Excessive firing of dyskinesia-associated striatal direct pathway neurons is gated by dopamine and excitatory synaptic input.

The striatum integrates dopaminergic and glutamatergic inputs to select preferred versus alternative actions. However, the precise mechanisms underlying this process remain unclear. One way to study action selection is to understand how it breaks down in pathological states. Here, we explored the cellular and synaptic mechanisms of levodopa-induced dyskinesia (LID), a complication of Parkinson's disease therapy characterized by involuntary movements. We used an activity-dependent tool (FosTRAP) in conjunction with a mouse model of LID to investigate functionally distinct subsets of striatal direct pathway medium spiny neurons (dMSNs). In vivo, levodopa differentially activates dyskinesia-associated (TRAPed) dMSNs compared to other dMSNs. We found this differential activation of TRAPed dMSNs is likely to be driven by higher dopamine receptor expression, dopamine-dependent excitability, and excitatory input from the motor cortex and thalamus. Together, these findings suggest how the intrinsic and synaptic properties of heterogeneous dMSN subpopulations integrate to support action selection.

Ventral pallidum GABA and glutamate neurons drive approach and avoidance through distinct modulation of VTA cell types.

The ventral pallidum (VP) contains GABA and glutamate neurons projecting to ventral tegmental area (VTA) whose stimulation drives approach and avoidance, respectively. Yet little is known about the mechanisms by which VP cell types shape VTA activity and drive behavior. Here, we found that both VP GABA and glutamate neurons were activated during approach to reward or by delivery of an aversive stimulus. Stimulation of VP GABA neurons inhibited VTA GABA, but activated dopamine and glutamate neurons. Remarkably, stimulation-evoked activation was behavior-contingent such that VTA recruitment was inhibited when evoked by the subject's own action. Conversely, VP glutamate neurons activated VTA GABA, as well as dopamine and glutamate neurons, despite driving aversion. However, VP glutamate neurons evoked dopamine in aversion-associated ventromedial nucleus accumbens (NAc), but reduced dopamine release in reward-associated dorsomedial NAc. These findings show how heterogeneous VP projections to VTA can be engaged to shape approach and avoidance behaviors.

Antagonism of kappa opioid receptors accelerates the development of L-DOPA-induced dyskinesia in a preclinical model of moderate dopamine depletion.

Levels of the opioid peptide dynorphin, an endogenous ligand selective for kappa-opioid receptors (KORs), its mRNA and pro-peptide precursors are differentially dysregulated in Parkinson's disease (PD) and following the development of l-DOPA-induced dyskinesia (LID). It remains unclear whether these alterations contribute to the pathophysiological mechanisms underlying PD motor impairment and the subsequent development of LID, or whether they are part of compensatory mechanisms. We sought to investigate nor-BNI, a KOR antagonist, 1) in the dopamine (DA)-depleted PD state, 2) during the development phase of LID, and 3) via measuring of tonic levels of striatal DA. While nor-BNI (3 mg/kg; s.c.) did not lead to functional restoration in the DA-depleted state, it affected the dose-dependent development of abnormal voluntary movements (AIMs) in response to escalating doses of l-DOPA in a rat PD model with a moderate striatal 6-hydroxdopamine (6-OHDA) lesion. We tested five escalating doses of l-DOPA (6, 12, 24, 48, 72 mg/kg; i.p.), and nor-BNI significantly increased the development of AIMs at the 12 and 24 mg/kg l-DOPA doses. However, after reaching the 72 mg/kg l-DOPA, AIMs were not significantly different between control and nor-BNI groups. In summary, while blocking KORs significantly increased the rate of development of LID induced by chronic, escalating doses of l-DOPA in a moderate-lesioned rat PD model, it did not contribute further once the overall severity of LID was established. While we observed an increase of tonic DA levels in the moderately lesioned dorsolateral striatum, there was no tonic DA change following administration of nor-BNI.

Antagonism of kappa opioid receptors accelerates the development of L-DOPA-induced dyskinesia in a preclinical model of moderate dopamine depletion.

Levels of the opioid peptide dynorphin, an endogenous ligand selective for kappa-opioid receptors (KORs), its mRNA and pro-peptide precursors are differentially dysregulated in Parkinson disease (PD) and following the development of L-DOPA-induced dyskinesia (LID). It remains unclear, whether these alterations contribute to the pathophysiological mechanisms underlying PD motor impairment and the subsequent development of LID, or whether they are part of compensatory mechanisms. We sought to investigate nor-BNI, a KOR antagonist, 1) in the dopamine (DA)-depleted PD state, 2) during the development phase of LID, and 3) with measuring tonic levels of striatal DA. Nor-BNI (3 mg/kg; s.c.) did not lead to functional restoration in the DA-depleted state, but a change in the dose-dependent development of abnormal voluntary movements (AIMs) in response to escalating doses of L-DOPA in a rat PD model with a moderate striatal 6-hydroxydopamine (6-OHDA) lesion. We tested five escalating doses of L-DOPA (6, 12, 24, 48, 72 mg/kg; i.p.), and nor-BNI significantly increased the development of AIMs at the 12 and 24 mg/kg L-DOPA doses. However, after dosing with 72 mg/kg L-DOPA, AIMs were not significantly different between control and nor-BNI groups. In summary, while blocking KORs significantly increased the rate of development of LID induced by chronic, escalating doses of L-DOPA in a moderate-lesioned rat PD model, it did not contribute further once the overall severity of LID was established. While we saw an increase of tonic DA levels in the moderately lesioned dorsolateral striatum, there was no tonic DA change following administration of nor-BNI.

Violent victimization at the intersections of sexual orientation, gender identity, and race: National Crime Victimization Survey, 2017-2019.

INTRODUCTION: Prior research has found that experiences with violence in the U.S. differ across individual demographic characteristics, including race, gender, and sexual orientation. However, peer reviewed studies have yet to examine the relationship between the intersections of race, gender, and sexual orientation, victimization risk, and characteristics of victimization. METHODS: We use data from three years (2017-2019) of the National Crime Victimization Survey, the primary source of information on criminal victimization in the United States, to examine victimization at the intersection of sexual orientation, gender, and race/ethnicity. We test whether non-Hispanic Black, Hispanic, and non-Hispanic White sexual and gender minority (SGM) persons aged 16 or over are victimized at greater rates than their non-SGM counterparts and assess whether there are differences between sexual minority females and males of each racial group. We further document characteristics of victimization such as reporting to the police by SGM status and race or ethnicity. RESULTS: We find that SGMs are disproportionately more likely to be victims of violent crime than non-SGM people, and these disparities are present across the assessed racial and ethnic groups (non-Hispanic Black odds ratio [OR] = 3.3, 90% CI [CI] = 1.36, 5.16; Hispanic OR = 4.5, CI = 2.25, 6.71; non-Hispanic White OR = 4.8, CI = 2.25, 6.71). However, sexual orientation disparities are statistically distinguishable for lesbian or bisexual (LB) non-Hispanic White and Hispanic females but not for non-Hispanic Black LB females. Among LB females, the overall differences in victimization were primarily driven by bisexual respondents. We further find racial and ethnic differences among SGM victims in the likelihood of having the victimization reported to the police, in the utilization of community (non-police) resources, and in other aspects of victimization experiences, such as whether arrests occurred or in the suspicion that the violent incident was a hate crime. CONCLUSIONS: Our findings raise indicate a complex picture of how sexual orientation, gender identity, sex, and race and ethnicity interact in victimizations and their characteristics that should be further explored.

Hate crimes against LGBT people: National Crime Victimization Survey, 2017-2019.

We estimate the prevalence and characteristics of violent hate crime victimization of lesbian, gay, bisexual, and transgender (LGBT) people in the United States, and we compare them to non-LGBT hate crime victims and to LGBT victims of violent non-hate crime. We analyze pooled 2017-2019 data from the National Crime Victimization Survey (n persons = 553, 925;n incidents = 32, 470), the first nationally representative and comprehensive survey on crime that allows identification of LGBT persons aged 16 or older. Descriptive and bivariate analysis show that LGBT people experienced 6.6 violent hate crime victimizations per 1,000 persons compared with non-LGBT people's 0.6 per 1,000 persons (odds ratio = 8.30, 95% confidence interval = 1.94, 14.65). LGBT people were more likely to be hate crime victims of sexual orientation or gender bias crime and less likely to be victims of race or ethnicity bias crimes compared to non-LGBT hate crime victims. Compared to non-LGBT victims, LGBT victims of hate crime were more likely to be younger, have a relationship with their assailant, and have an assailant who is white. Compared to LGBT victims of non-hate violence, more LGBT hate crime victims reported experiencing problems in their social lives, negative emotional responses, and physical symptoms of distress. Our findings affirm claims that hate crimes have adverse physical and psychological effects on victims and highlight the need to ensure that LGBT persons who experience hate crime get necessary support and services in the aftermath of the crime.

Antidiscrimination Interventions, Political Ads on Transgender Rights, and Public Opinion: Results From Two Survey Experiments on Adults in the United States.

Political advertisements can shift attitudes and behaviors to become more exclusionary toward social out-groups. However, people who engage in an antidiscrimination exercise in the context of an experiment may respond differently to such ads. What interventions might foster inclusive attitudes in the presence of political communications about social policy issues like transgender rights? We examined two scalable antidiscrimination exercises commonly used in applied settings: describing a personal narrative of discrimination and perspective-taking. We then showed people political ads that are favorable or opposed to transgender rights to determine whether those interventions moderate how receptive people are to the messages. Relying on two demographically representative survey experiments of adults in the United States (study 1 N = 1,291; study 2 N = 1,587), we found that personal recollections of discriminatory experiences did not reduce exclusionary attitudes, but perspective-taking had some effects, particularly among those who fully complied with the exercise. However, both studies revealed potential backfire effects; recalling a discriminatory experience induced negative attitudes among a subset of the participants, and participants who refused to perspective-take when prompted also held more negative attitudes. Importantly, political ads favorable toward transgender rights consistently resulted in more positive attitudes toward transgender people. Future work needs to carefully examine heterogeneous responses and resistance to antidiscrimination interventions and examine what particular aspects of the political ads induced the attitude change.

A coculture-coproduction system designed for enhanced carbon conservation through inter-strain CO2 recycling.

Carbon loss in the form of CO2 is an intrinsic and persistent challenge faced during conventional and advanced biofuel production from biomass feedstocks. Current mechanisms for increasing carbon conservation typically require the provision of reduced co-substrates as additional reducing equivalents. This need can be circumvented, however, by exploiting the natural heterogeneity of lignocellulosic sugars mixtures and strategically using specific fractions to drive complementary CO2 emitting vs. CO2 fixing pathways. As a demonstration of concept, a coculture-coproduction system was developed by pairing two catabolically orthogonal Escherichia coli strains; one converting glucose to ethanol (G2E) and the other xylose to succinate (X2S). 13C-labeling studies reveled that G2E + X2S cocultures were capable of recycling 24% of all evolved CO2 and achieved a carbon conservation efficiency of 77%; significantly higher than the 64% achieved when all sugars are instead converted to just ethanol. In addition to CO2 exchange, the latent exchange of pyruvate between strains was discovered, along with significant carbon rearrangement within X2S.

Gender Identity Disparities in Criminal Victimization: National Crime Victimization Survey, 2017-2018.

Objectives. To estimate the prevalence of personal and household victimizations among transgender people in the United States.Methods. We analyzed pooled 2017 and 2018 data from the National Crime Victimization Survey, the first nationally representative sample that allows identification of transgender respondents.Results. Transgender people experienced 86.2 victimizations per 1000 persons compared with cisgender people's 21.7 per 1000 persons (odds ratio [OR] = 4.24; 90% confidence interval [CI] = 1.49, 7.00). Households that had a transgender person had higher rates of property victimization (214.1 per 1000 households) than households with only cisgender people (108 per 1000 households; OR = 2.25; 90% CI = 1.19, 3.31). Transgender victims whose sex assigned at birth was male were more likely to perceive their victimization as a hate crime than cisgender victims whose sex assigned at birth was male. There were no disparities in reporting victimizations to authorities: only about half of the victimizations of both transgender and cisgender people were reported.Conclusions. Public policy and administration need to consider the unique vulnerabilities transgender people routinely encounter, resulting in disparities in criminal victimization.

Potential differences between the political attitudes of people with same-sex parents and people with different-sex parents: An exploratory assessment of first-year college students.

Children were often near the center of public debates about legal marriage recognition for same-sex couples. Obergefell v. Hodges (2015), the case that resulted in legal same-sex marriage recognition, stressed the importance of these children as one of many factors compelling the opinion. Estimates indicated same-sex couples were raising 200,000 children in the United States. Children raised by same-sex couples may be politically socialized in distinct ways compared to children of different-sex couples because lesbians, gay men, and bisexuals tend to hold distinct and progressive political viewpoints on a wide variety of issues. What are the political attitudes of people with same-sex parents? In this exploratory study, we analyze a large, representative survey of first-year college students across the United States; we find few differences between people with same-sex and different-sex parents, and some of those differences may be attributable to households and respondent characteristics. When on the rare occasion a difference exists, we find that people with same-sex female parents are more progressive, but people with same-sex male parents are more conservative. Gender differences also emerged, with some distinctive patterns between males with same-sex parents and females with same-sex parents.

The Delta-Specific Opioid Glycopeptide BBI-11008: CNS Penetration and Behavioral Analysis in a Preclinical Model of Levodopa-Induced Dyskinesia.

In previous work we evaluated an opioid glycopeptide with mixed µ/δ-opioid receptor agonism that was a congener of leu-enkephalin, MMP-2200. The glycopeptide analogue showed penetration of the blood-brain barrier (BBB) after systemic administration to rats, as well as profound central effects in models of Parkinson's disease (PD) and levodopa (L-DOPA)-induced dyskinesia (LID). In the present study, we tested the glycopeptide BBI-11008 with selective δ-opioid receptor agonism, an analogue of deltorphin, a peptide secreted from the skin of frogs (genus Phyllomedusa). We tested BBI-11008 for BBB-penetration after intraperitoneal (i.p.) injection and evaluated effects in LID rats. BBI-11008 (10 mg/kg) demonstrated good CNS-penetrance as shown by microdialysis and mass spectrometric analysis, with peak concentration levels of 150 pM in the striatum. While BBI-11008 at both 10 and 20 mg/kg produced no effect on levodopa-induced limb, axial and oral (LAO) abnormal involuntary movements (AIMs), it reduced the levodopa-induced locomotor AIMs by 50% after systemic injection. The N-methyl-D-aspartate receptor antagonist MK-801 reduced levodopa-induced LAO AIMs, but worsened PD symptoms in this model. Co-administration of MMP-2200 had been shown prior to block the MK-801-induced pro-Parkinsonian activity. Interestingly, BBI-11008 was not able to block the pro-Parkinsonian effect of MK-801 in the LID model, further indicating that a balance of mu- and delta-opioid agonism is required for this modulation. In summary, this study illustrates another example of meaningful BBB-penetration of a glycopeptide analogue of a peptide to achieve a central behavioral effect, providing additional evidence for the glycosylation technique as a method to harness therapeutic potential of peptides.

Victimization rates and traits of sexual and gender minorities in the United States: Results from the National Crime Victimization Survey, 2017.

Do sexual and gender minorities (SGMs) in the United States encounter disproportionate rates of victimization as compared with their cisgender, heterosexual counterparts? Answering this question has proved elusive because nationally representative victimization data have not included victims' sexual orientation or gender identity. The National Crime Victimization Survey, the nation's primary source of representative information on criminal victimization, began documenting sexual orientation and gender identity in 2016 and released data publicly for the first time in 2019. We find SGMs disproportionately are victims across a variety of crimes. The rate of violent victimization for SGMs is 71.1 victimizations per 1000 people compared with 19.2 victimizations per 1000 people for those who are not SGMs. SGMs are 2.7 times more likely to be a victim of violent crime than non-SGMs. These findings raise the importance of further considering sexual orientation and gender identity in victimization and interventions.

Preclinical evidence in support of repurposing sub-anesthetic ketamine as a treatment for L-DOPA-induced dyskinesia.

Parkinson's disease (PD) is the second most common neurodegenerative disease. Pharmacotherapy with L-DOPA remains the gold-standard therapy for PD, but is often limited by the development of the common side effect of L-DOPA-induced dyskinesia (LID), which can become debilitating. The only effective treatment for disabling dyskinesia is surgical therapy (neuromodulation or lesioning), therefore effective pharmacological treatment of LID is a critical unmet need. Here, we show that sub-anesthetic doses of ketamine attenuate the development of LID in a rodent model, while also having acute anti-parkinsonian activity. The long-term anti-dyskinetic effect is mediated by brain-derived neurotrophic factor-release in the striatum, followed by activation of ERK1/2 and mTOR pathway signaling. This ultimately leads to morphological changes in dendritic spines on striatal medium spiny neurons that correlate with the behavioral effects, specifically a reduction in the density of mushroom spines, a dendritic spine phenotype that shows a high correlation with LID. These molecular and cellular changes match those occurring in hippocampus and cortex after effective sub-anesthetic ketamine treatment in preclinical models of depression, and point to common mechanisms underlying the therapeutic efficacy of ketamine for these two disorders. These preclinical mechanistic studies complement current ongoing clinical testing of sub-anesthetic ketamine for the treatment of LID by our group, and provide further evidence in support of repurposing ketamine to treat individuals with PD. Given its clinically proven therapeutic benefit for both treatment-resistant depression and several pain states, very common co-morbidities in PD, sub-anesthetic ketamine could provide multiple therapeutic benefits for PD in the future.

Catabolic Division of Labor Enhances Production of D-Lactate and Succinate From Glucose-Xylose Mixtures in Engineered Escherichia coli Co-culture Systems.

Although biological upgrading of lignocellulosic sugars represents a promising and sustainable route to bioplastics, diverse and variable feedstock compositions (e.g., glucose from the cellulose fraction and xylose from the hemicellulose fraction) present several complex challenges. Specifically, sugar mixtures are often incompletely metabolized due to carbon catabolite repression while composition variability further complicates the optimization of co-utilization rates. Benefiting from several unique features including division of labor, increased metabolic diversity, and modularity, synthetic microbial communities represent a promising platform with the potential to address persistent bioconversion challenges. In this work, two unique and catabolically orthogonal Escherichia coli co-cultures systems were developed and used to enhance the production of D-lactate and succinate (two bioplastic monomers) from glucose-xylose mixtures (100 g L-1 total sugars, 2:1 by mass). In both cases, glucose specialist strains were engineered by deleting xylR (encoding the xylose-specific transcriptional activator, XylR) to disable xylose catabolism, whereas xylose specialist strains were engineered by deleting several key components involved with glucose transport and phosphorylation systems (i.e., ptsI, ptsG, galP, glk) while also increasing xylose utilization by introducing specific xylR mutations. Optimization of initial population ratios between complementary sugar specialists proved a key design variable for each pair of strains. In both cases, ∼91% utilization of total sugars was achieved in mineral salt media by simple batch fermentation. High product titer (88 g L-1 D-lactate, 84 g L-1 succinate) and maximum productivity (2.5 g L-1 h-1 D-lactate, 1.3 g L-1 h-1 succinate) and product yield (0.97 g g-total sugar-1 for D-lactate, 0.95 g g-total sugar-1 for succinate) were also achieved.

The XylR variant (R121C and P363S) releases arabinose-induced catabolite repression on xylose fermentation and enhances coutilization of lignocellulosic sugar mixtures.

Microbial production of fuels and chemicals from lignocellulosic biomass provides a promising alternative to conventional petroleum-derived routes. However, the heterogeneous sugar composition of lignocellulose prevents efficient microbial sugar co-fermentation due to carbon catabolite repression, which negatively affects production metrics. We previously discovered that a mutant copy of the transcriptional regulator XylR (P363S and R121C; denoted as XylR*) in Escherichia coli has a higher DNA-binding affinity than wild-type XylR, leading to a stronger activation of the d-xylose catabolic genes and a release from glucose-induced repression on xylose fermentation. Here, we showed that XylR* also releases l-arabinose-induced repression on xylose fermentation through altered transcriptional control, enhancing co-fermentation of arabinose-xylose sugar mixtures in wild-type E. coli. Integrating xylR* into an ethanologenic E. coli resulted in the coutilization of 96% of the provided glucose-xylose-arabinose mixtures (120 g/L total sugars supplied) with an ethanol yield higher than 90% of the theoretical maximum by simple batch fermentations.

Parallel experimental evolution reveals a novel repressive control of GalP on xylose fermentation in Escherichia coli.

Efficient xylose utilization will facilitate microbial conversion of lignocellulosic sugar mixtures into valuable products. In Escherichia coli, xylose catabolism is controlled by carbon catabolite repression (CCR). However, in E. coli such as the succinate-producing strain KJ122 with disrupted CCR, xylose utilization is still inhibited under fermentative conditions. To probe the underlying genetic mechanisms inhibiting xylose utilization, we evolved KJ122 to enhance its xylose fermentation abilities in parallel and characterized the potential convergent genetic changes shared by multiple independently evolved strains. Whole-genome sequencing revealed that convergent mutations occurred in the galactose regulon during adaptive laboratory evolution potentially decreasing the transcriptional level or the activity of GalP, a galactose permease. We showed that deletion of galP increased xylose utilization in both KJ122 and wild-type E. coli, demonstrating a common repressive role of GalP for xylose fermentation. Concomitantly, induced expression of galP from a plasmid repressed xylose fermentation. Transcriptome analysis using RNA sequencing indicates that galP inactivation increases transcription levels of many catabolic genes for secondary sugars including xylose and arabinose. The repressive role of GalP for fermenting secondary sugars in E. coli suggests that utilization of GalP as a substitute glucose transporter is undesirable for conversion of lignocellulosic sugar mixtures.

Engineering a Synthetic, Catabolically Orthogonal Coculture System for Enhanced Conversion of Lignocellulose-Derived Sugars to Ethanol.

Fermentation of lignocellulosic sugar mixtures is often suboptimal due to inefficient xylose catabolism and sequential sugar utilization caused by carbon catabolite repression. Unlike in conventional applications employing a single engineered strain, the alternative development of synthetic microbial communities facilitates the execution of complex metabolic tasks by exploiting the unique community features, including modularity, division of labor, and facile tunability. A series of synthetic, catabolically orthogonal coculture systems were systematically engineered, as derived from either wild-type Escherichia coli W or ethanologenic LY180. Net catabolic activities were effectively balanced by simple tuning of the inoculum ratio between specialist strains, which enabled coutilization (98% of 100 g L-1 total sugars) of glucose-xylose mixtures (2:1 by mass) for both culture systems in simple batch fermentations. The engineered ethanologenic cocultures achieved ethanol titer (46 g L-1), productivity (488 mg L-1 h-1), and yield (∼90% of theoretical maximum), which were all significantly increased compared to LY180 monocultures.

Recent trends in integrated bioprocesses: aiding and expanding microbial biofuel/biochemical production.

Microbial biosynthesis of fuels and chemicals represents a promising route for their renewable production. Product toxicity, however, represents a common challenge limiting the efficacy of this approach. Integrated bioprocesses incorporating in situ product separation are poised to help address this intrinsic problem, but suffer their own unique shortcomings. To improve and expand the utility of this versatile bioprocessing strategy, recent innovations have focused on developing more effective separation materials and novel process configurations, as well as adapting designs to accommodate semi-continuous modes of operation. As a result, integrated bioprocesses are finding new applications to aid the biosynthesis of an ever-growing list of bioproducts. Emerging applications, meanwhile, are exploring the further expansion of such designs to interface microbial and chemical catalysts, leading to new and versatile routes for the one-pot synthesis of an even greater diversity of renewable products.

The combination of the opioid glycopeptide MMP-2200 and a NMDA receptor antagonist reduced l-DOPA-induced dyskinesia and MMP-2200 by itself reduced dopamine receptor 2-like agonist-induced dyskinesia.

Dopamine (DA)-replacement therapy utilizing l-DOPA is the gold standard symptomatic treatment for Parkinson's disease (PD). A critical complication of this therapy is the development of l-DOPA-induced dyskinesia (LID). The endogenous opioid peptides, including enkephalins and dynorphin, are co-transmitters of dopaminergic, GABAergic, and glutamatergic transmission in the direct and indirect striatal output pathways disrupted in PD, and alterations in expression levels of these peptides and their precursors have been implicated in LID genesis and expression. We have previously shown that the opioid glycopeptide drug MMP-2200 (a.k.a. Lactomorphin), a glycosylated derivative of Leu-enkephalin mediates potent behavioral effects in two rodent models of striatal DA depletion. In this study, the mixed mu-delta agonist MMP-2200 was investigated in standard preclinical rodent models of PD and of LID to evaluate its effects on abnormal involuntary movements (AIMs). MMP-2200 showed antiparkinsonian activity, while increasing l-DOPA-induced limb, axial, and oral (LAO) AIMs by ∼10%, and had no effect on dopamine receptor 1 (D1R)-induced LAO AIMs. In contrast, it markedly reduced dopamine receptor 2 (D2R)-like-induced LAO AIMs. The locomotor AIMs were reduced by MMP-2200 in all three conditions. The N-methyl-d-aspartate receptor (NMDAR) antagonist MK-801 has previously been shown to be anti-dyskinetic, but only at doses that induce parkinsonism. When MMP-2200 was co-administered with MK-801, MK-801-induced pro-parkinsonian activity was suppressed, while a robust anti-dyskinetic effect remained. In summary, the opioid glycopeptide MMP-2200 reduced AIMs induced by a D2R-like agonist, and MMP-2200 modified the effect of MK-801 to result in a potent reduction of l-DOPA-induced AIMs without induction of parkinsonism.

Identifying psychological responses of stigmatized groups to referendums.

Public votes and referendums on the rights of marginalized communities are utilized in 27 states and occur with some regularity. However, research has only recently begun to examine the psychological consequences of these voter referendums for members of stigmatized groups, and a number of important questions remain regarding the internal validity and generalizability of the existing evidence. The current study advances this literature by combining survey data from a large probability-based sample conducted in 2012 [lesbian, gay, bisexual, and/or transgender (LGBT) n = 939; non-LGBT n = 31,067] with media market ad-buy data in states where marriage equality was on the ballot. Television media markets cross state boundaries, ensuring that there was an unintended group of people in 12 states who were exposed to the same-sex marriage discourse but who did not live in states with the voter referendum ("media market spillovers"). We take advantage of this unique data structure by comparing LGBT people in the media market spillovers to those residing in the same state but in nonspillover markets with no ad exposure. LGBT people are emotionally affected by these campaigns, and non-LGBT people are unaffected. LGBT people in markets with a cumulative total of 400 ads have a 34.0% greater probability of reporting stress than LGBT people not exposed to ads. Additionally, while the negative ads evoked sadness, positive ads evoked enjoyment and happiness. Thus, public votes on minority rights represent both a source of minority stress and resilience.