The Pandemic Paranoia Scale (PPS): factor structure and measurement invariance across languages.

BACKGROUND: Globally, the corona virus disease 2019 (COVID-19) pandemic has created an interpersonally threatening context within which other people have become a source of possible threat. This study reports on the development and validation of a self-report measure of pandemic paranoia; that is, heightened levels of suspicion and mistrust towards others due to the COVID-19 pandemic. METHODS: An international consortium developed an initial set of 28 items for the Pandemic Paranoia Scale (PPS), which were completed by participants from the UK (n = 512), USA (n = 535), Germany (n = 516), Hong Kong (n = 454) and Australia (n = 502) using stratified quota sampling (for age, sex and educational attainment) through Qualtrics and translated for Germany and Hong Kong. RESULTS: Exploratory factor analysis in the UK sample suggested a 25-item, three-factor solution (persecutory threat; paranoid conspiracy and interpersonal mistrust). Confirmatory factor analysis (CFA) on the remaining combined sample showed sufficient model fit in this independent set of data. Measurement invariance analyses suggested configural and metric invariance, but no scalar invariance across cultures/languages. A second-order factor CFA on the whole sample indicated that the three factors showed large loadings on a common second-order pandemic paranoia factor. Analyses also supported the test-retest reliability and internal and convergent validity. CONCLUSION: The PPS offers an internationally validated and reliable method for assessing paranoia in the context of a pandemic. The PPS has the potential to enhance our understanding of the impact of the pandemic, the nature of paranoia and to assist in identifying and supporting people affected by pandemic-specific paranoia.

[The effect of medical and psychotherapeutic treatment models for schizophrenia on stigma and recovery expectations]. / Die Wirkung medizinischer und psychotherapeutischer Behandlungskonzepte für Schizophrenie auf Stigma und Genesungserwartungen.

BACKGROUND: It is common practice to inform patients about causes and treatment models when starting psychiatric treatment or psychotherapy for schizophrenia. However, previous research indicates that focusing on etiological models increases stigmatizing beliefs. This raises the question of whether contemporary, medical or cognitive behavioral therapy (CBT)-based treatment models share this negative side effect. AIM: This experiment tested whether providing information about medical vs. CBT-based vs. combined treatment models affects stigmatizing attitudes towards schizophrenia and the expected efficacy of these treatments. METHODS: Participants received a case vignette of a person with schizophrenia including either: (1) no treatment details, or a description of treatment with (2) medication, (3) CBT, or (4) medication and CBT. Next, stigmatizing attitudes (stereotypes, affective reactions, and desired social distance) were assessed and participants rated the perceived effectiveness of different treatment methods. RESULTS: No treatment model showed an effect on stigmatizing attitudes. Medical and CBT treatment information (alone or in combination) had a positive effect on subjective efficacy ratings for the respective treatment. CONCLUSION: There appear to be no negative side effects of (biogenetic) models when presented in a context emphasizing recovery. Moreover, medication and CBT treatment information showed additive positive effects on the rating of treatment strategies. A combined treatment model integrating various evidence-based methods appears to be most useful in clinical practice.

A longitudinal mediation analysis of the effect of negative-self-schemas on positive symptoms via negative affect.

BACKGROUND: Cognitive models postulate that negative-self-schemas (NSS) cause and maintain positive symptoms and that negative affect mediates this link. However, only few studies have tested the temporal mediation claim systematically using an appropriate design. METHODS: A longitudinal cohort design in an online community sample (N = 962) from Germany, Indonesia, and the USA was used. NSS, negative affect and positive symptoms were measured at four time-points (T0-T3) over a 1-year period. Cross-lagged panel and longitudinal mediation analyses with structural equation modeling were used to test the temporal mediation. RESULTS: Independent cross-lagged panel models showed a significant unidirectional longitudinal path from NSS to positive symptoms (T2-T3, ß = 0.18, p < 0.01) and bidirectional longitudinal associations from NSS to negative affect (T0-T1, γ = 0.14, p < 0.01) and vice versa (T0-T1, γ = 0.19, p < 0.01). There was also a significant indirect pathway from NSS at baseline via negative affect at T1 and T2 to positive symptoms at T3 (unstandardized indirect effect coefficient = 0.020, p < 0.05, BCa CI 0.004-0.035), indicating mediation. CONCLUSIONS: Our findings support the postulated affective pathway from NSS to positive symptoms via negative affect. Specifically, our data indicate that NSS and negative affect influence each other and build up over the course of several months before leading on to positive symptoms. We conclude that interrupting this process by targeting NSS and negative affect early in the process could be a promising strategy to prevent the exacerbation of positive symptoms.

The specific social costs of expressive negative symptoms in schizophrenia: reduced smiling predicts interactional outcome.

OBJECTIVE: We tested whether people with schizophrenia and prominent expressive negative symptoms (ENS) show reduced facial expressions in face-to-face social interactions and whether this expressive reduction explains negative social evaluations of these persons. METHOD: We compared participants with schizophrenia with high ENS (n = 18) with participants with schizophrenia with low ENS (n = 30) and with healthy controls (n = 39). Participants engaged in an affiliative role-play that was coded for the frequency of positive and negative facial expression and rated for social performance skills and willingness for future interactions with the respective role-play partner. RESULTS: Participants with schizophrenia with high ENS showed significantly fewer positive facial expressions than those with low ENS and controls and were also rated significantly lower on social performance skills and willingness for future interactions. Participants with schizophrenia with low ENS did not differ from controls on these measures. The group difference in willingness for future interactions was significantly and independently mediated by the reduced positive facial expressions and social performance skills. CONCLUSION: Reduced facial expressiveness in schizophrenia is specifically related to ENS and has negative social consequences. These findings highlight the need to develop aetiological models and targeted interventions for ENS and its social consequences.

Symptoms, functioning and coping strategies in individuals with schizophrenia spectrum disorders who do not take antipsychotic medication: a comparative interview study.

BACKGROUND: A considerable proportion of people with schizophrenia spectrum disorders do not take antipsychotic medication but seem to be functioning well. However, little is known about this group. To test the assumption that absence of medication is compensated for by more effective coping and increased social support, this study compared symptoms, functioning, coping strategies and social support in non-medicated and medicated individuals with schizophrenia spectrum disorders. METHOD: In all, 48 participants with a DSM-IV schizophrenia spectrum disorder who were taking (n = 25) or not taking antipsychotic medication (n = 23) were included. Assessment consisted of self-ratings of symptoms, symptom-related distress and social support combined with a semi-structured interview that assessed general and social functioning, subjective evaluation of symptoms and coping strategies. RESULTS: Symptom severity and distress did not differ between the groups. However, the non-medicated participants had significantly higher levels of general functioning than medicated participants and a longer duration of being non-medicated was significantly associated with a higher level of general functioning. In contrast to the hypotheses, not taking medication was not associated with more effective coping strategies or with higher levels of social support. Medicated participants more frequently reported the use of professional help as a coping strategy. CONCLUSIONS: Our results corroborate previous studies finding improved functioning in individuals with schizophrenia spectrum disorders who do not take medication compared with those who take medication, but do not support the notion that this difference is explicable by better coping or higher levels of social support. Alternative explanations and avenues for research are discussed.

Prevalence of suicidal ideation in German psychotherapy outpatients: A large multicenter assessment.

BACKGROUND: Suicidal ideation is a major concern in clinical practice. Yet, little is known about prevalence rates of suicidal ideation in patients undergoing outpatient psychotherapeutic treatment. Therefore, the aim of the current study is to assess the prevalence of suicidal ideation in a large sample of psychotherapy outpatients in Germany. The data analyzed in this study is taken from the KODAP-project on the coordination of data collection and analysis at German university-based research and training outpatient clinics for psychotherapy. METHODS: A total of N = 10,357 adult outpatients (64.4 % female; age: M(SD) = 35.94 (13.54), range: 18-92 years of age) starting cognitive-behavioral therapy at one of 27 outpatient clinics in Germany were included in the current study. Prevalence of suicidal ideation was assessed with the Suicide Item (Item 9) of the Beck-Depression Inventory II. RESULTS: Suicidal ideation was reported by 36.7 % (n = 3795) of the participants. Borderline Personality Disorder, Posttraumatic Stress Disorder, and recurrent Major Depression were the diagnoses most strongly associated with the presence and severity of suicidal ideation. LIMITATION: Suicide ideation was assessed only with the respective item of the Beck Depression Inventory II. CONCLUSION: Suicidal ideation is very common among adult patients who start psychotherapy in Germany. A well-founded knowledge of risk assessment in suicidal patients and suicide-specific treatment options is therefore highly relevant.

Impact of stress on paranoia: an experimental investigation of moderators and mediators.

BACKGROUND: Vulnerability-stress models ascribe stress a pivotal role in the development of psychosis. However, moderating and mediating mechanisms translating stress into psychosis and the specificity of the association are not clearly established. It is hypothesized that stress will trigger paranoid ideation in vulnerable individuals through an increase in negative emotion. METHOD: Using a repeated-measures design, 64 healthy participants with varying levels of vulnerability [psychosis symptoms assessed by the Community Assessment of Psychic Experiences (CAPE)] were assigned to a stress and a non-stress condition in random order. Stress was induced by exposing participants to building-site noise (75 dB) applied concurrently with difficult knowledge questions. Symptoms of paranoia, depression and obsessive compulsive disorder (OCD) were assessed by state-adapted versions of clinical scales. RESULTS: In the stress condition there was an increase in paranoia, depression and negative emotion. Multilevel linear modeling (MLM) revealed the increase in paranoia under stress to be moderated by the level of vulnerability and mediated by anxiety. Although participants generally showed an increase in anxiety under stress, anxiety was more strongly related to paranoia in participants with higher baseline symptomatology. CONCLUSIONS: The results support and specify the role of emotional reactions to stressors on the pathway from vulnerability to psychosis and highlight the relevance of anxiety.

Decision making under uncertainty and mood induction: further evidence for liberal acceptance in schizophrenia.

BACKGROUND: Cognitive biases, especially jumping to conclusions (JTC), are ascribed a vital role in the pathogenesis of schizophrenia. This study set out to explore motivational factors for JTC using a newly developed paradigm. METHOD: Twenty-seven schizophrenia patients and 32 healthy controls were shown 15 classical paintings, divided into three blocks. Four alternative titles (one correct and three lure titles) had to be appraised according to plausibility (0-10). Optionally, participants could decide for one option and reject one or more alternatives. In random order across blocks, anxiety-evoking music, happy music or no music was played in the background. RESULTS: Patients with schizophrenia, particularly those with delusions, made more decisions than healthy subjects. In line with the liberal acceptance (LA) account of schizophrenia, the decision threshold was significantly lowered in patients relative to controls. Patients were also more prone than healthy controls to making a decision when the distance between the first and second best alternative was close. Furthermore, implausible alternatives were judged as significantly more plausible by patients. Anxiety-evoking music resulted in more decisions in currently deluded patients relative to non-deluded patients and healthy controls. CONCLUSIONS: The results confirm predictions derived from the LA account and assert that schizophrenia patients decide hastily under conditions of continued uncertainty. The fact that mood induction did not exert an overall effect could be due to the explicit nature of the manipulation, which might have evoked strategies to counteract their influence.

Regulation of myosin phosphatase by a specific interaction with cGMP- dependent protein kinase Ialpha.

Contraction and relaxation of smooth muscle are regulated by myosin light-chain kinase and myosin phosphatase through phosphorylation and dephosphorylation of myosin light chains. Cyclic guanosine monophosphate (cGMP)-dependent protein kinase Ialpha (cGKIalpha) mediates physiologic relaxation of vascular smooth muscle in response to nitric oxide and cGMP. It is shown here that cGKIalpha is targeted to the smooth muscle cell contractile apparatus by a leucine zipper interaction with the myosin-binding subunit (MBS) of myosin phosphatase. Uncoupling of the cGKIalpha-MBS interaction prevents cGMP-dependent dephosphorylation of myosin light chain, demonstrating that this interaction is essential to the regulation of vascular smooth muscle cell tone.

[Stigmatization of patients with schizophrenia: the influence of university courses on the attitudes of prospective psychologists and doctors]. / Stigmatisierung von Patienten mit Schizophrenie: Prägt das Studium die Einstellungen angehender Psychologen und Mediziner?

BACKGROUND: Some studies revealed that psychiatrists have more negative attitudes than psychologists towards patients with schizophrenia. This raises the question of whether different models of the aetiology of schizophrenia and the amount of personal contact influence the attitudes of mental health professionals. SAMPLE AND METHODS: Explicit and implicit attitudes towards schizophrenia were assessed in medical and psychology students (n=60 and n=61, respectively) as well as their familiarity with the disorder and their subjective models of its aetiology. RESULTS: Medical and psychology students showed a substantial level of negative attitudes. Personal contact was negatively associated with stereotypes among medical students and positively associated among psychology students. Positive attitudes were related to biogenetic causal beliefs among medical students and to psychosocial causal beliefs among psychology students. CONCLUSIONS: The results emphasise the need to adapt antistigma campaigns to target groups. They also indicate the superiority of a multidimensional aetiology over monocausal aetiological models in reducing stigma.

Smooth muscle cell expression of type I cyclic GMP-dependent protein kinase is suppressed by continuous exposure to nitrovasodilators, theophylline, cyclic GMP, and cyclic AMP.

A key component of the nitric oxide-cyclic guanosine monophosphate (cGMP) pathway in smooth muscle cells (SMC) is the type I GMP-dependent protein kinase (PK-G I). Activation of PK-G I mediates the reduction of cytoplasmic calcium concentrations and vasorelaxation. In this manuscript, we demonstrate that continuous exposure of SMC in culture to the nitrovasodilators S-nitroso-N-acetylpenicillamine (SNAP) or sodium nitroprusside (SNP) results in approximately 75% suppression of PK-G I mRNA by 48 h. PK-G I mRNA and protein were also suppressed by continuous exposure to cGMP analogues 8-bromo- and 8-(4-chlorophenylthio) guanosine-3,5-monophosphate or the cAMP analogue dibutyryl cAMP. These results suggest that activation of one or both of the cyclic nucleotide-dependent protein kinases mediates PK-G I mRNA suppression. Using isoform-specific cDNA probes, only the PK-G I alpha was detected in SMC, either at baseline or after suppression, while PK-G I beta was not detected, indicating that isoform switch was not contributing to the gene regulation. Using the transcription inhibitor actinomycin D, the PK-G I mRNA half-life in bovine SMC was observed to be 5 h. The half-life was not affected by the addition of SNAP to actinomycin D, indicating no effect on PK-G I mRNA stability. Nuclear runoff studies indicated a suppression of PK-G I gene transcription by SNAP. PK-G I suppression was also observed in vivo in rats given isosorbide dinitrate in the drinking water, with a dose-dependent suppression of PK-G I protein in the aorta. PK-G I antigen in whole rat lung extract was also suppressed by administration of isosorbide or theophylline in the drinking water. These data may contribute to our understanding of nitrovasodilator resistance, a phenomenon resulting from continuous exposure to nitroglycerin or other nitrovasodilators.

Effectiveness of psychoeducation for relapse, symptoms, knowledge, adherence and functioning in psychotic disorders: a meta-analysis.

Psychoeducation (PE) for schizophrenia and other psychotic disorders is widely adopted but insufficiently evaluated. So far, meta-analytic data has demonstrated efficacy for PE when interventions include family members. Whether PE directed solely at patients is also effective remains unclear. The current meta-analysis evaluates short- and long-term efficacy of PE with and without inclusion of families with regard to relapse, symptom-reduction, knowledge, medication adherence, and functioning. Randomized controlled trials comparing PE to standard care or non-specific interventions were included. A literature search in the Cochrane Library, PsycINFO and Medline retrieved 199 studies for closer examination, of which 18 studies, reporting on 19 comparisons, met the inclusion criteria. These studies were coded with regard to methodology, participants, interventions and validity. Effect sizes were integrated using the fixed effects model for homogeneous effects and the random effects model for heterogeneous effects. Independent of treatment modality, PE produced a medium effect at post-treatment for relapse and a small effect size for knowledge. PE had no effect on symptoms, functioning and medication adherence. Effect sizes for relapse and rehospitalization remained significant for 12 months after treatment but failed significance for longer follow-up periods. Interventions that included families were more effective in reducing symptoms by the end of treatment and preventing relapse at 7-12 month follow-up. Effects achieved for PE directed at patients alone were not significant. It is concluded that the additional effort of integrating families in PE is worthwhile, while patient-focused interventions alone need further improvement and research.

Childhood trauma and psychotic experiences in a general population sample: A prospective study on the mediating role of emotion regulation.

BACKGROUND: The causal role of childhood trauma for psychosis is well established, but the mechanisms that link trauma to psychosis are largely unknown. Since childhood trauma is known to cause difficulties in emotion regulation (ER) and patients with psychosis show impaired ER, we hypothesize that impaired ER explains why people with a background of trauma are prone to psychotic experiences. METHODS: The study used a longitudinal cohort design based on a community sample (N=562) from Germany, Indonesia, and the United States. Childhood trauma was assessed at baseline. ER and psychotic experiences (defined as positive symptom frequency and related distress) were measured repeatedly at a 4-, 8-, and 12-month follow-up. Cross-lagged panel and longitudinal mediation analyses with structural equation modeling were used to test the predictive value of ER on psychotic experiences and its mediating role in the association of childhood trauma and psychotic experiences. RESULTS: The cross-lagged paths from impaired ER to symptom distress (but not frequency) were significant. However, there was also evidence for the reverse causation from symptom frequency and distress to impaired ER. ER partially mediated the significant prospective paths from childhood trauma to symptom distress. CONCLUSION: The findings demonstrate that ER plays a role in translating childhood trauma into distressing psychotic experiences in later life. Moreover, the findings point to a maintenance mechanism in which difficulties in ER and symptom distress exacerbate each other. Thus, ER could be a promising target for interventions aimed at prevention of psychosis.

Internet gaming disorder in early adolescence: Associations with parental and adolescent mental health.

BACKGROUND: Internet gaming disorder (IGD) has been included in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Currently, associations between IGD in early adolescence and mental health are largely unexplained. In the present study, the relation of IGD with adolescent and parental mental health was investigated for the first time. METHODS: We surveyed 1095 family dyads (an adolescent aged 12-14 years and a related parent) with a standardized questionnaire for IGD as well as for adolescent and parental mental health. We conducted linear (dimensional approach) and logistic (categorical approach) regression analyses. RESULTS: Both with dimensional and categorical approaches, we observed statistically significant associations between IGD and male gender, a higher degree of adolescent antisocial behavior, anger control problems, emotional distress, self-esteem problems, hyperactivity/inattention and parental anxiety (linear regression model: corrected R2=0.41, logistic regression model: Nagelkerke's R2=0.41). CONCLUSIONS: IGD appears to be associated with internalizing and externalizing problems in adolescents. Moreover, the findings of the present study provide first evidence that not only adolescent but also parental mental health is relevant to IGD in early adolescence. Adolescent and parental mental health should be considered in prevention and intervention programs for IGD in adolescence.

What is the minimal dose of cognitive behavior therapy for psychosis? An approximation using repeated assessments over 45 sessions.

BACKGROUND: The general efficacy of cognitive behavior therapy for psychosis (CBTp) is well established. Although guidelines recommend that CBTp should be offered over a minimum of 16 sessions, the minimal number of sessions required to achieve significant changes in psychopathology has not been systematically investigated. Empirically informed knowledge of the minimal and optimal dose of CBTp is relevant in terms of dissemination and cost-effectiveness. METHODS: We approached the question of what constitutes an appropriate dose by investigating the dose (duration of CBTp)×response (symptomatic improvement) relationship for positive symptoms, negative symptoms and depression. Patients with psychotic disorders (n=58) were assessed over the course of 45 sessions of CBTp in a clinical practice setting. At baseline and after session 5, 15, 25, and 45, general psychopathology, psychotic symptoms, symptom distress and coping were assessed with self-report questionnaires. Additionally, individually defined target symptoms and coping were assessed after each session. RESULTS: Significant symptom improvement and reduction of symptom distress took place by session 15, and stayed fairly stable thereafter. The frequency of positive and negative symptoms reached a minimum by session 25. CONCLUSIONS: Our findings support recommendations to provide CBTp over a minimum of 16 sessions and indicate that these recommendations are generalizable to clinical practice settings. However, the findings also imply that 25 sessions are the more appropriate dose. This study contributes to an empirically informed discussion on the minimal and optimal dose of CBTp. It also provides a basis for planning randomized trials comparing briefer and longer versions of CBTp.

On the question of cyclic GMP as the mediator of the effects of acetylcholine on the heart.

The effects of acetylcholine and sodium nitroprusside on cyclic GMP levels, contractile force, and glycogen metabolism were investigated in the perfused rat heart. While both agents produced time- and concentration-dependent increases in cyclic GMP, only acetylcholine significantly decreased contractile force. Neither agent altered the basal cyclic AMP concentration, cyclic AMP-dependent protein kinase activity ratio, or phosphorylase activity. When dosages were adjusted to give approximately equal increases in cyclic GMP, acetylcholine attenuated the effect of epinephrine on contractile force and glycogen phosphorylase activity while nitroprusside did not antagonize the action of the beta-adrenergic agent on either parameter. The data suggest that increased cardiac cyclic GMP is not sufficient to completely explain the action of acetylcholine on either contractile force or its antagonism of epinephrine-induced increases in force or glycogen phosphorylase activity.

Cyclic GMP-dependent protein kinase expression in coronary arterial smooth muscle in response to balloon catheter injury.

Arterial smooth muscle cells undergo phenotypic and proliferative changes in response to balloon catheter injury. Nitric oxide (NO) and cGMP have been implicated in the inhibition of vascular smooth muscle cell proliferation and phenotypic modulation in cultured-cell studies. We have examined the expression of the major cGMP receptor protein in smooth muscle, cGMP-dependent protein kinase I (PKG), in response to balloon catheter injury in the swine coronary artery. On injury, there was a transient decrease in the expression of PKG in neointimal smooth muscle cells when compared with medial smooth muscle cells. The decrease in PKG expression was observed in the population of proliferating cells expressing the extracellular matrix protein osteopontin but not in cells present in the uninjured portion of the media. Coincident with the suppression of PKG expression in neointimal cells after injury, there was a marked increase in the expression of type II NO synthase (inducible NOS [iNOS], NOS-II) in the neointimal cells. These results suggest that PKG expression is transiently reduced in response to injury in the population of coronary arterial smooth muscle cells that are actively proliferating and producing extracellular matrix proteins. The reduction in PKG expression is also correlated temporally with increases in inflammatory activity in the injured vessels as assessed by iNOS expression. Coupled with our current knowledge regarding the role of PKG in the regulation of cultured cell phenotypes, these results imply that PKG may also regulate phenotypic modulation of vascular smooth muscle cells in vivo as well.

Localization of cyclic GMP-dependent protein kinase in human mononuclear phagocytes.

The presence and physiological role of cGMP-dependent protein kinase (G-kinase) was investigated in human mononuclear phagocytes. Western blots of monocyte extracts revealed a single polypeptide band that comigrated with purified bovine lung G-kinase. G-kinase was localized by immunofluorescence microscopy in freshly isolated adherent human monocytes, monocyte-derived macrophages cultured from 4 to 14 days, and alveolar macrophages. In monocytes, G-kinase was localized in granules or vesicles in the cytoplasm, at the microtubule organizing center, on filaments, and in the nucleus. In monocyte-derived macrophages, intense staining for G-kinase was found in the vicinity of the Golgi, in vesicles throughout the cytoplasm, and diffusely in the nucleus. Dual-label confocal laser scanning microscopy demonstrated that G-kinase was colocalized with the endoplasmic reticulum. For comparison, G-kinase was localized in alveolar macrophages that were adhered from 3 to 30 min. In these cells, G-kinase was prominent within the organelle-rich area pericortical to the nucleus. However, a well-defined area of intense staining was also observed at the cell periphery at early time points during adherence and spreading. Rhodamine-labeled phalloidin showed that this peripheral area was rich in F-actin. Cytochalasin D, but not nocodazole, inhibited G-kinase targeting to the cell margin. Furthermore, the guanylate cyclase inhibitor LY83583 inhibited alveolar macrophage spreading and staining for G-kinase at the cell periphery. These data suggest that G-kinase may play an important role in cGMP-mediated regulation involved in protein processing and cell motility.

Demonstration of Na+-dependent Ca2+ efflux using low concentrations of fluorometric Ca2+ probes.

The effects of different concentrations of the fluorometric Ca2+ probes, fura-2 and indo-1, on Ca2+ transients in cultured rat aortic smooth muscle cells were examined. When stimulated with the agonists, angiotensin II and arginine vasopressin, cells incubated with low concentrations of fura-2 or indo-1 (less than 1 microM) produced Ca2+ transients characterized by a small increase followed by a dramatic decrease in fluorescence below the original baseline. This effect of agonists was concentration-dependent, reversible, and blocked by receptor antagonists. In contrast to the agonists, stimulation of Ca2+ transients with depolarizing concentrations of K+ or with caffeine did not produce decreases in fluorescence and Ca2+ levels at any loading concentration of probe. The decrease in Ca2+ observed with agonists was dependent on the presence of extracellular Na+. These data suggest that under certain loading conditions, fluorescent Ca2+ indicators measure agonist-stimulated Ca2+ efflux mediated by a Na+/Ca2+ exchange mechanism.