-reported accounts of professional and personal COVID-19 experiences affecting well-being, and oncologist recommendations for well-being interventions that the cancer organization and professional societies (ASCO) might implement were explored. Qualitative interviews were analyzed using Framework Analysis. RESULTS: Twenty-five oncologists were interviewed: median age 44 years (range: 35-69 years), 52% female, 52% racial or ethnic minority, 76% medical oncologists, 64% married, and an average of 51.5 patients seen per week (range: 20-120). Five thematic consequences emerged: (1) impact of pre-COVID-19 burnout, (2) occupational or professional limitations and adaptations, (3) personal implications, (4) concern for the future of cancer care and the workforce, and (5) recommendations for physician well-being interventions. Underlying oncologist burnout exacerbated stressors associated with disruptions in care, education, research, financial practice health, and telemedicine. Many feared delays in cancer screening, diagnosis, and treatment. Oncologists noted personal and familial stressors related to COVID-19 exposure fears and loss of social support. Many participants strongly considered working part-time or taking early retirement. Yet, opportunities arose to facilitate personal growth and rise above pandemic adversity, fostering greater resilience. Recommendations for organizational well-being interventions included psychologic or peer support resources, flexible time-off, and ASCO and state oncology societies involvement to develop care guidelines, well-being resources, and mental health advocacy. CONCLUSION: Our study suggests that the COVID-19 pandemic has adversely affected oncologist burnout, fulfillment, practice health, cancer care, and workforce. It illuminates where professional organizations could play a significant role in oncologist well-being.

In addition to their well-known anxiolytic functions, benzodiazepines produce hyperphagia. Previously, we reported that the benzodiazepine, chlordiazepoxide (CDP), increased consumption of both normally-preferred and normally-avoided taste stimuli during long-term (1 h) tests, primarily through changes in licking microstructure patterns associated with hedonic taste evaluation, whereas there was little effect on licking microstructure measures associated with post-ingestive feedback. In this study, we further examined the hedonic and motivational specificity of CDP effects on ingestive behavior. We tested brief access (15 s) licking responses for tastants spanning all taste qualities after treatment with either CDP (5 or 10 mg/kg) or the non-benzodiazepine anxiolytic, buspirone (1.5 or 3 mg/kg). A between-subjects, counterbalanced design compared the CDP or buspirone effects on licking responses for water and a range of weak to strong concentrations of NaCl, Q-HCl, citric acid, MSG, saccharin, and capsaicin under water-restricted (23 h) conditions; and sucrose, saccharin, and MSG under water-replete conditions. In a dose dependent manner, CDP increased licking for taste stimuli that were normally-avoided after saline treatment, with a notable exception observed for the trigeminal stimulus, capsaicin, which was not affected at any concentration or drug dose, suggesting a taste-specific effect of CDP on orosensory processing. Under water-replete conditions, CDP dose-dependently increased licking to normally-accepted concentrations of sucrose, saccharin, and MSG. There was no effect of either drug on licks for water under either water-restricted or water-replete conditions. Buspirone slowed oromotor coordination by increasing brief interlick intervals, but it did not affect licking for any concentrations of the tastants. Overall, these results indicate that benzodiazepines selectively enhance the hedonic acceptance of gustatory orosensory stimuli, independent of general anxiolytic or oromotor coordination effects, or physiological states such as thirst.

The medial prefrontal cortex (mPFC) and the basolateral amygdala (BLA) have strong reciprocal connectivity. Projections from the BLA to the mPFC can drive innate, anxiety-related behaviors, but it is unclear whether reciprocal projections from the mPFC to BLA have similar roles. Here, we use optogenetics and chemogenetics to characterize the neurophysiological and behavioral alterations produced by chronic ethanol exposure and withdrawal on dorsal mPFC (dmPFC) and ventral mPFC (vmPFC) medial prefrontal cortical terminals in the BLA. We exposed adult male Sprague Dawley rats to chronic intermittent ethanol (CIE) using vapor chambers, measured anxiety-like behavior on the elevated zero maze, and used electrophysiology to record glutamatergic and GABAergic responses in BLA principal neurons. We found that withdrawal from a 7 d CIE exposure produced opposing effects at dmPFC (increased glutamate release) and vmPFC (decreased glutamate release) terminals in the BLA. Chemogenetic inhibition of dmPFC terminals in the BLA attenuated the increased anxiety-like behavior we observed during withdrawal. These data demonstrate that chronic ethanol exposure and withdrawal strengthen the synaptic connections between the dmPFC and BLA but weakens the vmPFC–BLA pathway. Moreover, facilitation of the dmPFC–BLA pathway during withdrawal contributes to anxiety-like behavior. Given the opposing roles of dmPFC–BLA and vmPFC–BLA pathways in fear conditioning, our results suggest that chronic ethanol exposure simultaneously facilitates circuits involved in the acquisition of and diminishes circuits involved with the extinction of withdrawal-related aversive behaviors.

Adolescent alcohol use in human populations dramatically increases the likelihood of adult alcohol use disorder. This adolescent vulnerability is recapitulated in preclinical models which provide important opportunities to understand basic neurobiological mechanisms. We provide here an overview of GABAergic and glutamatergic neurotransmission and our current understanding of the sensitivity of these systems to adolescent ethanol exposure. As a whole, the preclinical literature suggests that adolescent vulnerability may be directly related to region-specific neurobiological processes that continue to develop during adolescence. These processes include the activity of intrinsic circuits within diverse brain regions (primarily represented by GABAergic neurotransmission) and activity-dependent regulation of synaptic strength at glutamatergic synapses. Furthermore, GABAergic and glutamatergic neurotransmission within regions/circuits that regulate cognitive function, emotion, and their integration appears to be the most vulnerable to adolescent ethanol exposure. Finally, using documented behavioral differences between adolescents and adults with respect to acute ethanol, we highlight additional circuits and regions for future study.

A key feature of alcohol use disorder (AUD) is negative affect during withdrawal, which often contributes to relapse and is thought to be caused by altered brain function, especially in circuits that are important mediators of emotional behaviors. Both the agranular insular cortex (AIC) and the basolateral amygdala (BLA) regulate emotions and are sensitive to ethanol-induced changes in synaptic plasticity. The AIC and BLA are reciprocally connected, however, and the effects of chronic ethanol exposure on this circuit have yet to be explored. Here, we use a combination of optogenetics and electrophysiology to examine the pre- and postsynaptic changes that occur to AIC – BLA synapses following withdrawal from 7- or 10-days of chronic intermittent ethanol (CIE) exposure. While CIE/withdrawal did not alter presynaptic glutamate release probably from AIC inputs, withdrawal from 10, but not 7, days of CIE increased AMPA receptor-mediated postsynaptic function at these synapses. Additionally, NMDA receptor-mediated currents evoked by electrical stimulation of the external capsule, which contains AIC afferents, were also increased during withdrawal. Notably, a single subanesthetic dose of ketamine administered at the onset of withdrawal prevented the withdrawal-induced increases in both AMPAR and NMDAR postsynaptic function. Ketamine also prevented the withdrawal-induced increases in anxiety-like behavior measured using the elevated zero maze. Together, these findings suggest that chronic ethanol exposure increases postsynaptic function within the AIC – BLA circuit and that ketamine can prevent ethanol withdrawal-induced alterations in synaptic plasticity and negative affect.

The medial prefrontal cortex (mPFC) and the basolateral amygdala (BLA) have strong reciprocal connectivity. Projections from the BLA to the mPFC can bidirectionally modulate anxiety-related behaviors but it is unclear if the same is true for mPFC to BLA projections. Our laboratory is specifically interested in withdrawal-related anxiety-like behavior and the underlying synaptic plasticity. Here, we use optogenetics and chemogenetics to characterize the neurophysiological and behavioral alterations produced by chronic ethanol exposure and withdrawal on dorsal mPFC/prelimbic (dmPFC/PL) and ventral mPFC (vmPFC/IL) terminals in the BLA. We exposed adult male Sprague-Dawley rats to chronic intermittent ethanol (CIE) using vapor chambers, measured anxiety-like behavior on the elevated zero maze (EZM), and used electrophysiology to record glutamatergic and GABAergic responses in BLA principal neurons. We found that 24-hour withdrawal following a 7-day CIE exposure significantly increased the glutamate release probability from PL/dmPFC terminals, but significantly decreases the glutamate release probability from IL/vmPFC terminals. Chemogenetic inhibition of PL/dmPFC terminals in the BLA attenuated the increased withdrawal-dependent, anxiety-like behavior. These data demonstrate that chronic ethanol exposure and withdrawal strengthens the PL/dmPFC – BLA pathway but weakens the IL/vmPFC – BLA pathway. Moreover, we provide novel evidence that the PL/dmPFC – BLA pathway can modulate anxiety-like behavior. These findings suggest that mPFC-BLA circuits known to regulate the acquisition of aversive behaviors are up-regulated by chronic ethanol while those involved with the extinction of these behaviors are down-regulated.Significance StatementAccumulating evidence suggests that the medial prefrontal cortex and its projections to the basolateral amygdala bidirectionally modulate fear-related behaviors. Since the neuronal circuits for fear and anxiety are thought to overlap, we sought to examine the role of prelimbic and infralimbic subdivisions of the medial prefrontal cortex and their inputs to the basolateral amygdala in regulating anxiety. Specifically, we focused on alcohol withdrawal-induced anxiety-like behavior, which is a commonly reported cause of relapse in human alcoholics. In our study, we used optogenetics and chemogenetics to demonstrate, for the first time, that withdrawal from chronic ethanol exposure strengthens prelimbic synapses, but weakens infralimbic synapses in the basolateral amygdala and that inhibiting glutamate release from prelimbic terminal in the basolateral amygdala reduces anxiety-like behavior.

Thalamic projections to the lateral amygdala regulate the acquisition of conditioned aversive and reward-related behaviors. Recent work suggests that exposure to chronic ethanol up-regulates presynaptic function of lateral amygdala stria terminalis inputs which contain projections from somatosensory thalamic nuclei. To understand potential contributions by thalamic inputs and their role in the expression of withdrawal-associated aversive behaviors, we integrated optogenetic and chemogenetic approaches with in vitro measures of synaptic function and anxiety-like behavior. We found that expression of Channelrhodopsin in the caudal extension of the posterior thalamic group (cPO) produced monosynaptic glutamatergic synaptic responses in lateral amygdala principal neurons that could be inhibited by co-expression of the hM4-Gi-DREADD. Chronic ethanol exposure increased glutamate release from these cPO terminals but did not impact inhibition by the DREADD agonist, CNO. Systemic injection of CNO specifically reduced withdrawal-related increases in anxiety-like behaviors in animals expressing the Gi-DREADD in cPO. And, microinjection of CNO directly into the lateral amygdala mimicked this anti-anxiety effect. These findings suggest that the cPO-LA circuit is vulnerable to chronic ethanol exposure and plays an important role in regulating anxiety-like behavior following chronic ethanol exposure.

Oncologists face ethical challenges when patients use potentially harmful complementary and alternative medicine in addition to or instead of conventional treatments for their cancer. For example, a patient may forego effective cancer treatment in favor of alternative therapies and suffer significant harm as a result. Similarly, false beliefs about the efficacy of complementary therapies may complicate the process of shared decision making about cancer treatment. In this vignette, we discuss clinicians’ obligations and provide recommendations for ethically sound communication practices in this clinical context.

Adolescent alcohol use in human populations dramatically increases the likelihood of adult alcohol use disorder. This adolescent vulnerability is recapitulated in preclinical models which provide important opportunities to understand basic neurobiological mechanisms. We provide here an overview of GABAergic and glutamatergic neurotransmission and our current understanding of the sensitivity of these systems to adolescent ethanol exposure. As a whole, the preclinical literature suggests that adolescent vulnerability may be directly related to region-specific neurobiological processes that continue to develop during adolescence. These processes include the activity of intrinsic circuits within diverse brain regions (primarily represented by GABAergic neurotransmission) and activity-dependent regulation of synaptic strength at glutamatergic synapses. Furthermore, GABAergic and glutamatergic neurotransmission within regions/circuits that regulate cognitive function, emotion, and their integration appears to be the most vulnerable to adolescent ethanol exposure. Finally, using documented behavioral differences between adolescents and adults with respect to acute ethanol, we highlight additional circuits and regions for future study.

The current experiment examined the effects of 10 days of chronic intermittent ethanol (CIE) exposure on anxiety-like behavior and home cage ethanol intake using a 20% intermittent access (M, W, F) paradigm in male and female Long-Evans rats. Withdrawal from alcohol dependence contributes to relapse in humans and increases in anxiety-like behavior and voluntary ethanol consumption in preclinical models. Our laboratory has shown that 10 days of CIE exposure produces both behavioral and neurophysiological alterations associated with withdrawal in male rats; however, we have yet to examine the effects of this exposure regime on ethanol intake in females. During baseline, females consumed more ethanol than males but, unlike males, did not show escalations in intake. Rats were then exposed to CIE and were again given intermittent access to 20% ethanol. CIE males increased their intake compared to baseline, whereas air-exposed males did not. Ethanol intake in females was unaffected by CIE exposure. Notably, both sexes expressed significantly elevated withdrawal-associated anxiety-like behavior in the plus maze. Finally, rats were injected with the cannabinoid CB1 receptor antagonist, SR141716A (0, 1, 3, 10 mg/kg, i.p.) which reduced ethanol intake in both sexes. However, females appear to be more sensitive to lower doses of this CB1 receptor antagonist. Our results show that females consume more ethanol than males; however, they did not escalate their intake using the intermittent access paradigm. Unlike males, CIE exposure had no effect on drinking in females. It is possible that females may be less sensitive than males to ethanol-induced increases in drinking after a short CIE exposure. Lastly, our results demonstrate that males and females may have different pharmacological sensitivities to CB1 receptor blockade on ethanol intake, at least under the current conditions.

The basolateral amygdala (BLA) controls numerous behaviors, like anxiety and reward seeking, via the activity of glutamatergic principal neurons. These BLA neurons receive excitatory inputs primarily via two major anatomical pathways – the external capsule (EC), which contains afferents from lateral cortical structures, and the stria terminalis (ST), containing synapses from more midline brain structures. Chronic intermittent ethanol (CIE) exposure/withdrawal produces distinct alterations in these pathways. Specifically, 10 days of CIE (via vapor inhalation) increases presynaptic function at ST synapses and postsynaptic function at EC synapses. Given that 10-day CIE/withdrawal also increases anxiety-like behavior, we sought to examine the development of these alterations at these inputs using an exposure time-course in both male and female rats. Specifically, using 3, 7, and 10 days CIE exposure, we found that all three durations increase anxiety-like behavior in the elevated plus maze. At BLA synapses, increased presynaptic function at ST inputs required shorter exposure durations relative to post-synaptic alterations at EC inputs in both sexes. But, synaptic alterations in females required longer ethanol exposures compared to males. These data suggest that presynaptic alteration at ST-BLA afferents is an early neuroadaptation during repeated ethanol exposures. And, the similar patterns of presynaptic-then-postsynaptic facilitation across the sexes suggest the former may be required for the latter. These cooperative interactions may contribute to the increased anxiety-like behavior that is observed following CIE-induced withdrawal and may provide novel therapeutic targets to reverse withdrawal-induced anxiety.

Chronic alcohol exposure induces pronounced changes in GPCR-mediated G-protein signaling. Recent microarray and RNA-seq analyses suggest associations between alcohol abuse and the expression of genes involved in G-protein signaling. The activity of G-proteins (e.g. Gαi/o and Gαq) is negatively modulated by regulator of G-protein signaling (RGS) proteins which are implicated in drugs of abuse including alcohol. The present study used 7 days of chronic intermittent ethanol exposure followed by 24 hour withdrawal (CIE) to investigate changes in mRNA and protein levels of G-protein subunit isoforms and RGS protein subtypes in rat prefrontal cortex, a region associated with cognitive deficit attributed to excessive alcohol drinking. We found that this ethanol paradigm induced differential expression of Gα subunits and RGS subtypes. For example, there were increased mRNA and protein levels of Gαi1/3 subunits and no changes in the expression of Gαs and Gαq subunits in ethanol-treated animals. Moreover, CIE increased the mRNA but not the protein levels of Gαo. Additionally, a modest increase in Gαi2 mRNA level by CIE was accompanied by a pronounced increase in its protein level. Interestingly, we found that CIE increased mRNA and protein levels of RGS2, RGS4, RGS7 and RGS19 but had no effect on the expression of RGS5, RGS6, RGS8, RGS12 or RGS17. Changes in the expression of Gα subunits and RGS subtypes could contribute to the functional alterations of certain GPCRs following chronic ethanol exposure. The present study suggests that RGS proteins may be potential new targets for intervention of alcohol abuse via modification of Gα-mediated GPCR function.

Cocaine is a commonly abused central nervous system stimulant that enhances dopamine (DA) neurotransmission through its ability to block dopamine transporters (DATs). Recent evidence suggests there may be an interaction between DATs and D2/D3 autoreceptors that modulates cocaine's effects. The purpose of this study was to explore how D2/D3 autoreceptors modulate the ability of cocaine to inhibit DA uptake through DATs on pre-synaptic DA terminals. Using fast-scan cyclic voltammetry in brain slices containing the nucleus accumbens core from male and female C57BL/6J mice, we first sought to examine the effects of global autoreceptor blockade using the non-selective D2/D3 autoreceptor antagonist, raclopride. We found that the ability of cocaine to inhibit DA uptake was increased by raclopride and that this effect was consistent across sexes. Furthermore, using D2 (L-741,626) or D3 (SB-277011-A) autoreceptor selective antagonists, we discovered that blockade of D3, but not D2, autoreceptors was responsible for the increased cocaine potency. Alterations in cocaine potency were attributable to alterations in uptake inhibition, rather than cocaine effects on vesicular DA release, suggesting that these results may be a product of a functional D3/DAT interaction apart from the canonical inhibitory actions of D3 autoreceptors on DA release. In addition, application of D2 (sumanirole) and D3 (PD 128907) autoreceptor-specific agonists had inverse effects, whereby D2 autoreceptor activation decreased cocaine potency and D3 autoreceptor activation had no effect. Together, these data show that DA autoreceptors dynamically regulate cocaine potency at the DAT, which is important for understanding cocaine's rewarding and addictive properties. We propose a model whereby presynaptic dopamine autoreceptors dynamically modulate cocaine potency through two separate mechanisms. We demonstrate that D2 agonists decrease cocaine potency, whereas D3 antagonists increase cocaine potency, likely through an allosteric mechanism outside of their canonical actions on dopamine release. These findings give important and novel insight into the contribution of D2/D3 autoreceptors to dopamine transporter function.

Negative affect promotes dysregulated alcohol consumption in non-dependent and alcohol-dependent animals, and cues associated with negative affective states induce withdrawal-like symptoms in rats. This study was designed to test the hypotheses that: (1) the kappa-opioid receptor (KOR) system mediates phenotypes related to alcohol withdrawal and withdrawal-like negative affective states and (2) cues associated with negative affective states would result in dysregulated alcohol consumption when subsequently presented alone. To accomplish these goals, intracerebroventricular infusion of the KOR antagonist nor-binaltorphimine (nor-BNI) was assessed for the ability to attenuate the increase in 22-kHz ultrasonic vocalizations (USVs) associated with alcohol withdrawal and KOR activation in adult male wistar rats. Furthermore, cues associated with a KOR agonist-induced negative affective state were assessed for the ability to dysregulate alcohol consumption and the efficacy of intracerebroventricular KOR antagonism to reduce such dysregulation was evaluated. KOR antagonism blocked the increased number of 22-kHz USVs observed during acute alcohol withdrawal and a KOR agonist (U50,488) resulted in a nor-BNI reversible increase in 22-kHz USVs (mimicking an alcohol-dependent state). Additionally, cues associated with negative affective states resulted in escalated alcohol self-administration, an effect that was nor-BNI sensitive. Taken together, this study implicates negative affective states induced by both alcohol withdrawal and conditioned stimuli as being produced, in part, by activity of the DYN/KOR system.