Summary
Background
Changing patterns of exposure lead to changes in the spectrum of contact allergy in the general population and in patients patch tested for suspected contact allergy. The main ...contact allergens (haptens) are assembled in the so‐called ‘baseline series’.
Objectives
To present the current spectrum of contact allergy to baseline series allergens, and its temporal development over the last 12 years, based on data collected by the 56 active departments of the trinational Information Network of Departments of Dermatology (IVDK).
Methods
Patch‐test data, along with core demographic and clinical information, subdivided into 4‐year periods for all patients patch tested with the baseline series in the IVDK, were analysed descriptively. Moreover, log‐binomial regression analysis addressed temporal trends of specific contact allergies, adjusted for potentially confounding factors.
Results
Among the 125 436 patients tested with the German baseline series, the most common allergens were nickel (14·7%), fragrance mix I (8·1%), Myroxylon pereirae resin (7·5%) and cobalt (5·2%), with no conclusive trend. The rise and fall of contact allergy to methylchloroisothiazolinone/methylisothiazolinone (MI), following (self‐) regulation in the European Union, reflected the MI contact allergy epidemic. Propolis showed a marked upward trend with a prevalence of 3·94% during the period 2015–2018.
Conclusions
Decreases in sensitization prevalence likely reflect reduced exposure, with some lag, as seen with hydroxyisohexyl 3‐cyclohexene carboxaldehyde. If no (sufficient) decrease can be observed despite interventions, such as for nickel and chromium, affected subgroups should be identified and their causative exposures explored. Finally, increases such as that observed with propolis, certainly warrant targeted investigation of the exposures driving sensitization, and possibly intervention.
What is already known about this topic?
Contact allergy is prevalent in the general population.
Surveillance based on clinical data offers timely information on trends concerning certain allergens or subgroups at risk.
What does this study add?
This analysis provides an update of the current contact allergy prevalence in Central Europe, including time trends.
This study describes the demographic and clinical profile of patients tested from 2007 to 2018.
This research identifies contact allergens that require (further) preventive efforts.
Linked Comment: Schuttelaar. Br J Dermatol 2020; 183:800–801.
What is already known about this topic?
Contact allergy is prevalent in the general population.
Surveillance based on clinical data offers timely information on trends concerning certain allergens or subgroups at risk.
What does this study add?
This analysis provides an update of the current contact allergy prevalence in Central Europe, including time trends.
This study describes the demographic and clinical profile of patients tested from 2007 to 2018.
This research identifies contact allergens that require (further) preventive efforts.
Linked Comment: Schuttelaar. Br J Dermatol 2020; 183:800–801.
Plain language summary available online
Respond to this article
Glutamate inputs to nucleus accumbens (NAc) facilitate conditioned drug-seeking behavior and primarily originate from medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and ventral ...subiculum of the hippocampus (vSub). These regions express Fos (a marker of neural activity) during cue-induced reinstatement of cocaine seeking, but only subpopulations of neurons within these regions drive drug seeking. One way to identify and functionally distinguish neural subpopulations activated during drug-seeking is to examine their projection targets. In rats, we examined Fos expression during cue-induced reinstatement of cocaine- and sucrose-seeking in prelimbic cortex (PL), infralimbic cortex (IL), BLA, and vSub neurons that project to NAc core (NAcC) or NAc shell (NAcSh). Neurons in PL, BLA, and vSub that project to NAcC, but not NAcSh, expressed Fos during cue-induced cocaine seeking, but not sucrose seeking. However, only activation of the PL-NAcC pathway positively correlated with cocaine reinstatement behavior, unlike BLA or vSub inputs to NAcC. To confirm a functional role for the PL-NAcC pathway, and to test the hypothesis that this pathway is recruited in a dopamine-dependent manner, we used a pharmacological disconnection approach whereby dopamine signaling was blocked in PL and glutamate signaling was blocked in the contralateral NAcC. This disconnection attenuated cue-induced reinstatement of cocaine seeking but had no effect on reinstatement of sucrose seeking. Our results highlight a role for the PL-NAcC pathway in cocaine seeking and show that these glutamatergic projections are recruited in a dopamine-dependent manner to drive reinstatement.
Relapse represents a significant barrier to the successful treatment of cocaine addiction. Here, we characterize the relative activation of glutamatergic inputs to nucleus accumbens during cued reinstatement of cocaine seeking versus sucrose seeking. Prelimbic cortex (PL) projections to nucleus accumbens core (NAcC) uniquely expressed Fos in a manner that positively correlated with cocaine-seeking, but not sucrose-seeking, behavior. Additional functional experiments showed that the PL-NAcC pathway was recruited by drug-associated cues in a dopamine-dependent manner to drive cocaine-seeking, but not sucrose-seeking, behavior. These data highlight PL neurons that project to NAcC, and their regulation by dopamine, as potential targets for therapeutics designed to treat cocaine relapse that do not affect natural reward seeking.
Rationale
Amygdala-related circuitry helps translate learned Pavlovian associations into appetitive and aversive motivation, especially upon subsequent encounters with cues.
Objectives
We asked ...whether μ-opioid stimulation via microinjections of the specific agonist
d
-Ala
2
,
N
-MePhe
4
, Gly-ol)-enkephalin (DAMGO) in central nucleus of amygdala (CeA), or the adjacent basolateral amygdala (BLA) would magnify sucrose or sex “wanting”, guided by available cues.
Materials and methods
CeA or BLA DAMGO enhancement of cue-triggered “wanting” was assessed using Pavlovian to instrumental transfer (PIT). Unconditioned food “wanting” was measured via intake, and male sexual “wanting” for an estrous female was measured in a sexual approach test. Sucrose hedonic taste “liking” was measured in a taste reactivity test.
Results
CeA (but not BLA) DAMGO increased the intensity of phasic peaks in instrumental sucrose seeking stimulated by Pavlovian cues over precue levels in PIT, while suppressing seeking at other moments. CeA DAMGO also enhanced food intake, as well as sexual approach and investigation of an estrous female by males. DAMGO “wanting” enhancements were localized to CeA, as indicated by “Fos plume”-based anatomical maps for DAMGO causation of behavioral effects. Despite increasing “wanting”, CeA DAMGO decreased the hedonic impact or “liking” for sucrose in a taste reactivity paradigm.
Conclusions
CeA μ-opioid stimulation specifically enhances incentive salience, which is dynamically guided to food or sex by available cues.
Background
Preventive measures to decrease the frequency and intensity of anaphylactic events are essential to provide optimal care for allergic patients. Aggravating factors may trigger or increase ...the severity of anaphylaxis and therefore need to be recognized and avoided.
Objective
To identify and prioritize factors associated with an increased risk of developing severe anaphylaxis.
Methods
Data from the Anaphylaxis Registry (122 centers in 11 European countries) were used in logistic regression models considering existing severity grading systems, elicitors, and symptoms to identify the relative risk of factors on the severity of anaphylaxis.
Results
We identified higher age and concomitant mastocytosis (OR: 3.1, CI: 2.6‐3.7) as the most important predictors for an increased risk of severe anaphylaxis. Vigorous physical exercise (OR: 1.5, CI: 1.3‐1.7), male sex (OR: 1.2, CI: 1.1‐1.3), and psychological burden (OR: 1.4, CI: 1.2‐1.6) were more often associated with severe reactions. Additionally, intake of beta‐blockers (OR: 1.9, CI: 1.5‐2.2) and ACE‐I (OR: 1.28, CI: 1.05, 1.51) in temporal proximity to allergen exposition was identified as an important factor in logistic regression analysis.
Conclusion
Our data suggest it may be possible to identify patients who require intensified preventive measures due to their relatively higher risk for severe anaphylaxis by considering endogenous and exogenous factors.
The ventral pallidum is centrally positioned within mesocorticolimbic reward circuits, and its dense projection to the ventral tegmental area (VTA) regulates neuronal activity there. However, the ...ventral pallidum is a heterogeneous structure, and how this complexity affects its role within wider reward circuits is unclear. We found that projections to VTA from the rostral ventral pallidum (RVP), but not the caudal ventral pallidum (CVP), were robustly Fos activated during cue-induced reinstatement of cocaine seeking--a rat model of relapse in addiction. Moreover, designer receptor-mediated transient inactivation of RVP neurons, their terminals in VTA or functional connectivity between RVP and VTA dopamine neurons blocked the ability of drug-associated cues (but not a cocaine prime) to reinstate cocaine seeking. In contrast, CVP neuronal inhibition blocked cocaine-primed, but not cue-induced, reinstatement. This double dissociation in ventral pallidum subregional roles in drug seeking is likely to be important for understanding the mesocorticolimbic circuits underlying reward seeking and addiction.
Ventral tegmental area (VTA) dopamine neurons are crucial for appetitive responses to Pavlovian cues, including cue-induced reinstatement of drug seeking. However, it is unknown which VTA inputs help ...activate these neurons, transducing stimuli into salient cues that drive drug-seeking behavior. Here we examined 56 VTA afferents from forebrain and midbrain that are Fos activated during cue-induced reinstatement. We injected the retrograde tracer cholera toxin β subunit (CTb) unilaterally into rostral or caudal VTA of male rats. All animals were trained to self-administer cocaine, then extinguished of this behavior. On a final test day, animals were exposed to response-contingent cocaine-associated cues, extinction conditions, a non-cocaine-predictive CS-, or a novel environment, and brains were processed to visualize CTb and Fos immunoreactivity to identify VTA afferents activated in relation to behaviors. VTA-projecting neurons in subregions of medial accumbens shell, ventral pallidum, elements of extended amygdala, and lateral septum (but not prefrontal cortex) were activated specifically during cue-induced cocaine seeking, and some of these were also activated proportionately to the degree of cocaine seeking. Surprisingly, though efferents from the lateral hypothalamic orexin field were also Fos activated during reinstatement, these were largely non-orexinergic. Also, VTA afferents from the rostromedial tegmental nucleus and lateral habenula were specifically activated during extinction and CS- tests, when cocaine was not expected. These findings point to a select set of subcortical nuclei which provide reinstatement-related inputs to VTA, translating conditioned stimuli into cocaine-seeking behavior.
Rationale
Glutamate and orexin/hypocretin systems are involved in Pavlovian cue-triggered drug seeking.
Objectives
Here, we asked whether orexin and glutamate interact within ventral tegmental area ...(VTA) to promote reinstatement of extinguished cocaine seeking in a rat self-administration paradigm.
Methods/results
We first found that bilateral VTA microinjections of the orexin 1 receptor (OX1R) antagonist SB-334867 (SB) or a cocktail of the AMPA and NMDA glutamate receptor antagonists CNQX/AP-5 reduced reinstatement of cocaine seeking elicited by cues. In contrast, neither of these microinjections nor systemic SB reduced cocaine-primed reinstatement. Additionally, unilateral VTA OX1R blockade combined with contralateral VTA glutamate blockade attenuated cue-induced reinstatement, indicating that VTA orexin and glutamate are simultaneously necessary for cue-induced reinstatement. We further probed the receptor specificity of glutamate actions in VTA, finding that CNQX, but not AP-5, dose-dependently attenuated cue-induced reinstatement, indicating that AMPA but not NMDA receptor transmission is required for this type of cocaine seeking. Given the necessary roles of both OX1 and AMPA receptors in VTA for cue-induced cocaine seeking, we hypothesized that these signaling pathways interact during this behavior. We found that PEPA, a positive allosteric modulator of AMPA receptors, completely reversed the SB-induced attenuation of reinstatement behavior. Intra-VTA PEPA alone did not alter cue-induced reinstatement, indicating that potentiating AMPA activity with this drug specifically compensates for OX1R blockade, rather than simply inducing or enhancing reinstatement itself.
Conclusions
These findings show that cue-induced, but not cocaine-primed, reinstatement of cocaine seeking is dependent upon orexin and AMPA receptor interactions in VTA.
Ventral tegmental area (VTA) dopamine (DA) neurons perform diverse functions in motivation and cognition, but their precise roles in addiction-related behaviors are still debated. Here, we targeted ...VTA DA neurons for bidirectional chemogenetic modulation during specific tests of cocaine reinforcement, demand, and relapse-related behaviors in male rats, querying the roles of DA neuron inhibitory and excitatory G-protein signaling in these processes. Designer receptor stimulation of G
signaling, but not G
signaling, in DA neurons enhanced cocaine seeking via functionally distinct projections to forebrain limbic regions. In contrast, engaging inhibitory G
signaling in DA neurons blunted the reinforcing and priming effects of cocaine, reduced stress-potentiated reinstatement, and altered behavioral strategies for cocaine seeking and taking. Results demonstrate that DA neurons play several distinct roles in cocaine seeking, depending on behavioral context, G-protein-signaling cascades, and DA neuron efferent targets, highlighting their multifaceted roles in addiction.
G-protein-coupled receptors are crucial modulators of ventral tegmental area (VTA) dopamine neuron activity, but how this metabotropic signaling impacts the complex roles of dopamine in reward and addiction is poorly understood. Here, we bidirectionally modulate dopamine neuron G-protein signaling with DREADDs (designer receptors exclusively activated by designer drugs) during a variety of cocaine-seeking behaviors, revealing nuanced, pathway-specific roles in cocaine reward, effortful seeking, and relapse-like behaviors. G
and G
stimulation activated dopamine neurons, but only G
stimulation robustly enhanced cocaine seeking. G
inhibitory signaling reduced some, but not all, types of cocaine seeking. Results show that VTA dopamine neurons modulate numerous distinct aspects of cocaine addiction- and relapse-related behaviors, and point to potential new approaches for intervening in these processes to treat addiction.
Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for ...human applications as well. The prototypical DREADD agonist clozapine N-oxide (CNO) lacks brain entry and converts to clozapine, making it difficult to apply in basic and translational applications. Here we report the development of two novel DREADD agonists, JHU37152 and JHU37160, and the first dedicated
F positron emission tomography (PET) DREADD radiotracer,
FJHU37107. We show that JHU37152 and JHU37160 exhibit high in vivo DREADD potency.
FJHU37107 combined with PET allows for DREADD detection in locally-targeted neurons, and at their long-range projections, enabling noninvasive and longitudinal neuronal projection mapping.
PDF
