The Socioeconomic Implications of Isolated Tibial and Femoral Fractures from Road Traffic Injuries in Uganda.

BACKGROUND: The purpose of this study was to determine the socioeconomic implications of isolated tibial and femoral fractures caused by road traffic injuries in Uganda. METHODS: This prospective longitudinal study included adult patients who were admitted to Uganda's national referral hospital with an isolated tibial or femoral fracture. The primary outcome was the time to recovery following injury. We assessed recovery using 4 domains: income, employment status, health-related quality of life (HRQoL) recovery, and school attendance of the patients' dependents. RESULTS: The majority of the study participants (83%) were employed, and they were the main income earner for their household (74.0%) at the time of injury, earning a mean annual income of 2,375 U.S. dollars (USD). All of the patients had been admitted with the intention of surgical treatment; however, because of resource constraints, only 56% received operative treatment. By 2 years postinjury, only 63% of the participants had returned to work, and 34% had returned to their previous income level. Overall, the mean monthly income was 62% less than preinjury earnings, and participants had accumulated 1,069 USD in debt since the injury; 41% of the participants had regained HRQoL scores near their baseline, and 62% of school-aged dependents, enrolled at the time of injury, were in school at 2 years postinjury. CONCLUSIONS: At 2 years postinjury, only 12% of our cohort of Ugandan patients who had sustained an isolated tibial or femoral fracture from a road traffic injury had recovered both economically and physically. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Non-suicidal self-injury within the school context: Multilevel analysis of teachers' support and peer climate.

BACKGROUND: Recent studies regarding non-suicidal self-injury (NSSI) among adolescents have focused primarily on individual characteristics (e.g., depressive symptoms) and background factors (e.g., parental relationship), whereas less emphasis has been given to the role of school-related factors in NSSI. Therefore, the purpose of the current study was to explore the relationships between teachers' support, peer climate, and NSSI within the school context. METHODS: The sample consisted of 594 high school students nested within 27 regular classes (54.4% boys; mean age 14.96, SD=1.33 years). The students were evaluated for NSSI behaviors, perception of teacher support, peer climate, relationships with mothers, and depressive symptoms using validated scales. RESULTS: The primary analysis used hierarchical linear modeling (HLM), controlling for gender and age. The main findings indicated that teacher support was positively associated with NSSI at the classroom-level (OR=6.15, 95% CI=2.05-18.5) but negatively associated at the student-level (OR=0.66, 95% CI=0.49-0.89). There was a trend toward an association between positive peer climate and NSSI at the classroom-level (OR=0.43, 95% CI=0.18-1.05), while negative peer climate was associated with NSSI at the student-level (OR=1.37, 95% CI=1.00-1.87). CONCLUSIONS: School-related factors are associated with NSSI behaviors among students. Teachers and educators should focus on both individual-level and classroom-level perceptions of school context. Students who feel supported by their teachers and who are exposed to a positive peer climate are less likely to engage in NSSI.

RGS2 expression predicts amyloid-ß sensitivity, MCI and Alzheimer's disease: genome-wide transcriptomic profiling and bioinformatics data mining.

Alzheimer's disease (AD) is the most frequent cause of dementia. Misfolded protein pathological hallmarks of AD are brain deposits of amyloid-ß (Aß) plaques and phosphorylated tau neurofibrillary tangles. However, doubts about the role of Aß in AD pathology have been raised as Aß is a common component of extracellular brain deposits found, also by in vivo imaging, in non-demented aged individuals. It has been suggested that some individuals are more prone to Aß neurotoxicity and hence more likely to develop AD when aging brains start accumulating Aß plaques. Here, we applied genome-wide transcriptomic profiling of lymphoblastoid cells lines (LCLs) from healthy individuals and AD patients for identifying genes that predict sensitivity to Aß. Real-time PCR validation identified 3.78-fold lower expression of RGS2 (regulator of G-protein signaling 2; P=0.0085) in LCLs from healthy individuals exhibiting high vs low Aß sensitivity. Furthermore, RGS2 showed 3.3-fold lower expression (P=0.0008) in AD LCLs compared with controls. Notably, RGS2 expression in AD LCLs correlated with the patients' cognitive function. Lower RGS2 expression levels were also discovered in published expression data sets from postmortem AD brain tissues as well as in mild cognitive impairment and AD blood samples compared with controls. In conclusion, Aß sensitivity phenotyping followed by transcriptomic profiling and published patient data mining identified reduced peripheral and brain expression levels of RGS2, a key regulator of G-protein-coupled receptor signaling and neuronal plasticity. RGS2 is suggested as a novel AD biomarker (alongside other genes) toward early AD detection and future disease modifying therapeutics.

Economic loss due to traumatic injury in Uganda: The patient's perspective.

INTRODUCTION: Traumatic injury is a growing public health concern globally, and is a major cause of death and disability worldwide. The purpose of this study was to quantify the socioeconomic impact of lower extremity fractures in Uganda. METHODS: All adult patients presenting acutely to Uganda's national referral hospital with a single long bone lower extremity fracture in October 2013 were recruited. Consenting patients were surveyed at admission and again at six-months and 12-months post-injury. The primary outcome was the cumulative 12-month post-injury loss in income. Secondary outcome measures included the change in health-related quality of life (HRQoL) and the injury's effect on school attendance for the patients' dependents. RESULTS: Seventy-four patients were recruited during the study period. Sixty-four (86%) of the patients were available for 12-months of follow-up. Compared to pre-injury earnings, patients lost 88.4% ($1822 USD) of their annual income in the 12-months following their injury. To offset this loss in income, patients borrowed an average of 28% of their pre-injury annual income. Using the EuroQol-5D instrument, the mean HRQoL decreased from 0.91 prior to the injury to 0.39 (p<0.0001) at 12-months post-injury. Ninety-three percent of school-aged dependents missed at least one month of school during their guardian's recovery and only 61% had returned to school by 12-months post-injury. CONCLUSION: This study demonstrates that lower extremity fractures in Uganda had a profound impact on the socioeconomic status of the individuals in our sample population, as well as the socioeconomic health of the family unit.

A study on the mechanism by which MDMA protects against dopaminergic dysfunction after minimal traumatic brain injury (mTBI) in mice.

Driving under methylenedioxymethamphetamine (MDMA) influence increases the risk of being involved in a car accident, which in turn can lead to traumatic brain injury. The behavioral deficits after traumatic brain injury (TBI) are closely connected to dopamine pathway dysregulation. We have previously demonstrated in mice that low MDMA doses prior to mTBI can lead to better performances in cognitive tests. The purpose of this study was to assess in mice the changes in the dopamine system that occurs after both MDMA and minimal traumatic brain injury (mTBI). Experimental mTBI was induced using a concussive head trauma device. One hour before injury, animals were subjected to MDMA. Administration of MDMA before injury normalized the alterations in tyrosine hydroxylase (TH) levels that were observed in mTBI mice. This normalization was also able to lower the elevated dopamine receptor type 2 (D2) levels observed after mTBI. Brain-derived neurotrophic factor (BDNF) levels did not change following injury alone, but in mice subjected to MDMA and mTBI, significant elevations were observed. In the behavioral tests, haloperidol reversed the neuroprotection seen when MDMA was administered prior to injury. Altered catecholamine synthesis and high D2 receptor levels contribute to cognitive dysfunction, and strategies to normalize TH signaling and D2 levels may provide relief for the deficits observed after injury. Pretreatment with MDMA kept TH and D2 receptor at normal levels, allowing regular dopamine system activity. While the beneficial effect we observe was due to a dangerous recreational drug, understanding the alterations in dopamine and the mechanism of dysfunction at a cellular level can lead to legal therapies and potential candidates for clinical use.

Genome-wide expression profiling of human lymphoblastoid cell lines implicates integrin beta-3 in the mode of action of antidepressants.

Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depression. However, the link between inhibition of serotonin reuptake and remission from depression remains controversial: in spite of the rapid onset of serotonin reuptake inhibition, remission from depression takes several weeks, presumably reflecting synaptogenesis/neurogenesis and neuronal rewiring. We compared genome-wide expression profiles of human lymphoblastoid cell lines from unrelated individuals following treatment with 1 µM paroxetine for 21 days with untreated control cells and examined which genes and microRNAs (miRNAs) showed the most profound and consistent expression changes. ITGB3, coding for integrin beta-3, showed the most consistent altered expression (1.92-fold increase, P=7.5 × 10(-8)) following chronic paroxetine exposure. Using genome-wide miRNA arrays, we observed a corresponding decrease in the expression of two miRNAs, miR-221 and miR-222, both predicted to target ITGB3. ITGB3 is crucial for the activity of the serotonin transporter (SERT), the drug target of SSRIs. Moreover, it is presumably required for the neuronal guidance activity of CHL1, whose expression was formerly identified as a tentative SSRI response biomarker. Further genes whose expression was significantly modulated by chronic paroxetine are also implicated in neurogenesis. Surprisingly, the expression of SERT or serotonin receptors was not modified. Our findings implicate ITGB3 in the mode of action of SSRI antidepressants and provide a novel link between CHL1 and the SERT. Our observations suggest that SSRIs may relieve depression primarily by promoting neuronal synaptogenesis/neurogenesis rather than by modulating serotonin neurotransmission per se.

The effect of chronic methylphenidate administration on presynaptic dopaminergic parameters in a rat model for ADHD.

Dysregulations in monoaminergic systems have been implicated in attention deficit/hyperactivity disorder. The spontaneous hypertensive rats (SHR) are used as an animal model for ADHD. Juvenile SHR rats exhibited low dopamine transporter (DAT) density, low vesicular monoamine transporter 2 (VMAT2) density and lower unstimulated dopamine (DA) release in comparison to their corresponding WKY controls. Chronic methylphenidate treatment of the young SHR rats was associated with lower DAT density and lower unstimulated basal dopamine release but with enhanced potassium- and amphetamine-induced dopamine release. These neurochemical alterations might be relevant to the pathophysiology and to the beneficial effect of methylphenidate in ADHD.

Critical role of the embryonic mid-hindbrain organizer in the behavioral response to amphetamine and methylphenidate.

The embryonic mid-hindbrain organizer, which is composed of a transient cell population in the brainstem, controls the development of dopaminergic and serotonergic neurons. Different genes determining the position and activity of this embryonic structure have been implicated in dopamine- and serotonin-associated disorders. Mouse mutants with a caudally shifted mid-hindbrain organizer, are hyperactive, show increased numbers of dopaminergic neurons and a reduction in serotonergic cells. In the present study we used these mutants to gain insights into the genetic and developmental mechanisms underlying motor activity and the response to psychostimulants. To this end, we studied the motor activity of these animals after exposure to methylphenidate and amphetamine and characterized their dopaminergic and serotonergic innervation. Saline-treated mutants showed increased locomotion, more stereotypic behavior and a decrease in rearing compared to wild-type mice. This baseline level of activity was similar to behaviors observed in wild-type animals treated with high doses of psychostimulants. In mutants methylphenidate (5 or 30 mg/kg) or amphetamine (2 or 4 mg/kg) did not further increase activity or even caused a decrease of locomotor activity, in contrast to wild-type mice. Fluoxetine (5 or 10 mg/kg) reduced hyperactivity of mutants to levels observed in wild-types. Transmitter measurements, dopamine and serotonin transporter binding assays and autoradiography, indicated a subtle increase in striatal dopaminergic innervation and a marked general decrease of serotonergic innervation in mutants. Taken together, our data suggest that mice with an aberrantly positioned mid-hindbrain organizer show altered sensitivity to psychostimulants and that an increase of serotonergic neurotransmission reverses their hyperactivity. We conclude that the mid-hindbrain organizer, by orchestrating the formation of dopaminergic and serotonergic neurons, is an essential developmental parameter of locomotor activity and psychostimulant response.

Cocaine, but not amphetamine, short term treatment elevates the density of rat brain vesicular monoamine transporter 2.

We compared the effect of 5 days D-amphetamine (5 mg/kg/day i.p.) and cocaine (15 mg/kg/day i.p.) administration on the vesicular monoamine transporter 2 (VMAT2) density in rat brain. VMAT2 expression was assessed by [(3)H]dihydrotetrabenazine high affinity binding. Cocaine administration led to significant increases in VMAT2 density in both prefrontal cortex (+40%, p < 0.01) and striatum (+23%, p < 0.05), while amphetamine did not affect VMAT2 expression. The upregulation of VMAT2 may serve as compensatory mechanism aimed to enhance the vesicular monoamine storage capacity.

Elevated platelet vesicular monoamine transporter 2 in former heroin addicts maintained on methadone.

The brain vesicular monoamine transporter (VMAT2) is essential for neuronal monoamine storage and regulation of monoaminergic neurotransmission. We demonstrated previously a high degree of similarity between the pharmacodynamic characteristics of platelet and brain VMAT2. Opioids induce increase of dopamine release in limbic structures. In the present study we assessed the VMAT2 pharmacodynamic characteristics using high affinity [(3)H]dihydrotetrabenazine (TBZOH) binding to platelets of former male heroin addicts maintained on methadone (n = 12) compared to age-matched healthy controls (n = 13). A significant increase (19%, p < 0.05) in platelet VMAT2 density (Bmax) was observed in the methadone treated patients compared to controls. There was no significant difference in the affinity of [(3)H]TBZOH to its platelet binding site. The increased VMAT2 density may reflect a compensatory attempt to prevent vesicular depletion due to chronic methadone exposure.

The effect of psychostimulants on [3H]dopamine uptake and release in rat brain synaptic vesicles.

Amphetamine and its derivatives are psychostimulants active at the plasma membrane monoamine transporters. In the present study we assessed the interaction of parachloroamphetamine, D-amphetamine, fenfluramine and methylendioxymethamphetamine with brain vesicular monoamine transporter using purified rat striatal synaptic vesicles. All four psychostimulants inhibited vesicular [(3)H]dopamine uptake in a competitive and dose-dependent manner and had no effect on [(3)H]dihydrotetrabenazine binding. At higher concentrations the drugs enhanced [(3)H]dopamine vesicular efflux. Parachloroamphetamine was the most potent agent while methylendioxymethamphetamine was the weakest one. The vesicular activities may be relevant to their neurotoxicity.

Role of the orbital cortex and of the serotonergic system in a rat model of obsessive compulsive disorder.

The serotonergic system and the orbitofrontal cortex have been consistently implicated in the pathophysiology of obsessive compulsive disorder. Yet, the relations between these two systems and the ways they interact in producing obsessions and compulsions are poorly understood. The present study tested the hypothesis that pathology of the orbitofrontal cortex leads to a dysregulation of the serotonergic system which is manifested in compulsive behavior, using a new rat model of this disorder. In the model, 'compulsive' behavior is induced by attenuating a signal indicating that a lever-press response was effective in producing food. We found that lesion to the rat orbital cortex led to a selective increase in compulsive lever-pressing that was prevented by the serotonin re-uptake inhibitor, paroxetine, and was paralleled by an increase in the density of the striatal serotonin transporter, assessed using high affinity [3H]imipramine binding. These results suggest that the serotonergic system is involved in orbital lesion-induced compulsivity, and provide a possible account for the observed association between obsessions and compulsions and dysfunction of the orbitofrontal cortex and of the serotonergic system in obsessive compulsive disorder.

Changes in vesicular monoamine transporter (VMAT2) and synaptophysin in rat Substantia nigra and prefrontal cortex induced by psychotropic drugs.

We investigated the regulatory effect of the dopaminergic agent L-dopa, the mood stabilizer lithium and the nonselective monoamine oxidase inhibitor phenelzine on brain vesicular monoamine transporter (VMAT2) expression. Rats were treated chronically (21 days) with the three psychoactive drugs. VMAT2 gene expression at the protein level was assessed in the prefrontal cortex and striatum by autoradiography with high-affinity [(3)H]dihydrotetrabenazine ([(3)H]TBZOH) binding and at the mRNA level in the substantia nigra pars compacta by in situ hybridization. In addition, the effect of various treatments on the synaptophysin mRNA level was determined in the substantia nigra by in situ hybridization. Chronic administration of L-dopa resulted in a significant decrease (28%, p < 0.05) in the density of [(3)H]TBZOH binding in the prefrontal cortex but had no effect on VMAT2 and synaptophysin mRNA levels in the substantia nigra. Lithium treatment increased [(3)H]TBZOH-specific binding in the prefrontal cortex (23%, p < 0.05) but had no effect on VMAT2 and synaptophysin mRNA levels. Phenelzine did not modulate VMAT2 gene expression but reduced the synaptophysin mRNA level (19%, p < 0.05). The modulatory activities of these drugs, although relatively weak, may be relevant to the drug-induced synaptic and neuronal plasticity as well as to the molecular and cellular pathophysiology of monoamine-related neuropsychiatric disorders.

Characterization of high-affinity [3H]TBZOH binding to the human platelet vesicular monoamine transporter.

The present study indicates that human platelets can be used as an accessible peripheral model not only for the plasma membrane serotonin transporter, but also for the vesicular monoamine transporter. The vesicular monoamine transporter (VMAT2) is responsible for the accumulation of monoamines in the synaptic vesicles. VMAT2 differs from the plasma membrane transporters in its capability to recognize serotonin, histamine, norepinephrine and dopamine with almost the same affinity. Dihydrotetrabenazine (TBZOH) is a very potent inhibitor of VMAT2 that binds with high affinity to this transporter. [3H]TBZOH has been used as a ligand to label VMAT2 in human, bovine and rodent brain. In this study we characterized the pharmacodynamic and pharmacokinetic parameters of [3H]TBZOH binding in human platelets as compared to rat brain. The density (Bmax) and affinity (Kd) of [3H]TBZOH specific binding was assessed by Scatchard analysis. Association and dissociation rate constants (k(on), K(off)) were assessed by kinetic binding studies. In this study high-affinity and saturable binding sites for [3H]TBZOH were demonstrated in human platelets. Both the affinity of [3H]TBZOH to its binding site in platelets (Kd = 3.2+/-0.5 nM) and the kinetic rate constants (K(on) = 2.8 x 10(7) M(-1) min(-1); K(off) = 0.099 min(-1)) were similar to that in rat brain (Kd(striatum) = 1.5 nM; Kd(cerebral cortex) = 1.35 nM; K(on) = 2 x 10(7) M(-1) min(-1); K(off) = 0.069 min(-1)). Only the VMAT2 blockers tetrabenazine and reserpine inhibited [3H]TBZOH specific binding.

Effect of dehydroepiandrosterone and its sulfate metabolite on neuronal cell viability in culture.

BACKGROUND: The neurosteroids dehydroepiandrosterone (DHEA) and its sulfated metabolite (DHEAS) have been reported to possess neuroprotective as well as anti-tumoral activity in vitro and in vivo. OBJECTIVES: To compare the effect of the two neurohormones on cell viability in primary whole-brain fetal mouse culture and isolated neuronal culture, as well as in a human neuroblastoma cell line (SK-N-SH). METHODS: Cell viability and cell proliferation were determined with the neutral red and 3H-thymidine uptake methods. Apoptosis in propidium iodide-stained neuroblastoma cells was determined using flow cytometry. RESULTS: DHEA (1 nM-10 microM) decreased the viability of selected primary neuronal cells (33-95% after 24 and 72 hours) but not of whole-brain cultured cells (neuron + glia). DHEAS did not significantly modify cell viability in either primary culture. In a human neuroblastoma cell line, DHEA (1 nM-1 microM) decreased 3H-thymidine uptake (30-60%) and cell viability (23-52%) after 24 hours. DHEAS did not significantly modify, or only slightly stimulated, cell viability and uptake of 3H-thymidine (132% of controls). The combination of DHEA and DHEAS neutralized the toxic effect of DHEA in both primary neuronal culture and neuroblastoma cell line. Flow cytometric analysis of DNA fragmentation in neuroblastoma cells treated with 100 nM DHEA/DHEAS for 24 hours showed an increase in apoptotic events (31.9% and 26.3%, respectively, vs. control 2.54%). CONCLUSIONS: Our results do not confirm a neuroprotective role for DHEA and suggest that DHEA and DHEAS have a differential role; DHEA possesses a neurotoxic (expressed only in isolated neurons) and anti-proliferative effect; DHEAS demonstrates only a slight neuroprotective effect.

Suppression of serum gonadal steroids in rats by chronic treatment with dopamine and serotonin reuptake inhibitors.

The impact of chronic administration (3 weeks) of dopamine and serotonin reuptake inhibitors on serum gonadal steroid hormones and prolactin was studied in intact male and female rats. Both the dopamine and the serotonin reuptake inhibitors lowered serum estradiol and progesterone levels in the female rats. The dopamine transporter blockers suppressed testosterone serum levels in the male rats, whereas serotonin reuptake inhibitors induced only a non-significant reduction (30%) of this hormone. In contrast to the decrease in gonadal steroids, none of the serotonin or the dopamine reuptake blockers altered prolactin serum levels in either the male or female rats. It seems that the effect of these agents on ovarian and testicular hormones is related to the impact of the monoamine reuptake inhibitors on the hypothalamic-pituitary-gonadal axis.

Sparing by rasagiline (TVP-1012) of cholinergic functions and behavior in the postnatal anoxia rat.

Rasagiline (N-propargyl-1(R)aminoindan) is a selective and potent MAO-B inhibitor currently under development as the mesylate salt (TVP-1012) for the treatment of various neurologic disorders. Preliminary work in adult and senescent rats, either normal or hypoxia-lesioned, showed that chronic rasagiline treatment improved performance in memory and learning tasks, suggesting some beneficial effect on central cholinergic function. We have now used the postnatal anoxia-lesioned rat as a model of cholinergic dysfunction. In the neonatal rat, anoxia strongly affects the cholinergic system, which has not yet reached full maturation at this state of life. Rasagiline mesylate was administered from day 1 to completion of the study (day 60), first through nursing mother milk until weaning (day 21), then in drinking water, at the rate of 0.5 mg/kg/day. Drug access to the CNS was verified by analysis of MAO activity in brain (at 21 days). Treatment improved the juvenile hyperactivity syndrome associated with anoxia (at day 28). It improved performance in the passive avoidance test to normal control level (at day 40). It improved spatial memory performance in the Morris water maze to normal control level (at day 50). The untreated anoxia group failed in these tasks and was significantly inferior to either the normal control and rasagiline-treated anoxia groups. Determination of ChAT activity in the caudate and hippocampus of rats from each of these groups gave the following results (pmol ACh/mg protein/min). Caudate: normal control, 588 +/- 56; anoxia, 398 +/- 54; rasagiline-treated anoxia, 536 +/- 35. Hippocampus: normal control, 380 +/- 31; anoxia, 275 +/- 47; rasagiline-treated anoxia, 325 +/- 35. Results are mean +/- SD from each of seven to nine different donors in a group. Thus, improvement in memory and learning tasks of the rasagiline-treated anoxia group finds correspondence in the activity of the cholinergic marker ChAT in two brain regions that have prominent cholinergic innervation.

Regulation of rat brain vesicular monoamine transporter by chronic treatment with ovarian hormones.

Ovarian steroids play an important role in neuroregulation and in the pathophysiology of various neuropsychiatric disorders. Most of the studies focused on the impact of gonadal steroids on post-synaptic receptors and plasma membrane transporters. In the present study, we evaluated the effect of chronic treatment with ovarian steroids on the expression of rat brain vesicular monoamine transporter (VMAT2). Ovariectomized rats were treated for 21 days with estradiol, progesterone or both. VMAT2 gene expression was assessed on the protein level by high affinity [3H]dihydrotetrabenazine ([3H]TBZOH) binding using autoradiography and on the mRNA level by in situ hybridization. Progesterone administration led to a decrease in [3H]TBZOH binding in the middle striatum and in the nucleus accumbens and to a parallel decrease in VMAT2 mRNA level in the substantia nigra pars compacta and dorsal raphè nuclei. Chronic estradiol treatment reduced VMAT2 mRNA level in the dorsal raphè and [3H]TBZOH binding in middle part of the striatum and nucleus accumbens but did not affect VMAT2 mRNA level in the substantia nigra pars compacta. Simultaneous administration of both ovarian steroids did not modulate VMAT2 mRNA in the substantia nigra pars compacta as well as [3H]TBZOH binding in the striatum or the nucleus accumbens but reduced VMAT2 mRNA level in the dorsal raphè. It appears that ovarian steroids may play a crucial role in the regulation of VMAT2 gene expression in the dopamine and serotonin systems. This modulatory activity may be relevant to synaptic and neuronal plasticity as well as to the molecular and cellular pathophysiology of gender-specific neuropsychiatric disorders.

Significant inhibition of spontaneous IgA secretion by selective peripheral-type benzodiazepine receptor ligands.

The in vitro effect of benzodiazepine (BZ) receptor ligands on the secretion of immunoglobulin isotypes IgM, IgG, and IgA by human peripheral blood mononuclear cells (PBMCs) was examined. It was found that the specific peripheral-type BZ receptor (PBR) ligands (Ro5-4864 and PK 11195) inhibit the spontaneous secretion of IgA by human PBMCs in a dose-dependent manner, in the micromolar range. The decreased secretion of IgG and IgM induced by these ligands did not reach significant levels. The mixed BZ ligands (diazepam and flunitrazepam) had no consistent or significant effect on the production of the three immunoglobulin isotypes tested in the current study. The central-type ligand (clonazepam) did not affect IgM, IgG, or IgA secretion. The significant inhibitory effect of PBR ligands was confined to the spontaneous secretion of IgA by human PBMCs, and no such effect was detected in cells stimulated by pokeweed mitogen to produce immunoglobulins. It seems that PBR ligands are capable of suppressing spontaneous IgA secretion, but fail to affect the augmented production induced by mitogen.