The impact of COVID-19 on cognition in severe cases highlights the need for comprehensive neuropsychological evaluations in all survivors

Katherine E. Burdick & Caitlin E. Millett

doi : 10.1038/s41386-021-00995-7

Neuropsychopharmacology volume 46, page2225 (2021)

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Opioid overdose and tolerance: is the recruitment of ?-arrestin to the µ-receptor involved?

Alexander Gillis & Macdonald J. Christie

doi : 10.1038/s41386-021-01121-3

Neuropsychopharmacology volume 46, pages2226–2227 (2021)

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The GABA-B receptor agonist baclofen helps patients with alcohol use disorder: why these findings matter

Lorenzo Leggio & Raye Z. Litten

doi : 10.1038/s41386-021-01142-y

Neuropsychopharmacology volume 46, pages2228–2229 (2021)

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Choosing appropriate language to reduce the stigma around mental illness and substance use disorders

Nora D. Volkow, Joshua A. Gordon & George F. Koob

doi : 10.1038/s41386-021-01069-4

Neuropsychopharmacology volume 46, pages2230–2232 (2021)

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Bridging the gap: preparing the next generation of brain scientists to communicate with the general public and lawmakers

Saurav D. Singh & Hilary A. Marusak

doi : 10.1038/s41386-021-01084-5

Neuropsychopharmacology volume 46, pages2233–2234 (2021)

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Frequency and profile of objective cognitive deficits in hospitalized patients recovering from COVID-19

Abhishek Jaywant, W. Michael Vanderlind, George S. Alexopoulos, Chaya B. Fridman, Roy H. Perlis & Faith M. Gunning

doi : 10.1038/s41386-021-00978-8

Neuropsychopharmacology volume 46, pages2235–2240 (2021)

Early reports and case series suggest cognitive deficits occurs in some patients with COVID-19. We evaluated the frequency, severity, and profile of cognitive dysfunction in patients recovering from prolonged COVID-19 hospitalization who required acute inpatient rehabilitation prior to discharge. We analyzed cross-sectional scores from the Brief Memory and Executive Test (BMET) in a cohort of N?=?57 COVID-19 patients undergoing inpatient rehabilitation, calculating the frequency of impairment based on neuropsychologist diagnosis and by age-normed BMET subtests. In total, 43 patients (75%) were male, 35 (61%) were non-white, and mean age was 64.5 (SD?=?13.9) years. In total, 48 (84%) were previously living at home independently. Two patients had documented preexisting cognitive dysfunction; none had known dementia. Patients were evaluated at a mean of 43.2 (SD?=?19.2) days after initial admission. In total, 50 patients (88%) had documented hypoxemic respiratory failure and 44 (77%) required intubation.  Forty-six patients (81%) had cognitive impairment, ranging from mild to severe. Deficits were common in working memory (26/47 [55%] of patients), set-shifting (21/44 [47%]), divided attention (18/39 [46%]), and processing speed (14/35 [40%]). Executive dysfunction was not significantly associated with intubation length or the time from extubation to assessment, psychiatric diagnosis, or preexisting cardiovascular/metabolic disease. Attention and executive functions are frequently impaired in COVID-19 patients who require acute rehabilitation prior to discharge. Though interpretation is limited by lack of a comparator group, these results provide an early benchmark for identifying and characterizing cognitive difficulties after COVID-19. Given the frequency and pattern of impairment, easy-to-disseminate interventions that target attention and executive dysfunctions may be beneficial to this population.

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Pharmacological and genetic manipulations at the µ-opioid receptor reveal arrestin-3 engagement limits analgesic tolerance and does not exacerbate respiratory depression in mice

Li He, Sarah W. Gooding, Elinor Lewis, Lindsey C. Felth, Anirudh Gaur & Jennifer L. Whistler

doi : 10.1038/s41386-021-01054-x

Neuropsychopharmacology volume 46, pages2241–2249 (2021)

Opioid drugs are widely used analgesics that activate the G protein-coupled µ-opioid receptor, whose endogenous neuropeptide agonists, endorphins and enkephalins, are potent pain relievers. The therapeutic utility of opioid drugs is hindered by development of tolerance to the analgesic effects, requiring dose escalation for persistent pain control and leading to overdose and fatal respiratory distress. The prevailing hypothesis is that the intended analgesic effects of opioid drugs are mediated by µ-opioid receptor signaling to G protein, while the side-effects of respiratory depression and analgesic tolerance are caused by engagement of the receptor with the arrestin-3 protein. Consequently, opioid drug development has focused exclusively on identifying agonists devoid of arrestin-3 engagement. Here, we challenge the prevailing hypothesis with a panel of six clinically relevant opioid drugs and mice of three distinct genotypes with varying abilities to promote morphine-mediated arrestin-3 engagement. With this genetic and pharmacological approach, we demonstrate that arrestin-3 recruitment does not impact respiratory depression, and effective arrestin-3 engagement reduces, rather than exacerbates, the development of analgesic tolerance. These studies suggest that future development of safer opioids should focus on identifying opioid ligands that recruit both G protein and arrestin-3, thereby mimicking the signaling profile of most endogenous µ-opioid receptor agonists.

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Efficacy and tolerability of baclofen in a U.S. community population with alcohol use disorder: a dose-response, randomized, controlled trial

James C. Garbutt, Alexei B. Kampov-Polevoy, Cort Pedersen, Melissa Stansbury, Robyn Jordan, Laura Willing & Robert J. Gallop

doi : 10.1038/s41386-021-01055-w

Neuropsychopharmacology volume 46, pages2250–2256 (2021)

Identification of new medications for alcohol use disorder (AUD) is important for improving treatment options. Baclofen, a GABAB agonist, has been identified as a potential pharmacotherapy for AUD. In a 16-week double-blind, randomized, placebo-controlled trial, we investigated 30 and 90?mg/day of baclofen compared to placebo and examined effects of dose, sex, and level of pretreatment drinking. One hundred and twenty participants with DSM-IV alcohol dependence (age 46.1 (sd?=?10.1) years, 51.7% male) were randomized after exclusion for unstable medical/psychiatric illness and/or dependence on drugs other than nicotine. Seventy-three participants completed the trial. A main effect of baclofen was found [%HDD (F(2,112)?=?4.16, p?=?0.018, d?=?0.51 95%CI (0.06–0.95), 13.6 fewer HDD) and %ABST (F(2,112)?=?3.68, p?=?0.028, d?=?0.49 95%CI (0.04–0.93), 12.9 more abstinent days)] and was driven by the 90?mg/day dose. A sex?×?dose interaction effect was present for both %HDD (F(2,110)?=?5.48, p?=?0.005) and %ABST (F(2,110)?=?3.19, p?=?0.045). Men showed a marginally positive effect for 90?mg/day compared to PBO (%HDD t(110)?=?1.88, p?=?0.063, d?=?0.36 95%CI (?0.09–0.80), 15.8 fewer HDD days; %ABST t(110)?=?1.68 (p?=?0.096, d?=?0.32 95%CI (?0.12–0.76), 15.7 more ABST)) with no effect for 30?mg/day. Women showed a positive effect for 30?mg/day (%HDD, t(110)?=?3.19, p?=?0.002, d?=?0.61 95%CI (0.16–1.05), 26.3 fewer HDD days; %ABST t(110)?=?2.73, p?=?0.007, d?=?0.52 95%CI (0.07–0.96), 25.4 more ABST days) with marginal effects for 90?mg/day on %ABST (p?=?0.06) with drop-outs/dose reduction from sedative side-effects of 59% in women at 90?mg/day compared to 5% for men. These findings support the hypothesis that baclofen has efficacy in AUD and suggest that dose and sex be further explored as potential moderators of baclofen response and tolerability.

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Treatment of mixed depression with theta-burst stimulation (TBS): results from a double-blind, randomized, sham-controlled clinical trial

Diego Freitas Tavares, Paulo Suen, Carla Garcia Rodrigues dos Santos, Doris Hupfeld Moreno, Leandro Da Costa Lane Valiengo, Izio Klein, Lucas Borrione, Pamela Marques Forte, André R. Brunoni & Ricardo Alberto Moreno

doi : 10.1038/s41386-021-01080-9

Neuropsychopharmacology volume 46, pages2257–2265 (2021)

Mixed depression is probably different in terms of clinical course and response to treatment. Repetitive transcranial magnetic stimulation (rTMS) is well established in non-mixed depression, and theta-burst stimulation (TBS) protocol is replacing conventional protocols because of noninferiority and reduced delivery time. However, TBS has not been adequately studied in mixed states. This study was a double-blind, six-week, sham-controlled, and randomized clinical trial of bilateral TBS targeting the right and left dorsolateral prefrontal cortex, respectively. Adults with bipolar and major depressive disorder experiencing an acute mixed depression were eligible if they had not benefited from a first- or second-line treatment for acute unipolar or bipolar depression recommended by the Canadian Network for Mood and Anxiety Treatments. Out of 100 patients included, 90 composed modified intention-to-treat sample, which was patients that completed at least one week of the intervention. There were no significant differences in Montgomery-Asberg depression rating scale score changes (least squares mean difference between groups at week 3, ?0.06 [95% CI,???3.39 to 3.51; P?=?0.97] in favor of sham TBS). Response and remission rates per MADRS were also not statistically different among active and sham groups (35.7% vs. 43.7%, and 28.5% vs. 37.5% respectively at week 6, ps?>?0.51). No other analyses from baseline to weeks 3 or 6 revealed significant time?x?group interaction or mean differences among groups in the mITT sample. Bilateral TBS targeting the DLPFC is not efficacious as an add-on treatment of acute bipolar and unipolar mixed depression. ClinicalTrials.govIdentifier: NCT04123301

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Neuroimaging correlates and predictors of response to repeated-dose intravenous ketamine in PTSD: preliminary evidence

Agnes Norbury, Sarah B. Rutter, Abigail B. Collins, Sara Costi, Manish K. Jha, Sarah R. Horn, Marin Kautz, Morgan Corniquel, Katherine A. Collins, Andrew M. Glasgow, Jess Brallier, Lisa M. Shin, Dennis S. Charney, James W. Murrough & Adriana Feder

doi : 10.1038/s41386-021-01104-4

Neuropsychopharmacology volume 46, pages2266–2277 (2021)

Promising initial data indicate that the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine may be beneficial in post-traumatic stress disorder (PTSD). Here, we explore the neural correlates of ketamine-related changes in PTSD symptoms, using a rich battery of functional imaging data (two emotion-processing tasks and one task-free scan), collected from a subset of participants of a randomized clinical trial of repeated-dose intravenous ketamine vs midazolam (total N?=?21). In a pre-registered analysis, we tested whether changes in an a priori set of imaging measures from a target neural circuit were predictive of improvement in PTSD symptoms, using leave-one-out cross-validated elastic-net regression models (regions of interest in the target circuit consisted of the dorsal and rostral anterior cingulate cortex, ventromedial prefrontal cortex, anterior hippocampus, anterior insula, and amygdala). Improvements in PTSD severity were associated with increased functional connectivity between the ventromedial prefrontal cortex (vmPFC) and amygdala during emotional face-viewing (change score retained in model with minimum predictive error in left-out subjects, standardized regression coefficient [?] = 2.90). This effect was stronger in participants who received ketamine compared to midazolam (interaction ??=?0.86), and persisted following inclusion of concomitant change in depressive symptoms in the analysis model (??=?0.69). Improvement following ketamine was also predicted by decreased dorsal anterior cingulate activity during emotional conflict regulation, and increased task-free connectivity between the vmPFC and anterior insula (?s?=??2.82, 0.60). Exploratory follow-up analysis via dynamic causal modelling revealed that whilst improvement in PTSD symptoms following either drug was associated with decreased excitatory modulation of amygdala?vmPFC connectivity during emotional face-viewing, increased top-down inhibition of the amygdala by the vmPFC was only observed in participants who improved under ketamine. Individuals with low prefrontal inhibition of amygdala responses to faces at baseline also showed greater improvements following ketamine treatment. These preliminary findings suggest that, specifically under ketamine, improvements in PTSD symptoms are accompanied by normalization of hypofrontal control over amygdala responses to social signals of threat.

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Impact of exogenous estradiol on task-based and resting-state neural signature during and after fear extinction in healthy women

Zhenfu Wen, Mira Z. Hammoud, J. Cobb Scott, Jagan Jimmy, Lily Brown, Marie-France Marin, Anu Asnaani, Ruben C. Gur, Edna B. Foa & Mohammed R. Milad

doi : 10.1038/s41386-021-01158-4

Neuropsychopharmacology volume 46, pages2278–2287 (2021)

Fluctuations of endogenous estrogen modulates fear extinction, but the influence of exogenous estradiol is less studied. Moreover, little focus has been placed on the impact of estradiol on broad network connectivity beyond the fear extinction circuit. Here, we examined the effect of acute exogenous estradiol administration on fear extinction-induced brain activation, whole-brain functional connectivity (FC) during the fear extinction task and post-extinction resting-state. Ninety healthy women (57 using oral contraceptives [OC], 33 naturally cycling [NC]) were fear conditioned on day 1. They ingested an estradiol or placebo pill prior to extinction learning on day 2 (double-blind design). Extinction memory was assessed on day 3. Task-based functional MRI data were ascertained on days 2 and 3 and resting-state data were collected post-extinction on day 2 and pre-recall on day 3. Estradiol administration significantly modulated the neural signature associated with fear extinction learning and memory, consistent with prior studies. Importantly, estradiol administration induced significant changes in FC within multiple networks, including the default mode and somatomotor networks during extinction learning, post-extinction, and during extinction memory recall. Exploratory analyses revealed that estradiol impacted ventromedial prefrontal cortex (vmPFC) activation and FC differently in the NC and OC women. The data implicate a more diffused and significant effect of acute estradiol administration on multiple networks. Such an effect might be beneficial to modulating attention and conscious processes in addition to engaging neural processes associated with emotional learning and memory consolidation.

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Accumbofrontal tract integrity is related to early life adversity and feedback learning

Bryan V. Kennedy, Jamie L. Hanson, Nicholas J. Buser, Wouter van den Bos, Karen D. Rudolph, Richard J. Davidson & Seth D. Pollak

doi : 10.1038/s41386-021-01129-9

Neuropsychopharmacology volume 46, pages2288–2294 (2021)

Abuse, neglect, exposure to violence, and other forms of early life adversity (ELA) are incredibly common and significantly impact physical and mental development. While important progress has been made in understanding the impacts of ELA on behavior and the brain, the preponderance of past work has primarily centered on threat processing and vigilance while ignoring other potentially critical neurobehavioral processes, such as reward-responsiveness and learning. To advance our understanding of potential mechanisms linking ELA and poor mental health, we center in on structural connectivity of the corticostriatal circuit, specifically accumbofrontal white matter tracts. Here, in a sample of 77 youth (Mean age?=?181 months), we leveraged rigorous measures of ELA, strong diffusion neuroimaging methodology, and computational modeling of reward learning. Linking these different forms of data, we hypothesized that higher ELA would be related to lower quantitative anisotropy in accumbofrontal white matter. Furthermore, we predicted that lower accumbofrontal quantitative anisotropy would be related to differences in reward learning. Our primary predictions were confirmed, but similar patterns were not seen in control white matter tracts outside of the corticostriatal circuit. Examined collectively, our work is one of the first projects to connect ELA to neural and behavioral alterations in reward-learning, a critical potential mechanism linking adversity to later developmental challenges. This could potentially provide windows of opportunity to address the effects of ELA through interventions and preventative programming.

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Sex differences in myelin content of white matter tracts in adolescents with depression

Tiffany C. Ho, Lucinda M. Sisk, Artenisa Kulla, Giana I. Teresi, Melissa M. Hansen, Hua Wu & Ian H. Gotlib

doi : 10.1038/s41386-021-01078-3

Neuropsychopharmacology volume 46, pages2295–2303 (2021)

Depression is a chronic and debilitating condition that often emerges during adolescence, a period of significant brain maturation. Few studies, however, have examined how mechanisms of neuroplasticity, including myelination, are affected by adolescent-onset depression. Here, we used multimodal MR imaging to characterize myelin, indexed by R1, in white matter tracts previously associated with depression and compare 48 adolescents with lifetime depression (45 with current depression, 3 remitted) and 35 healthy controls in R1. Compared to healthy controls, R1 was higher in adolescents with lifetime depression in the uncinate fasciculus and corpus callosum genu (all ?s?>?0.42; all ps?<?0.037). Sex significantly moderated the association between depression and R1 in the left uncinate fasciculus and corpus callosum genu (all ?s?>?0.86; all ps?<?0.02), such that depressed female adolescents had significantly higher R1 in these tracts than did healthy female adolescents (all ?s?>?0.82; all ps?<?0.0012). In contrast, depressed and non-depressed male adolescents did not differ in R1 in these tracts (all ps?>?0.32). While fractional anisotropy (FA), a commonly examined measure of white matter organization based on diffusion-weighted MRI, in the left uncinate was positively associated with lifetime depression in our sample (??=?0.56; p?=?0.016), we found no evidence of sex-specific effects of depression in FA. Our results suggest that R1 is more sensitive to sex-specific effects of depression than FA, particularly in female adolescents. Given evidence that myelin inhibits synapse formation and reduces brain plasticity, our findings implicate experience-driven regional myelination as a mechanism underlying depression during periods of significant neural maturation such as adolescence.

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Transcriptome-based polygenic score links depression-related corticolimbic gene expression changes to sex-specific brain morphology and depression risk

Amy E. Miles, Fernanda C. Dos Santos, Enda M. Byrne, Miguel E. Renteria, Andrew M. McIntosh, Mark J. Adams, Giorgio Pistis, Enrique Castelao, Martin Preisig, Bernhard T. Baune, K. Oliver Schubert, Cathryn M. Lewis, Lisa A. Jones, Ian Jones, Rudolf Uher, Jordan W. Smoller, Roy H. Perlis, Douglas F. Levinson, James B. Potash, Myrna M. Weissman, Jianxin Shi, Glyn Lewis, Brenda W. J. H. Penninx, Dorret I. Boomsma, Steven P. Hamilton, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Etienne Sibille, Ahmad R. Hariri & Yuliya S. Nikolova

doi : 10.1038/s41386-021-01189-x

Neuropsychopharmacology volume 46, pages2304–2311 (2021)

Studies in post-mortem human brain tissue have associated major depressive disorder (MDD) with cortical transcriptomic changes, whose potential in vivo impact remains unexplored. To address this translational gap, we recently developed a transcriptome-based polygenic risk score (T-PRS) based on common functional variants capturing ‘depression-like’ shifts in cortical gene expression. Here, we used a non-clinical sample of young adults (n?=?482, Duke Neurogenetics Study: 53% women; aged 19.8?±?1.2 years) to map T-PRS onto brain morphology measures, including Freesurfer-derived subcortical volume, cortical thickness, surface area, and local gyrification index, as well as broad MDD risk, indexed by self-reported family history of depression. We conducted side-by-side comparisons with a PRS independently derived from a Psychiatric Genomics Consortium (PGC) MDD GWAS (PGC-PRS), and sought to link T-PRS with diagnosis and symptom severity directly in PGC-MDD participants (n?=?29,340, 59% women; 12,923 MDD cases, 16,417 controls). T-PRS was associated with smaller amygdala volume in women (t?=??3.478, p?=?0.001) and lower prefrontal gyrification across sexes. In men, T-PRS was associated with hypergyrification in temporal and occipital regions. Prefrontal hypogyrification mediated a male-specific indirect link between T-PRS and familial depression (b?=?0.005, p?=?0.029). PGC-PRS was similarly associated with lower amygdala volume and cortical gyrification; however, both effects were male-specific and hypogyrification emerged in distinct parietal and temporo-occipital regions, unassociated with familial depression. In PGC-MDD, T-PRS did not predict diagnosis (OR?=?1.007, 95% CI?=?[0.997–1.018]) but correlated with symptom severity in men (rho?=?0.175, p?=?7.957?×?10?4) in one cohort (N?=?762, 48% men). Depression-like shifts in cortical gene expression have sex-specific effects on brain morphology and may contribute to broad depression vulnerability in men.

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White matter in prolonged glucocorticoid response to psychological stress in schizophrenia

Eric L. Goldwaser, Joshua Chiappelli, Mark D. Kvarta, Xiaoming Du, Zachary B. Millman, Bhim M. Adhikari, Hugh O’Neill, Jessica Sewell, Samantha Lightner, Shreya Vodapalli, Yizhou Ma, Heather Bruce, Shuo Chen, Yunlong Tan, Peter Kochunov & L. Elliot Hong

doi : 10.1038/s41386-021-01077-4

Neuropsychopharmacology volume 46, pages2312–2319 (2021)

Stress is implicated in psychosis etiology and exacerbation, but pathogenesis toward brain network alterations in schizophrenia remain unclear. White matter connects limbic and prefrontal regions responsible for stress response regulation, and white matter tissues are also vulnerable to glucocorticoid aberrancies. Using a novel psychological stressor task, we studied cortisol stress responses over time and white matter microstructural deficits in schizophrenia spectrum disorder (SSD). Cortisol was measured at baseline, 0-, 20-, and 40-min after distress induction by a psychological stressor task in 121 SSD patients and 117 healthy controls (HC). White matter microstructural integrity was measured by 64-direction diffusion tensor imaging. Fractional anisotropy (FA) in white matter tracts were related to cortisol responses and then compared to general patterns of white matter tract deficits in SSD identified by mega-analysis. Differences between 40-min post-stress and baseline, but not acute reactivity post-stress, was significantly elevated in SSD vs HC, time?×?diagnosis interaction F2.3,499.9?=?4.1, p?=?0.013. All SSD white matter tracts were negatively associated with prolonged cortisol reactivity but all tracts were positively associated with prolonged cortisol reactivity in HC. Individual tracts most strongly associated with prolonged cortisol reactivity were also most impacted in schizophrenia in general as established by the largest schizophrenia white matter study (r?=??0.56, p?=?0.006). Challenged with psychological stress, SSD and HC mount similar cortisol responses, and impairments arise in the resolution timeframe. Prolonged cortisol elevations are associated with the white matter deficits in SSD, in a pattern previously associated with schizophrenia in general.

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Lower cholinergic basal forebrain volumes link with cognitive difficulties in schizophrenia

Mihai Avram, Michel J. Grothe, Lena Meinhold, Claudia Leucht, Stefan Leucht, Stefan Borgwardt, Felix Brandl & Christian Sorg

doi : 10.1038/s41386-021-01070-x

Neuropsychopharmacology volume 46, pages2320–2329 (2021)

A potential pathophysiological mechanism of cognitive difficulties in schizophrenia is a dysregulated cholinergic system. Particularly, the cholinergic basal forebrain nuclei (BFCN), the source of cortical cholinergic innervation, support multiple cognitive functions, ranging from attention to decision-making. We hypothesized that BFCN structural integrity is altered in schizophrenia and associated with patients’ attentional deficits. We assessed gray matter (GM) integrity of cytoarchitectonically defined BFCN region-of-interest in 72 patients with schizophrenia and 73 healthy controls, matched for age and gender, from the COBRE open-source database, via structural magnetic resonance imaging (MRI)–based volumetry. MRI-derived measures of GM integrity (i.e., volumes) were linked with performance on a symbol coding task (SCT), a paper-pencil-based metric that assesses attention, by correlation and mediation analysis. To assess the replicability of findings, we repeated the analyses in an independent dataset comprising 26 patients with schizophrenia and 24 matched healthy controls. BFCN volumes were lower in patients (t(139)=2.51, p?=?0.01) and significantly associated with impaired SCT performance (r?=?0.31, p?=?0.01). Furthermore, lower BFCN volumes mediated the group difference in SCT performance. When including global GM volumes, which were lower in patients, as covariates-of-no-interest, these findings disappeared, indicating that schizophrenia did not have a specific effect on BFCN relative to other regional volume changes. We replicated these findings in the independent cohort, e.g., BFCN volumes were lower in patients and mediated patients’ impaired SCT performance. Results demonstrate lower BFCN volumes in schizophrenia, which link with patients’ attentional deficits. Data suggest that a dysregulated cholinergic system might contribute to cognitive difficulties in schizophrenia via impaired BFCN.

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Release of endogenous dynorphin opioids in the prefrontal cortex disrupts cognition

Antony D. Abraham, Sanne M. Casello, Selena S. Schattauer, Brenden A. Wong, Grace O. Mizuno, Karan Mahe, Lin Tian, Benjamin B. Land & Charles Chavkin

doi : 10.1038/s41386-021-01168-2

Neuropsychopharmacology volume 46, pages2330–2339 (2021)

Following repeated opioid use, some dependent individuals experience persistent cognitive deficits that contribute to relapse of drug-taking behaviors, and one component of this response may be mediated by the endogenous dynorphin/kappa opioid system in neocortex. In C57BL/6 male mice, we find that acute morphine withdrawal evokes dynorphin release in the medial prefrontal cortex (PFC) and disrupts cognitive function by activation of local kappa opioid receptors (KORs). Immunohistochemical analyses using a phospho-KOR antibody confirmed that both withdrawal-induced and optically evoked dynorphin release activated KOR in PFC. Using a genetically encoded sensor based on inert KOR (kLight1.2a), we revealed the in vivo dynamics of endogenous dynorphin release in the PFC. Local activation of KOR in PFC produced multi-phasic disruptions of memory processing in an operant-delayed alternation behavioral task, which manifest as reductions in response number and accuracy during early and late phases of an operant session. Local pretreatment in PFC with the selective KOR antagonist norbinaltorphimine (norBNI) blocked the disruptive effect of systemic KOR activation during both early and late phases of the session. The early, but not late phase disruption was blocked by viral excision of PFC KORs, suggesting an anatomically dissociable contribution of pre- and postsynaptic KORs. Naloxone-precipitated withdrawal in morphine-dependent mice or optical stimulation of pdynCre neurons using Channelrhodopsin-2 disrupted delayed alternation performance, and the dynorphin-induced effect was blocked by local norBNI. Our findings describe a mechanism for control of cortical function during opioid dependence and suggest that KOR antagonism could promote abstinence.

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Kappa opioid receptor modulation of excitatory drive onto nucleus accumbens fast-spiking interneurons

Benjamin C. Coleman, Kevin M. Manz & Brad A. Grueter

doi : 10.1038/s41386-021-01146-8

Neuropsychopharmacology volume 46, pages2340–2349 (2021)

The dynorphin/kappa opioid receptor (KOR) system within the nucleus accumbens (NAc) contributes to affective states. Parvalbumin fast-spiking interneurons (PV-FSIs), a key component of feedforward inhibition, participate in integration of excitatory inputs to the NAc by robustly inhibiting select populations of medium spiny output neurons, therefore greatly influencing NAc dependent behavior. How the dynorphin/KOR system regulates feedforward inhibition in the NAc remains unknown. Here, we elucidate the molecular mechanisms of KOR inhibition of excitatory transmission onto NAc PV-FSIs using a combination of whole-cell patch-clamp electrophysiology, optogenetics, pharmacology, and a parvalbumin reporter mouse. We find that postsynaptic KOR stimulation induces long-term depression (LTD) of excitatory synapses onto PV-FSI by stimulating the endocytosis of AMPARs via a PKA and calcineurin-dependent mechanism. Furthermore, KOR regulation of PV-FSI synapses are input specific, inhibiting thalamic but not cortical inputs. Finally, following acute stress, a protocol known to elevate dynorphin/KOR signaling in the NAc, KOR agonists no longer inhibit excitatory transmission onto PV-FSI. In conclusion, we delineate pathway-specific mechanisms mediating KOR control of feedforward inhibitory circuits in the NAc and provide evidence for the recruitment of this system in response to stress.

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The protective effect of operant social reward on cocaine self-administration, choice, and relapse is dependent on delay and effort for the social reward

Marco Venniro, Leigh V. Panlilio, David H. Epstein & Yavin Shaham

doi : 10.1038/s41386-021-01148-6

Neuropsychopharmacology volume 46, pages2350–2357 (2021)

Social reinforcement-based treatments are effective for many, but not all, people with addictions to drugs. We recently developed an operant rat model that mimics features of one such treatment, the community-reinforcement approach. In this model, rats uniformly choose social interaction over methamphetamine or heroin. Abstinence induced by social preference protects against the incubation of drug-seeking that would emerge during forced abstinence. Here, we determined whether these findings generalize to cocaine and whether delaying or increasing effort for social interaction could reveal possibly human-relevant individual differences in responsiveness. We trained male and female rats for social self-administration (6 days) and then for cocaine self-administration, initially for 2-h/day for 4 days, and then for 12-h/day continuously or intermittently for 8 days. We assessed relapse to cocaine seeking after 1 and 15 days. Between tests, the rats underwent either forced abstinence or social-choice-induced abstinence. After establishing stable social preference, we manipulated the delay for both rewards or for social reward alone, or the response requirements (effort) for social reward. Independent of cocaine-access conditions and sex, operant social interaction inhibited cocaine self-administration and prevented incubation of cocaine seeking. Preference for social access was decreased by the delay of both rewards or social reward alone, or by increased response requirements for social reward, with notable individual variability. This choice procedure can identify mechanisms of individual differences in an animal model of cocaine use and could thereby help screen medications for people who are relatively unresponsive to treatments based on rewarding social interaction.

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Astrocyte-derived TNF and glutamate critically modulate microglia activation by methamphetamine

Teresa Canedo, Camila Cabral Portugal, Renato Socodato, Tiago Oliveira Almeida, Ana Filipa Terceiro, Joana Bravo, Ana Isabel Silva, João Duarte Magalhães, Sónia Guerra-Gomes, João Filipe Oliveira, Nuno Sousa, Ana Magalhães, João Bettencourt Relvas & Teresa Summavielle

doi : 10.1038/s41386-021-01139-7

Neuropsychopharmacology volume 46, pages2358–2370 (2021)

Methamphetamine (Meth) is a powerful illicit psychostimulant, widely used for recreational purposes. Besides disrupting the monoaminergic system and promoting oxidative brain damage, Meth also causes neuroinflammation, contributing to synaptic dysfunction and behavioral deficits. Aberrant activation of microglia, the largest myeloid cell population in the brain, is a common feature in neurological disorders triggered by neuroinflammation. In this study, we investigated the mechanisms underlying the aberrant activation of microglia elicited by Meth in the adult mouse brain. We found that binge Meth exposure caused microgliosis and disrupted risk assessment behavior (a feature that usually occurs in individuals who abuse Meth), both of which required astrocyte-to-microglia crosstalk. Mechanistically, Meth triggered a detrimental increase of glutamate exocytosis from astrocytes (in a process dependent on TNF production and calcium mobilization), promoting microglial expansion and reactivity. Ablating TNF production, or suppressing astrocytic calcium mobilization, prevented Meth-elicited microglia reactivity and re-established risk assessment behavior as tested by elevated plus maze (EPM). Overall, our data indicate that glial crosstalk is critical to relay alterations caused by acute Meth exposure.

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