Unique pharmacodynamic properties and low abuse liability of the µ-opioid receptor ligand (S)-methadone.

(R,S)-methadone ((R,S)-MTD) is a µ-opioid receptor (MOR) agonist comprised of (R)-MTD and (S)-MTD enantiomers. (S)-MTD is being developed as an antidepressant and is considered an N-methyl-D-aspartate receptor (NMDAR) antagonist. We compared the pharmacology of (R)-MTD and (S)-MTD and found they bind to MORs, but not NMDARs, and induce full analgesia. Unlike (R)-MTD, (S)-MTD was a weak reinforcer that failed to affect extracellular dopamine or induce locomotor stimulation. Furthermore, (S)-MTD antagonized motor and dopamine releasing effects of (R)-MTD. (S)-MTD acted as a partial agonist at MOR, with complete loss of efficacy at the MOR-galanin Gal1 receptor (Gal1R) heteromer, a key mediator of the dopaminergic effects of opioids. In sum, we report novel and unique pharmacodynamic properties of (S)-MTD that are relevant to its potential mechanism of action and therapeutic use. One-sentence summary: (S)-MTD, like (R)-MTD, binds to and activates MORs in vitro, but (S)-MTD antagonizes the MOR-Gal1R heteromer, decreasing its abuse liability.

Complexes of Ghrelin GHS-R1a, GHS-R1b, and Dopamine D1 Receptors Localized in the Ventral Tegmental Area as Main Mediators of the Dopaminergic Effects of Ghrelin.

Ghrelin receptor, also known as growth hormone secretagogue receptor (GHS-R1a), is coexpressed with its truncated isoform GHS-R1b, which does not bind ghrelin or signal, but oligomerizes with GHS-R1a, exerting a complex modulatory role that depends on its relative expression. D1 dopamine receptor (D1R) and D5R constitute the two D1-like receptor subtypes. Previous studies showed that GHS-R1b also facilitates oligomerization of GHS-R1a with D1R, conferring GHS-R1a distinctive pharmacological properties. Those include a switch in the preferred coupling of GHS-R1a from Gq to Gs and the ability of D1R/D5R agonists and antagonists to counteract GHS-R1a signaling. Activation of ghrelin receptors localized in the ventral tegmental area (VTA) seems to play a significant role in the contribution of ghrelin to motivated behavior. In view of the evidence indicating that dopaminergic cells of the VTA express ghrelin receptors and D5R, but not D1R, we investigated the possible existence of functional GHS-R1a:GHS-R1b:D5R oligomeric complexes in the VTA. GHS-R1a:GHS-R1b:D5R oligomers were first demonstrated in mammalian transfected cells, and their pharmacological properties were found to be different from those of GHS-R1a:GHS-R1b:D1R oligomers, including weak Gs coupling and the ability of D1R/D5R antagonists, but not agonists, to counteract the effects of ghrelin. However, analyzing the effect of ghrelin in the rodent VTA on MAPK activation with ex vivo experiments, on somatodendritic dopamine release with in vivo microdialysis and on the activation of dopaminergic cells with patch-clamp electrophysiology, provided evidence for a predominant role of GHS-R1a:GHS-R1b:D1R oligomers in the rodent VTA as main mediators of the dopaminergic effects of ghrelin.SIGNIFICANCE STATEMENT The activation of ghrelin receptors localized in the ventral tegmental area (VTA) plays a significant role in the contribution of ghrelin to motivated behavior. We present evidence that indicates these receptors form part of oligomeric complexes that include the functional ghrelin receptor GHS-R1a, its truncated nonsignaling isoform GHS-R1b, and the dopamine D1 receptor (D1R). The binding of ghrelin to these complexes promotes activation of the dopaminergic neurons of the VTA by activation of adenylyl cyclase-protein kinase A signaling, which can be counteracted by both GHS-R1a and D1R antagonists. Our study provides evidence for a predominant role of GHS-R1a:GHS-R1b:D1R oligomers in rodent VTA as main mediators of the dopaminergic effects of ghrelin.

Pharmacological targeting of G protein-coupled receptor heteromers.

A main rationale for the role of G protein-coupled receptor (GPCR) heteromers as targets for drug development is the putative ability of selective ligands for specific GPCRs to change their pharmacological properties upon GPCR heteromerization. The present study provides a proof of concept for this rationale by demonstrating that heteromerization of dopamine D1 and D3 receptors (D1R and D3R) influences the pharmacological properties of three structurally similar selective dopamine D3R ligands, the phenylpiperazine derivatives PG01042, PG01037 and VK4-116. By using D1R-D3R heteromer-disrupting peptides, it could be demonstrated that the three D3R ligands display different D1R-D3R heteromer-dependent pharmacological properties: PG01042, acting as G protein-biased agonist, counteracted D1R-mediated signaling in the D1R-D3R heteromer; PG01037, acting as a D3R antagonist cross-antagonized D1R-mediated signaling in the D1R-D3R heteromer; and VK4-116 specifically acted as a ß-arrestin-biased agonist in the D1R-D3R heteromer. Molecular dynamics simulations predicted potential molecular mechanisms mediating these qualitatively different pharmacological properties of the selective D3R ligands that are dependent on D1R-D3R heteromerization. The results of in vitro experiments were paralleled by qualitatively different pharmacological properties of the D3R ligands in vivo. The results supported the involvement of D1R-D3R heteromers in the locomotor activation by D1R agonists in reserpinized mice and L-DOPA-induced dyskinesia in rats, highlighting the D1R-D3R heteromer as a main pharmacological target for L-DOPA-induced dyskinesia in Parkinson's disease. More generally, the present study implies that when suspecting its pathogenetic role, a GPCR heteromer, and not its individual GPCR units, should be considered as main target for drug development.

Spin Infrequently Occurs in Abstracts of Systematic Reviews For The Pharmacological Treatment of Type 2 Diabetes Mellitus.

AIMS: Currently, there is a growing body of research demonstrating that spin - the misinterpretation and distortion of a study's findings - is common in different fields of medicine. To our knowledge, no study has investigated its presence in systematic reviews focused on diabetic therapies. METHODS: We performed a cross-sectional study by searching MEDLINE and Embase for systematic reviews focused on pharmacologic treatments for type 2 diabetes mellitus. Our search retrieved 26,490 records, from which 199 studies were extracted in a masked, duplicate fashion. Each study was evaluated for the nine most severe types of spin and other study design parameters. Spin was presented as frequencies and odds ratios to identify associations between study characteristics. RESULTS: Spin was identified in the abstracts of 15 systematic reviews (15/199, 7.5%). Spin type 5 was the most common type identified (7/199, 3.5%). Spin types 1, 2, 4, and 8 were not identified. In the last 5 years (2016-2021), 7 systematic reviews contained spin within their abstract. There was no association between spins presence and any extracted study characteristic . CONCLUSIONS: Our findings show that spin infrequently occurs in abstracts of systematic reviews focused on pharmacologic therapies for type 2 diabetes mellitus. However, any amount of spin can lead to the distortion of a reader's interpretation of the study's findings. Thus, we provide recommendations with rationale to prevent spin in future systematic reviews.

Functional µ-Opioid-Galanin Receptor Heteromers in the Ventral Tegmental Area.

The neuropeptide galanin has been shown to interact with the opioid system. More specifically, galanin counteracts the behavioral effects of the systemic administration of µ-opioid receptor (MOR) agonists. Yet the mechanism responsible for this galanin-opioid interaction has remained elusive. Using biophysical techniques in mammalian transfected cells, we found evidence for selective heteromerization of MOR and the galanin receptor subtype Gal1 (Gal1R). Also in transfected cells, a synthetic peptide selectively disrupted MOR-Gal1R heteromerization as well as specific interactions between MOR and Gal1R ligands: a negative cross talk, by which galanin counteracted MAPK activation induced by the endogenous MOR agonist endomorphin-1, and a cross-antagonism, by which a MOR antagonist counteracted MAPK activation induced by galanin. These specific interactions, which represented biochemical properties of the MOR-Gal1R heteromer, could then be identified in situ in slices of rat ventral tegmental area (VTA) with MAPK activation and two additional cell signaling pathways, AKT and CREB phosphorylation. Furthermore, in vivo microdialysis experiments showed that the disruptive peptide selectively counteracted the ability of galanin to block the dendritic dopamine release in the rat VTA induced by local infusion of endomorphin-1, demonstrating a key role of MOR-Gal1R heteromers localized in the VTA in the direct control of dopamine cell function and their ability to mediate antagonistic interactions between MOR and Gal1R ligands. The results also indicate that MOR-Gal1R heteromers should be viewed as targets for the treatment of opioid use disorders. SIGNIFICANCE STATEMENT: The µ-opioid receptor (MOR) localized in the ventral tegmental area (VTA) plays a key role in the reinforcing and addictive properties of opioids. With parallel in vitro experiments in mammalian transfected cells and in situ and in vivo experiments in rat VTA, we demonstrate that a significant population of these MORs form functional heteromers with the galanin receptor subtype Gal1 (Gal1R), which modulate the activity of the VTA dopaminergic neurons. The MOR-Gal1R heteromer can explain previous results showing antagonistic galanin-opioid interactions and offers a new therapeutic target for the treatment of opioid use disorder.

Targeting hypersensitive corticostriatal terminals in restless legs syndrome.

OBJECTIVE: The first aim was to demonstrate a previously hypothesized increased sensitivity of corticostriatal glutamatergic terminals in the rodent with brain iron deficiency (BID), a pathogenetic model of restless legs syndrome (RLS). The second aim was to determine whether these putative hypersensitive terminals could constitute a significant target for drugs effective in RLS, including dopamine agonists (pramipexole and ropinirole) and α2 δ ligands (gabapentin). METHODS: A recently introduced in vivo optogenetic-microdialysis approach was used, which allows the measurement of the extracellular concentration of glutamate upon local light-induced stimulation of corticostriatal glutamatergic terminals. The method also allows analysis of the effect of local perfusion of compounds within the same area being sampled for glutamate. RESULTS: BID rats showed hypersensitivity of corticostriatal glutamatergic terminals (lower frequency of optogenetic stimulation to induce glutamate release). Both hypersensitive and control glutamatergic terminals were significant targets for locally perfused pramipexole, ropinirole, and gabapentin, which significantly counteracted optogenetically induced glutamate release. The use of selective antagonists demonstrated the involvement of dopamine D4 and D2 receptor subtypes in the effects of pramipexole. INTERPRETATION: Hypersensitivity of corticostriatal glutamatergic terminals can constitute a main pathogenetic mechanism of RLS symptoms. Selective D4 receptor agonists, by specifically targeting these terminals, should provide a new efficient treatment with fewer secondary effects. Ann Neurol 2017;82:951-960.

Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor heterotetramer.

Adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromers are key modulators of striatal neuronal function. It has been suggested that the psychostimulant effects of caffeine depend on its ability to block an allosteric modulation within the A2AR-D2R heteromer, by which adenosine decreases the affinity and intrinsic efficacy of dopamine at the D2R. We describe novel unsuspected allosteric mechanisms within the heteromer by which not only A2AR agonists, but also A2AR antagonists, decrease the affinity and intrinsic efficacy of D2R agonists and the affinity of D2R antagonists. Strikingly, these allosteric modulations disappear on agonist and antagonist coadministration. This can be explained by a model that considers A2AR-D2R heteromers as heterotetramers, constituted by A2AR and D2R homodimers, as demonstrated by experiments with bioluminescence resonance energy transfer and bimolecular fluorescence and bioluminescence complementation. As predicted by the model, high concentrations of A2AR antagonists behaved as A2AR agonists and decreased D2R function in the brain.

Local Control of Extracellular Dopamine Levels in the Medial Nucleus Accumbens by a Glutamatergic Projection from the Infralimbic Cortex.

It is generally assumed that infralimbic cortex (ILC) and prelimbic cortex, two adjacent areas of the medial prefrontal cortex (mPFC) in rodents, provide selective excitatory glutamatergic inputs to the nucleus accumbens (NAc) shell and core, respectively. It is also generally believed that mPFC influences the extracellular levels of dopamine in the NAc primarily by an excitatory collateral to the ventral tegmental area (VTA). In the present study, we first established the existence of a selective functional connection between ILC and the posteromedial portions of the VTA (pmVTA) and the mNAc shell (pmNAc shell), by measuring striatal neuronal activation (immunohistochemical analysis of ERK1/2 phosphorylation) and glutamate release (in vivo microdialysis) upon ILC electrical stimulation. A novel optogenetic-microdialysis approach allowed the measurement of extracellular concentrations of glutamate and dopamine in the pmNAc shell upon local light-induced stimulation of glutamatergic terminals from ILC. Cortical electrical and local optogenetic stimulation produced significant increases in the extracellular concentrations of glutamate and dopamine in the pmNAc shell. Local blockade of glutamate release by perfusion of an adenosine A2A receptor antagonist in the pmNAc shell blocked the dopamine release induced by local optogenetic stimulation but only partially antagonized dopamine release induced by cortical electrical stimulation. The results demonstrate that ILC excitatory afferents directly modulate the extracellular concentration of dopamine in the pmNAc shell, but also support the involvement of an indirect mechanism of dopamine control, through a concomitant ILC-mediated activation of the pmVTA. Significance statement: We established the existence of a functional connection between the infralimbic cortex (ILC) and the posteromedial portions of the ventral tegmental area (pmVTA) and the medial nucleus acumbens shell (pmNAc shell). A novel optogenetic-microdialysis approach allowed us to demonstrate that local glutamate release from glutamatergic terminals from the ILC exert a significant modulation of extracellular concentration of dopamine in the pmNAc shell. This mechanism provides the frame for a selective cortical-mediated tonic dopaminergic modulation of specific striatal compartments.

Low- but Not High-Frequency LFP Correlates with Spontaneous BOLD Fluctuations in Rat Whisker Barrel Cortex.

Resting-state magnetic resonance imaging (rsMRI) is thought to reflect ongoing spontaneous brain activity. However, the precise neurophysiological basis of rsMRI signal remains elusive. Converging evidence supports the notion that local field potential (LFP) signal in the high-frequency range correlates with fMRI response evoked by a task (e.g., visual stimulation). It remains uncertain whether this relationship extends to rsMRI. In this study, we systematically modulated LFP signal in the whisker barrel cortex (WBC) by unilateral deflection of rat whiskers. Results show that functional connectivity between bilateral WBC was significantly modulated at the 2 Hz, but not at the 4 or 6 Hz, stimulus condition. Electrophysiologically, only in the low-frequency range (<5 Hz) was the LFP power synchrony in bilateral WBC significantly modulated at 2 Hz, but not at 4- or 6-Hz whisker stimulation, thus distinguishing these 2 experimental conditions, and paralleling the findings in rsMRI. LFP power synchrony in other frequency ranges was modulated in a way that was neither unique to the specific stimulus conditions nor parallel to the fMRI results. Our results support the hypothesis that emphasizes the role of low-frequency LFP signal underlying rsMRI.

A parenting education program for women in treatment for opioid-use disorder at an outpatient medical practice.

Opioid use during pregnancy poses serious risks for the mother and the unborn child. Opioid-use disorder may be managed with medication-assisted treatment (MAT) in an outpatient setting, but few MAT practices specifically address the challenges faced by pregnant women. This article describes a medical office-based educational support group for women in MAT for opioid-use disorder who were pregnant and/or parenting young children. Focus groups were conducted to elicit patient feedback. Women indicated that they found the educational support groups beneficial and offered suggestions. In-office educational support groups for pregnant women in treatment for opioid-use disorder are feasible and well received.

Orexin-corticotropin-releasing factor receptor heteromers in the ventral tegmental area as targets for cocaine.

Release of the neuropeptides corticotropin-releasing factor (CRF) and orexin-A in the ventral tegmental area (VTA) play an important role in stress-induced cocaine-seeking behavior. We provide evidence for pharmacologically significant interactions between CRF and orexin-A that depend on oligomerization of CRF1 receptor (CRF1R) and orexin OX1 receptors (OX1R). CRF1R-OX1R heteromers are the conduits of a negative crosstalk between orexin-A and CRF as demonstrated in transfected cells and rat VTA, in which they significantly modulate dendritic dopamine release. The cocaine target σ1 receptor (σ1R) also associates with the CRF1R-OX1R heteromer. Cocaine binding to the σ1R-CRF1R-OX1R complex promotes a long-term disruption of the orexin-A-CRF negative crosstalk. Through this mechanism, cocaine sensitizes VTA cells to the excitatory effects of both CRF and orexin-A, thus providing a mechanism by which stress induces cocaine seeking.

Equilibrative nucleoside transporter ENT1 as a biomarker of Huntington disease.

The initial goal of this study was to investigate alterations in adenosine A2A receptor (A2AR) density or function in a rat model of Huntington disease (HD) with reported insensitivity to an A2AR antagonist. Unsuspected negative results led to the hypothesis of a low striatal adenosine tone and to the search for the mechanisms involved. Extracellular striatal concentrations of adenosine were measured with in vivo microdialysis in two rodent models of early neuropathological stages of HD disease, the Tg51 rat and the zQ175 knock-in mouse. In view of the crucial role of the equilibrative nucleoside transporter (ENT1) in determining extracellular content of adenosine, the binding properties of the ENT1 inhibitor [3H]-S-(4-Nitrobenzyl)-6-thioinosine were evaluated in zQ175 mice and the differential expression and differential coexpression patterns of the ENT1 gene (SLC29A1) were analyzed in a large human cohort of HD disease and controls. Extracellular striatal levels of adenosine were significantly lower in both animal models as compared with control littermates and striatal ENT1 binding sites were significantly upregulated in zQ175 mice. ENT1 transcript was significantly upregulated in HD disease patients at an early neuropathological severity stage, but not those with a higher severity stage, relative to non-demented controls. ENT1 transcript was differentially coexpressed (gained correlations) with several other genes in HD disease subjects compared to the control group. The present study demonstrates that ENT1 and adenosine constitute biomarkers of the initial stages of neurodegeneration in HD disease and also predicts that ENT1 could constitute a new therapeutic target to delay the progression of the disease.

Dorsolateral caudate nucleus differentiates cocaine from natural reward-associated contextual cues.

Chronic drug administration induces neuroplastic changes within brain circuits regulating cognitive control and/or emotions. Following repeated pairings between drug intake and environmental cues, increased sensitivity to or salience of these contextual cues provoke conscious or unconscious craving and enhance susceptibility to relapse. To explore brain circuits participating in such experience-induced plasticity, we combined functional MRI with a preclinical drug vs. food self-administration (SA) withdrawal model. Specifically, two groups of rats were trained to associate odor cues with the availability of i.v. cocaine or oral sucrose, respectively. After 20 d of cocaine or sucrose SA followed by prolonged (30 d) forced abstinence, animals were presented with odor cues previously associated with or without (S+/S-) reinforcer (cocaine/sucrose) availability while undergoing functional MRI scans. ANOVA results demonstrate that a learning effect distinguishing S+ from S- was seen in the insula and nucleus accumbens, with the insula response reflecting the individual history of cocaine SA intake. A main effect of group, distinguishing cocaine from sucrose, was seen in the medial prefrontal cortex (infralimbic, prelimbic, and cingulate cortex) and dorsolateral striatum. Critically, only the dorsomedial striatum demonstrated a double dissociation between the two SA groups and learning (S+ vs. S-). These findings demonstrate altered cortico-limbic-striatal reward-related processing to learned, environment reward-associated contextual odor cues, which may serve as potential biomarkers for therapeutic interventions.

Terpenes and terpenoids in chemical sensitivity.

UNLABELLED: CONTEXT : Terpenes and terpenoids are a diverse class of organic compounds produced by a variety of plants, particularly conifers. Chemically sensitive patients can be targeted by terpenes and terpenoids, resulting in a triggering of symptoms and pathology. Often patients cannot clear their symptoms from exposure to chemicals unless terpenes and terpenoids are avoided and neutralized along with chemical avoidance and treatment. OBJECTIVE: This article evaluates the presence, diagnosis, and treatment of terpenes exposure in chemically sensitive patients. DESIGN: A double-blind, placebo-controlled, 2-part study was designed to establish the chemically sensitive state of the patients in part 1, followed by a second set of challenges to determine each patient's concurrent sensitivity to terpenes and terpenoids in part 2. In all of the challenges, normal saline was used as a control. A case report illustrates the history of 1 patient and describes the authors' treatment methods. SETTING: The study was developed and conducted at the Environmental Health Center of Dallas (EHC-D) because the environment within the center is 5 times less polluted than the surrounding environments, as determined by quantitative air analysis and particulate counts. PARTICIPANTS: A total of 45 chemically sensitive patients at EHC-D with odor sensitivity to terpenes. The cohort included 18 males and 27 females, aged 24-62 y.Intervention • Patients were deadapted (4 d) and evaluated in a 5-times-less-polluted environment, which was evaluated using air analysis and particulate counts. After deadaptation, the patients were challenged by inhalation in a controlled, less-polluted glass steel booth inside an environmentally controlled room with an ambient air dose of the toxics in the order of parts per billion (PPB) and parts per million (PPM). These toxics included formaldehyde, pesticide, cigarette smoke, ethanol, phenol, chlorine, new sprint, perfume, and placebo. They were also challenged intradermally with extracts of volatile organic compounds (VOCs), including formaldehyde, orris root, ethanol, phenol, cigarette smoke, chlorine, newsprint, perfume, terpenes, terpenoids, and placebo. OUTCOME MEASURES: Inhaled challenges recorded pulse, blood pressure, peak bronchial flow, and other signs and symptoms 30 min before and at 15-min intervals for 2 h postchallenge. Intradermal challenges recorded wheal size and the provocation of signs and symptoms. RESULTS : Different numbers of patients were tested for each terpenes source because of time-related factors or the cumulative effect of testing, which made patients unable to continue. Of 45 chemically sensitive patients in the study, 43 demonstrated sensitivity to terpenes. CONCLUSIONS: This particular patient group was positive for a number of toxic and nontoxic chemicals provoking their symptoms. This study shows there was a connection between VOCs, other chemicals, and terpenes in chemically sensitive patients in a prospective cohort study. It has also shown the potential for terpenes to exacerbate symptoms of chemical sensitivity. Further research on this topic is recommended.

Development of a National Ménière's Disease Registry: A Feasibility Study.

Ménière's disease is a disabling condition causing vertigo and hearing loss yet remains incompletely understood. Registry studies have the potential to answer important questions about phenotypes and natural history of clinical conditions. The aim of this study was to explore the feasibility of a patient-centered national Ménière's disease registry. This was an observational study carried out at 4 state-funded hospitals and 4 independent clinics, within 3 distinct urban and rural regions within the UK. Adults with Ménière's disease were eligible to participate. A range of patient reported data, questionnaire data and clinical data (audiometric, radiological, and specialist balance testing data) was inputted into a bespoke database. The study recruited 411 participants. The majority of participants chose online recruitment (73%) and 27% chose via paper-based methods for participation. A small majority (57%) of participants were female. 96% of participants were of white ethnicity. Data completeness from online or postal data collection was similar. Around 20% of participants had audiological evidence of bilateral Ménière's disease. This feasibility study has successfully piloted methods for recruitment of hundreds of participants diagnosed with Ménière's disease. Participants actively contributed their data to a robust and extensive data collection platform. The positive outcomes from this initial feasibility study are anticipated to serve as a foundation for the future expansion of the registry. This expansion holds the potential to address a broad spectrum of request, encompassing all aspects of the nature of Ménière's disease.

Unique pharmacodynamic properties and low abuse liability of the µ-opioid receptor ligand (S)-methadone.

(R,S)-methadone ((R,S)-MTD) is a racemic µ-opioid receptor (MOR) agonist comprised of (R)-MTD and (S)-MTD enantiomers used for the treatment of opioid use disorder (OUD) and pain. (R)-MTD is used as an OUD treatment, has high MOR potency, and is believed to mediate (R,S)-MTD's therapeutic efficacy. (S)-MTD is in clinical development as an antidepressant and is considered an N-methyl-D-aspartate receptor (NMDAR) antagonist. In opposition to this purported mechanism of action, we found that (S)-MTD does not occupy NMDARs in vivo in rats. Instead, (S)-MTD produced MOR occupancy and induced analgesia with similar efficacy as (R)-MTD. Unlike (R)-MTD, (S)-MTD was not self-administered and failed to increase locomotion or extracellular dopamine levels indicating low abuse liability. Moreover, (S)-MTD antagonized the effects of (R)-MTD in vivo and exhibited unique pharmacodynamic properties, distinct from those of (R)-MTD. Specifically, (S)-MTD acted as a MOR partial agonist with a specific loss of efficacy at the MOR-galanin 1 receptor (Gal1R) heteromer, a key mediator of the dopaminergic effects of opioids. In sum, we report novel and unique pharmacodynamic properties of (S)-MTD that are relevant to its potential mechanism of action and therapeutic use, as well as those of (R,S)-MTD.

Fibromyalgia: unspeakable suffering, a prevalence study of alexithymia.

BACKGROUND: Fibromyalgia patients often present with multiple somatic concerns in a pattern suggestive of underlying depression. The psychological construct of alexithymia complicates the recognition of psychiatric disorders. OBJECTIVE: To measure the prevalence of alexithymia among fibromyalgia patients and compare this with the prevalence among general medicine and rheumatoid arthritis patients. METHODS: The Toronto alexithymia scale (TAS-20) and the Beck depression inventory (BDI) were administered to 50 patients in each of three experimental groups: fibromyalgia, general medicine and rheumatoid arthritis. Logistic regression was used to test for differences in the prevalence of alexithymia among experimental groups, first unadjusted and then adjusted for baseline and demographic variables. In addition, ANOVA was used to analyze the numeric scores of the TAS-20, the BDI and the three alexithymia components measured by the TAS-20. RESULTS: The prevalence of alexithymia in fibromyalgia patients (44%) was significantly higher than in either the general medicine group (8%; P=0.001) or the rheumatoid arthritis group (21%; P=0.023). Alexithymia was strongly associated with moderate to severe depression χ2=49.3, P<0.001), and when the mood disturbance was controlled for, no group differences were detected. CONCLUSION: Fibromyalgia patients are more likely than general medicine patients or patients with rheumatoid arthritis to have difficulty identifying and describing feelings, and to have higher alexithymia scores. Moderate to severe depression is also more prevalent in fibromyalgia patients, and, when controlled for, the difference in alexithymia scores becomes insignificant.

Akathisia and Restless Legs Syndrome: Solving the Dopaminergic Paradox.

Akathisia is an urgent need to move that is associated with treatment with dopamine receptor blocking agents (DRBAs) and with restless legs syndrome (RLS). The pathogenetic mechanism of akathisia has not been resolved. This article proposes that it involves an increased presynaptic dopaminergic transmission in the ventral striatum and concomitant strong activation of postsynaptic dopamine D1 receptors, which form complexes (heteromers) with dopamine D3 and adenosine A1 receptors. It also proposes that in DRBA-induced akathisia, increased dopamine release depends on inactivation of autoreceptors, whereas in RLS it depends on a brain iron deficiency-induced down-regulation of striatal presynaptic A1 receptors.

Temporary disruption of the rat blood-brain barrier with a monoclonal antibody: a novel method for dynamic manganese-enhanced MRI.

Manganese (Mn(2+)) has limited permeability through the blood-brain barrier (BBB). Opening the BBB such that a sufficient amount of Mn(2+) enters the extracellular space is a critical step for dynamic manganese-enhanced magnetic resonance imaging (ME-MRI) experiments. The traditional BBB opening method uses intracarotid hyperosmolar stress which results in suboptimal BBB opening, and practically is limited to nonsurvival experiments due to substantial surgical trauma. In the present ME-MRI study, we investigate the feasibility of opening the BBB with an antibody that targets the endothelial barrier antigen (EBA) specifically expressed by rat endothelial cells. Results demonstrate that intravenous infusion of the anti-EBA agent SMI-71 leads to BBB disruption of the whole brain as detected by ME-MRI and confirmed by Evans blue dye staining. Physiologically, injection of SMI-71 leads to a hypertensive response followed by a sustained hypotensive response in animals anesthetized with urethane alone. Incorporating isoflurane partially mitigated both pressor responses. In general, BBB disruption via intravenous infusion of SMI-71 is straightforward and obviates technical difficulties associated with intracarotid hyperosmolar stress, opening new possibilities for in vivo neuroimaging with ME-MRI. The data also suggest that ME-MRI may be used as an imaging method to assess BBB integrity complementary to the Evans blue dye method, a classical but highly invasive technique, permitting longitudinal assessment of the integrity of the BBB on the same animal.

Synchronized delta oscillations correlate with the resting-state functional MRI signal.

Synchronized low-frequency spontaneous fluctuations of the functional MRI (fMRI) signal have recently been applied to investigate large-scale neuronal networks of the brain in the absence of specific task instructions. However, the underlying neural mechanisms of these fluctuations remain largely unknown. To this end, electrophysiological recordings and resting-state fMRI measurements were conducted in alpha-chloralose-anesthetized rats. Using a seed-voxel analysis strategy, region-specific, anesthetic dose-dependent fMRI resting-state functional connectivity was detected in bilateral primary somatosensory cortex (S1FL) of the resting brain. Cortical electroencephalographic signals were also recorded from bilateral S1FL; a visual cortex locus served as a control site. Results demonstrate that, unlike the evoked fMRI response that correlates with power changes in the gamma bands, the resting-state fMRI signal correlates with the power coherence in low-frequency bands, particularly the delta band. These data indicate that hemodynamic fMRI signal differentially registers specific electrical oscillatory frequency band activity, suggesting that fMRI may be able to distinguish the ongoing from the evoked activity of the brain.