Effects of electroconvulsive shock on the function, circuitry, and transcriptome of dentate gyrus granule neurons.

Therapeutic use of electroconvulsive shock (ECS) is 75% effective for the remission of treatment-resistant depression. Like other more common forms of antidepressant treatment such as fluoxetine, ECS has been shown to increase neurogenesis in the hippocampal dentate gyrus of rodent models. Yet the question of how ECS-induced neurogenesis supports improvement of depressive symptoms remains unknown. Here, we show that ECS-induced neurogenesis is necessary to improve depressive-like behavior of mice exposed to chronic corticosterone (Cort). We then use slice electrophysiology to show that optogenetic stimulation of adult-born neurons produces a greater hyperpolarization in mature granule neurons after ECS vs Sham treatment. We identify that this hyperpolarization requires the activation of metabotropic glutamate receptor 2 (mGluR2). Consistent with this finding, we observe reduced expression of the immediate early gene cFos in the granule cell layer of ECS vs Sham subjects. We then show that mGluR2 knockdown specifically in ventral granule neurons blunts the antidepressant-like behavioral effects of ECS. Using single nucleus RNA sequencing, we reveal major transcriptomic shifts in granule neurons after treatment with ECS+Cort or fluoxetine+Cort vs Cort alone. We identify a population of immature cells which has greater representation in both ECS+Cort and fluoxetine+Cort treated samples vs Cort alone. We also find global differences in ECS-vs fluoxetine-induced transcriptomic shifts. Together, these findings highlight a critical role for immature granule cells and mGluR2 signaling in the antidepressant action of ECS.

Pharmacological Enhancement of Adult Hippocampal Neurogenesis Improves Behavioral Pattern Separation in Young and Aged Mice.

BACKGROUND: Impairments in behavioral pattern separation (BPS)-the ability to distinguish between similar contexts or experiences-contribute to memory interference and overgeneralization seen in many neuropsychiatric conditions, including depression, anxiety, PTSD, dementia, and age-related cognitive decline. While BPS relies on the dentate gyrus and is sensitive to changes in adult hippocampal neurogenesis (AHN), its significance as a pharmacological target has not been tested. METHODS: In this study, we applied a human neural stem cell high-throughput screening cascade to identify compounds that increase human neurogenesis. One compound with a favorable profile, RO6871135, was then tested in BPS in mice. RESULTS: Chronic treatment with RO6871135, 7.5 mg/kg increased AHN and improved BPS in a fear discrimination task in both young and aged mice. RO6871135 treatment also lowered innate anxiety-like behavior, which was more apparent in mice exposed to chronic corticosterone. Ablation of AHN by hippocampal irradiation supported a neurogenesis-dependent mechanism for RO6871135-induced improvements in BPS. To identify possible mechanisms of action, in vitro and in vivo kinase inhibition and chemical proteomics assays were performed. These tests indicated that RO6871135 inhibited CDK8, CDK11, CaMK2a, CaMK2b, MAP2K6, and GSK3b. An analog compound also demonstrated high affinity for CDK8, CaMK2a, and GSK3b. CONCLUSIONS: These studies demonstrate a method for empirical identification and preclinical testing of novel neurogenic compounds that can improve BPS, and points to possible novel mechanisms that can be interrogated for the development of new therapies to improve specific endophenotypes such as impaired BPS.

Effect of Tongxie Yaofang on Expressions of Colon SERT and Liver 5-HT2AR Proteins in Rats with Ulcerative Colitis Model of Liver Stagnation and Spleen Deficiency / 中国实验方剂学杂志

Objective:To observe the effect of Tongxie Yaofang on the expressions of colon serotonin transporter （SERT）， liver 5-hydroxytryptamine_2A receptor （5-HT_2AR） protein， serum 5-HT and inflammatory factors in ulcerative colitis （UC） model rats of liver stagnation and spleen deficiency， in order to explore the basis of syndrome of liver stagnation and spleen deficiency and the intervention mechanism of Tongxie Yaofang. Method:Fifty male SD rats were randomly divided into blank control group， model group， high， medium and low-dose Tongxie Yaofang group （10，5，2.5 g·kg^-1）， and salazosulacil group （0.3 g·kg^-1）. The ulcerative colitis model of liver depression and spleen deficiency was established by 2，4，6-trinitrobenzene sulfonic acid （TNBS）/ethanol solution enema + restraint stress + diet loss. After successful modeling， the samples were collected after 21 days of drug intervention. Htoxylin eosin （HE） staining and oil red staining were used to observe the pathological changes of colon and liver in each group. Serum interleukin-6 （IL-6）， IL-9， 5-HT and superoxide dismutase （SOD） were detected by enzyme linked immunosorbent assay （ELISA）. Protein expressions of SERT in the colons and 5-HT_2AR in liver of rats were detected by Western blot. Result:Compared with the normal group， obvious ulcers were formed in the colon and lipid droplets in the liver increased in the model group， serum levels of IL-6， IL-9 and 5-HT in the model group increased， while the level of SOD decreased （<italic>P</italic><0.05）. The protein expression of SERT in colon decreased， whereas the protein expression of 5-HT_2AR in liver increased （<italic>P</italic><0.05）. Compare with model group， the pathological damage of colon was improved， and the formation of lipid droplets in liver was reduced in high， medium-dose Tongxie Yaofang groups and sulfasalazine group. The serum levels of IL-6， IL-9 and 5-HT decreased， while the level of SOD increased in Tongxie Yaofang group and sulfasalazine group （<italic>P</italic><0.05）. The protein expression of SERT in colon increased in high，low-dose Tongxie Yaofang groups and sulfasalazine group， and the protein expression of 5-HT_2AR in liver decreased in medium， low dose Tongxie Yaofang groups and sulfasalazine group （<italic>P</italic><0.05）. Conclusion:Tongxie Yaofang may reduce the content of 5-HT， and regulate the intestinal motility and sensory system by up-regulating the expression of SERT in the colon， inhibit the expressions of IL-6，IL-9 and other inflammatory factors， and play an anti-inflammatory role， reduce the content of 5-HT and the expression of 5-HT_2AR in the liver， increase the level of SOD， regulate emotion and lipid metabolism in the liver， and then exert the intervention effect on ulcerative colitis with liver depression and spleen deficiency on the whole.

Posterior cingulate cortex can be a regulatory modulator of the default mode network in task-negative state.

In recent years, the regulation of brain networks and interactions between different brain regions have become important issues in neuroscience. Effective connectivity can be employed to understand the modulatory mechanisms of brain networks. Previous studies have used the task-positive mode to examine effective connectivity between brain regions and very few studies have considered the task-negative mode to explore effective connectivity using electroencephalography (EEG). In the present study, high-density EEG experiments were conducted in 85 participants to measure EEG effective connectivity in relevant default mode network (DMN) brain regions (i.e., the medial prefrontal cortex [mPFC], posterior cingulate cortex [PCC], precuneus, and right frontal and left occipital regions) to observe the effects of different task-negative modes (eyes-open/eyes-closed state) and personality traits (introversion/extroversion). The results showed that in the eyes-closed state, the PCC had significantly increased effective connectivity and played a prominent role as a regulatory modulator of outflow to other regions mediated by alpha rhythms. The mPFC was a regulatory modulator of outflow in the eyes-open state mediated by delta rhythms. The introvert group showed stronger co-modulations in the relevant DMN regions than the extrovert group.

Mismatch negativity impairment is associated with deficits in identifying real-world environmental sounds in schizophrenia.

BACKGROUND: Patients with schizophrenia (SZ) have impairments in processing auditory information that have been linked to deficits in cognitive and psychosocial functioning. Dysfunction in auditory sensory processing in SZ has been indexed by mismatch negativity (MMN), an event-related potential evoked by a rare, deviant stimulus embedded within a sequence of identical standard stimuli. Although MMN deficits in SZ have been studied extensively, relatively little is known about how these deficits relate to accurately identifying real-world, ecologically-salient sounds. METHODS: MMN was assessed in SZ patients (n=21) and non-psychiatric comparison subjects (NCS; n=16). Participants were also assessed in their ability to identify common environmental sounds using a subset of 80 sound clips from the International Affective Digitized Sounds 2nd Ed collection. RESULTS: SZ patients made significantly more errors in environmental sound identification (p<0.001, d=0.86) and showed significantly reduced MMN amplitude deficits in MMN compared to NCS (p<0.01, d=0.97). In SZ patients, MMN deficits were associated with significantly greater environmental sound identification errors (r=0.61, p<0.01). CONCLUSIONS: Impairments in early auditory information processing in schizophrenia account for significant proportions of variance in the ability to identify real-world, functionally relevant environmental sounds. This study supports the view that interventions targeting deficits in low-level auditory sensory processing may also impact more complex cognitive brain processes relevant to psychosocial disability.

Self-fixating polypropylene/poly(lactic acid) mesh for treatment of chronic pain following tension-free repair of inguinal hernia / 中国组织工程研究

BACKGROUND:Increasing clinical studies have reported the application of self-fixating mesh in the tension-free repair of inguinal hernia,but whether the self-fixating mesh is superior to the common suture mesh is still in dispute.OBJECTIVE:To compare the effects of self-fixating polypropylene/poly(lactic acid) mesh and polypropylene mesh on chronic pain after tension-free repair of inguinal hernia.METHODS:A total of 90 male patients with primary inguinal hernia were randomly divided into two groups:self-fixating mesh and control groups (n=45 per group).All patients underwent tension-free hernioplasty followed by self-fixating polypropylene/poly(lactic acid) mesh in the self-fixating mesh group and polypropylene mesh in the control group.Operation time and length of hospital stay were recorded;complications and recurrence rate in the two groups were observed at 6 months after operation;and postoperative pain and chronic pain were assessed by the visual analog scale (VAS) at postoperative 1,10 days,1,3,6 months.RESULTS AND CONCLUSION:(1) Compared with the control group,the operation time was shorter in the self-fixating mesh group (P ＜ 0.05),but there was no significant difference in the length of hospital stay between the two groups.(2) The VAS scores showed no significant difference between the two groups at postoperative 1 day,but the VAS scores were significantly better in the self-fixating mesh group than the control group at 10 days,postoperative 1,3,6 months (P ＜ 0.05).(3) During the 6-month follow-up,there were no urinary retention,subcutaneous hematoma,wound infection and recurrence in the two groups except five patients in the control group who complained of a foreign body sensation.To conclude,compared with the traditional polypropylene mesh,the use of self-fixating polypropylene/poly(lactic acid) mesh can shorten operation time and reduce pain and discomfort of patients with unilateral inguinal hernia undergoing tension-free hemioplasty.

The secondary metabolites from a mutant 3d10-01 derived from Penicilliumchrysogenum S-3-25 by diethyl sulfate mutagenesis / 国际药学研究杂志

Objective To investigate the secondary metabolites from diethyl sulfate(DES)mutant 3d10-01 derived from Peni-cillium chrysogenum S-3-25. Methods The secondary metabolites were isolated by multiple separation techniques,such as silica gel,Sephadex LH-20 column chromatography and HPLC. The structures of the compounds were determined by ESI-MS and NMR spectroscopic data. The antitumor activity was assayed by the MTT method. HPLC-UV analysis was used to determine if compounds 1-7 were newly produced by the mutant. Results Seven secondary metabolites,including methyl 2,4-dihydroxy-3,5,6-trimethylbenzo-ate(1),6-hydroxymethyl-2,2-dimethylchromanone(2),regiolone(3),(3S,4S)-3,4-dihydro-3,4,8-trihydroxy(2H)naphthalenone (4),cerebroside C(5),cerebroside D(6)and dankasterone A(7),were isolated from the fermentation products of the mutant 3d10-01. Compounds 1,4 and 7 showed strong inhibitory effects on the five tested cell lines,but 2,3 and 6 only exhibited the proliferation of HL-60 cells to some extent. Compounds 1-4 and 7 were newly produced by the mutant 3d10-01. Conclusion Compounds 1-7 are firstly isolated from P. chrysogenum. The inhibitory effects on certain tested antitumor cell lines of compounds 1-4,6 and 7 are report-ed for the first time.

Childhood predictors of persistent ADHD in early adulthood: Results from the first follow-up study in China.

It is known that childhood attention-deficit/hyperactivity disorder (ADHD) persists into adulthood. Previous studies have demonstrated that gender, ADHD symptoms, functional impairment severity, medication treatment, IQ, comorbid with oppositional defiant disorder, conduct disorder and follow-up periods were associated with ADHD persistence in longitudinal samples of western population. In this study, we attempted to widely investigate the predictors particularly in a Chinese Han ADHD cohort. 399 children who met DSM-IV ADHD criteria were followed up into early adulthood. Ordinal logistic regression combined with survival analysis were conducted to examine the association of retrospectively reported childhood factors with adult ADHD persistence based on both categorical indicators and quantitative traits. 46.37% of the participants still met ADHD criteria in adulthood. Logistic models and survival analyses indicated that ADHD combined type appeared as a significant risk factor for ADHD persistence while superior IQ played a protective role even after controlling for the other potential confounders. When quantitative traits were applied, a number of hyperactivity/impulsivity symptoms and IQ still made significant contributions. In conclusion, our results indicated the syndromic continuity of ADHD. Further, a number of hyperactivity/impulsivity symptoms were a risk factor while higher IQ was protective for ADHD persistence.

Application of several physicochemical techniques in natural products to elucidate stereochemistry / 国际药学研究杂志

The difficulty in the structure elucidation of natural products is in the elucidation of stereochemistry, especially the determination of absolute configuration, which generally involves the key techniques of structure elucidation of natural products. This paper shows some examples of our work in elucidating the stereochemistry of new chiral natural products by the application of several physicochemical techniques, such as the dimolybdenum tetraacetate [Mo2(OAc)4] induced CD (ICD, Snatzke’s method), empirical rules of classical CD, modified Mosher’s method, theoretical ECD calculation and modified Marfey’s analysis. The fundamental rules of the techniques and our experiences in the application of these techniques are also described for related researcher’s reference in relevant studies.

Galloyl glucosidic constituents of choerospondias axillaries and their in vitro anti-tumor, anti-hypoxia and anti-bacteria activities / 国际药学研究杂志

Objective To investigate gallic acid-derived chemical constituents of Choerospondias axillaries (Roxb.) Burtt. et Hill., and evaluate their in vitro anti-tumor, anti-hypoxia and anti-bacteria activities. Methods The aimed chemical constituents were isolated by various chromatographic means, and their structures were identified by physicochemical and spectroscopic data. MTT method was employed to evaluate anti-tumor and anti-hypoxia activities. Antibacterial activities were tested by paper disc method. Results Seven compounds 1-7 were isolated from the stem barks of Choerospondias axillaries (Roxb.) Burtt. et Hill. and identified as gallic acid (1)gallic acid ethyl ether (2)l-0-galloyl-β-A-glucose (3)1, 6-di-0-galloyl-β-D-glucose (4)1, 4-di-0- galloyl-β-D-glucose (5)1,4,6-tri-0-galloyl-β-β-glucose (6), and 1, 3, 4, 6-tetra-0-galloyl-β-D-glucose (7). Compounds 1, 2 and 4-6 significantly inhibited K562 cells with the IC50 values of 2.9, 14.6, 39.1, 40.2, 41.2 mg/ml, respectively, and 3 and 7 also showed a slight inhibition of the K562 cells with the inhibition rate of 20.8% and 30.1V at 100 !g/ml respectively. Compounds 1-7 showed protective effects on anoxia-induced injury in cultured ECY304 and PC12 cells at the concentrations showing no significant cytotoxicity, and 5-7 also showed an antibacterial effect on Staphylococcus aureus ATCC6538 to a certain extent. Conclusion Compounds 2-7 were isolated from the genus Choerospondias for the first time. It was the first time to report 1-7 as anti-tumor and anti-hypoxia constituents of Choerospondias axillaries, and the anti-hypoxia activity for 1-7 was also recorded for the first time in the present study.

Stereochemical and neuroanatomical selectivity of pramipexole effects on sensorimotor gating in rats.

BACKGROUND: In rats, prepulse inhibition (PPI) of acoustic startle is disrupted by systemic administration of dopaminergic agonists, such as the dopamine D3 receptor (D3R)-preferential agonist pramipexole (PPX). PPX has D3R-active (S) and -inactive (R) stereoisomers. Here, we tested the neuroanatomical and stereochemical selectivity of PPX effects on PPI. METHODS: (S)-PRA or (R)-PRA (0, 0.47, 1.42, 4.73 µmol/kg) was injected sc 15 min prior to PPI testing in adult male Sprague Dawley rats. In separate rats, (S)-PPX (0, 3, 10 µg/0.5µl/side, ic) was infused into the nucleus accumbens (NAc), caudodorsal striatum (CS), or olfactory tubercle/Islands of Calleja (ICj) 15 min prior to PPI testing. D3R expression in these brain regions was assessed using quantitative rt-PCR. The PPI-disruptive effects of systemic (S)-PPX were also tested after pretreatment with the D3R-selective antagonist, U99194 (10mg/kg). RESULTS: Systemic administration of PPX stereoisomers demonstrated a dose-dependent effect of (S)-PPX on PPI, while (R)-PPX had no effect on PPI. PPX decreased PPI when infused into the NAc and ICj, but not the CS. Quantitative rt-PCR revealed D3R expression in ICj>NAc>CS. The PPI-disruptive effects of PPX were prevented by U99194. CONCLUSION: The PPI-reducing effects of PPX are stereospecific for the D3R-active (S)-isomer, neuroanatomically preferential for the D3R-rich ventral vs. D3R poor caudodorsal striatum, and prevented by pharmacologic D3R blockade. These findings are consistent with the conclusion that PPX disrupts PPI via stimulation of mesolimbic D3Rs.

Disparate effects of pramipexole on locomotor activity and sensorimotor gating in Sprague-Dawley rats.

Prepulse inhibition (PPI) of acoustic startle and locomotor activity are both widely studied in the preclinical development of dopaminergic agents, including those acting at D3 dopamine receptors. In mice, the dopamine D3 receptor-preferential agonist pramipexole (PPX) alters locomotor activity in a biphasic manner at doses that have no effect on PPI. The present study examined the time-course of PPX effects on locomotion and PPI in rats. In adult male Sprague-Dawley rats, PPX (0, 0.1, 0.3, 1.0mg/kg) was injected prior to measurement of locomotor activity for 90 min in photobeam chambers. Based on disparate early vs. late effects of PPX on locomotion, the effects of PPX (0 vs. 0.3mg/kg) on PPI were tested 20 and 80 min after injection. All doses of PPX decreased locomotor activity for 30 min compared to vehicle, and the higher doses stimulated hyperlocomotion later in the session; the late hyperlocomotion, but not the early hypolocomotion, was blocked by the D2-selective antagonist, L741626 (1.0mg/kg sc). In contrast to its locomotor effects, PPX caused a similar reduction in PPI at 20 and 80 min after administration. These findings suggest both a temporal and pharmacological dissociation between PPX effects on locomotor activity and PPI; these two behavioral measures contribute non-redundant information to the investigation of D3-related behavioral pharmacology.

Parametric approaches towards understanding the effects of the preferential D3 receptor agonist pramipexole on prepulse inhibition in rats.

The preferential dopamine D3 receptor agonist pramipexole (PRA) disrupts prepulse inhibition (PPI) of acoustic startle, an operational measure of sensorimotor gating, in rats. Drug effects on PPI are sensitive to numerous experimental variables; proceeding with in-depth analyses of drug effects without a clear understanding of these variables is inefficient. The present studies characterized the impact on PRA-induced PPI deficits by a range of experimental parameters. As shown previously, PRA reduced both PPI and startle magnitude beginning 5-15 min post-injection; PRA effects on PPI were statistically significant through 35 min post-injection, while those on startle magnitude were still significant 65 min post-injection. PRA-induced PPI deficits were evident under conditions that matched startle magnitude in vehicle and PRA conditions and were independent of PRA-induced changes in prepulse-elicited motor activity. Additionally, PRA-induced PPI deficits did not differ significantly between uni- vs. cross-modal stimuli or between male vs. female rats, with no robust effect of estrous phase in females. These findings demonstrate that PRA effects on PPI are observed across several different experimental conditions and are dissociable from changes in startle magnitude or prepulse-elicited responses. Recommendations are made regarding "optimal" experimental conditions for studying the neurobiology of PRA-induced changes in PPI in rats.

The effects of the dopamine D2 agonist sumanirole on prepulse inhibition in rats.

Dopamine agonists reduce prepulse inhibition (PPI) of startle in rats. While it is used to predict antipsychotic efficacy, the specific receptor subtypes mediating this effect of dopamine agonists remain unclear. We characterized the effects of sumanirole, a highly selective D2 agonist, on PPI in rats. Sumanirole decreased PPI at 60-120 ms prepulse intervals, and increased PPI at 10-20 ms intervals. PPI deficits were antagonized by low doses of the preferential D2 antagonist L741626, supporting a D2 mechanism of action. Sumanirole is a valuable tool for parsing the role of dopamine receptor subtypes in the regulation of PPI.

The effects of pramipexole on prepulse inhibition and locomotor activity in C57BL/6J mice.

Pramipexole (PRA) is a preferential D3R agonist that, in rats and humans, modifies prepulse inhibition (PPI) of the acoustic startle reflex, an operational measure of sensorimotor gating. The ability to use similar PPI measures across species, and the relative ease of genetic manipulations in mice, suggests that molecular studies of the D3R regulation of sensorimotor gating might be best pursued in mice. Here, we evaluate the effects of PRA on PPI and locomotion in C57BL/6J mice, the background strain for many gene knockout mouse models. Male C57BL/6J mice were tested for PPI and locomotor activity after injection of PRA. No significant effects of PRA on PPI were observed at any dose (0.1-10.0 mg/kg), but a significant reduction in startle magnitude was observed after 10 mg/kg PRA. In contrast, the D1/2 agonist, apomorphine (5 mg/kg) significantly reduced PPI in these mice. At doses of PRA that did not alter startle magnitude (0.3, 1, 3 mg/kg), significant decreases in the amount of locomotor and investigatory behavior were observed. Distinct from findings in rats and humans, it seems that either: (i) PRA does not activate D3Rs in C57BL/6J mice, or (ii) D3R agonists are not sufficient to alter PPI in this mouse strain.

Screening for bioactive mutants with antitumor activity from an actinomycetic wild-type strain without antitumor activity by antibiotic-resistant mutation technique and by coupled with chemical mutagen-induced mutation / 军事医学科学院院刊

Objective To obtain antibiotic-resistant mutants producing metabolites with antitumor activity from wild-type actinomycete strains without antitumor activity. Methods An actinomycete strain L35-1 was used as an initial strain for obtaining antibiotic-resistant mutants, which is a marine-derived wild-type strain without antitumor activity with an inhibition rate of 2.8% at the 1000 μg/ml of high sample concentration on K562 cells. The antibiotic-resistant mutants both from auto-mutagenesis and chemical mutagen-induced mutagenesis were selected by single colony isolation on antibiotic-containing plates according to the method for obtaining drug-resistant mutants in ribosome engineering. The antitumor activity was assayed by the MTT method using K562 cells for the mutants with aqueous acetone extracts of the whole broth of their fermentation.Results A total of 114 neomycin-resistant (ner) and 68 streptomycin-resistant (str) mutants, all from auto-mutagenesis, was obtained on drug-containing plates. Among them, the 7 ner and 3 str mutants appeared to be bioactive with an inhibition rate above 20% at the 100 μg/ml sample concentration on K562 cells. On the other hand, 41 str and 32 ner mutants from DES-induced mutagenesis and 46 ner mutants from NTG-induced mutagenesis were obtained by mutagen-induced mutation coupled with the single colony isolation on antibiotic-containing plates, among which, one str mutant from DES-induced mutagenesis and one ner mutant from NTG-induced mutagenesis were bioactive with an inhibition rate over 20% at the 100 μg/ml sample concentration on K562 cells. Conclusions The present result has revealed that the wild-type actinomycete strains without bioactivity might become a great source initial strains to obtain bioactive mutants by drug-resistant mutation technique.

Pramipexole effects on startle gating in rats and normal men.

BACKGROUND: Dopamine D3 receptors regulate sensorimotor gating in rats, as evidenced by changes in prepulse inhibition (PPI) of startle after acute administration of D3 agonists and antagonists. In this study, we tested the effects of the D3-preferential agonist, pramipexole, on PPI in normal men and Sprague-Dawley rats. MATERIALS AND METHODS: Acoustic startle and PPI were tested in clinically normal men, comparing the effects of placebo vs. 0.125 mg (n = 20) or placebo vs. 0.1875 mg (n = 20) pramipexole, in double blind, crossover designs. These measures were also tested in male Sprague-Dawley rats using a parallel design [vehicle vs. 0.1 mg/kg (n = 8), vehicle vs. 0.3 mg/kg (n = 8) or vehicle vs. 1.0 mg/kg pramipexole (n = 8)]. Autonomic and subjective measures of pramipexole effects and several personality instruments were also measured in humans. RESULTS: Pramipexole increased drowsiness and significantly increased PPI at 120-ms intervals in humans; the latter effect was not moderated by baseline PPI or personality scale scores. In rats, pramipexole causes a dose-dependent reduction in long-interval (120 ms) PPI, while low doses actually increased short-interval (10-20 ms) PPI. Effects of pramipexole on PPI in rats were independent of baseline PPI and changes in startle magnitude. CONCLUSION: The preferential D3 agonist pramipexole modifies PPI in humans and rats. Unlike indirect DA agonists and mixed D2/D3 agonists, pramipexole increases long-interval PPI in humans, in a manner that is independent of baseline PPI and personality measures. These findings are consistent with preclinical evidence for differences in the D2- and D3-mediated regulation of sensorimotor gating.

Using prepulse inhibition to detect functional D3 receptor antagonism: effects of WC10 and WC44.

Prepulse inhibition of startle (PPI) is an operational measure of sensorimotor gating that is impaired in schizophrenia. Treatment with mixed dopamine D2/D3 antagonists diminishes schizophrenia symptoms, and opposes dopamine agonist-induced PPI deficits in rats. There are reasons to believe that functional D3 receptor antagonists might offer more favorable therapeutic profiles compared to current antipsychotics. However, D3-related drug discovery is hampered by the absence of assays sensitive to D3-mediated (antipsychotic) properties in vivo. Here, we characterized two putative D3-active compounds - WC10 and WC44 - in a PPI-based screening assay, comparing the sensitivity of test compounds to oppose PPI deficits induced by the mixed D1/D2-like agonist apomorphine vs. the preferential D3 agonist pramipexole in rats. WC10, WC44 (0, 1, 3, 10 mg/kg, each), and the preferential D2 antagonist L741,626 (0, 1 mg/kg) were studied, in combination with apomorphine (0, 0.5 mg/kg), or pramipexole (0, 1 mg/kg). L741,626 prevented apomorphine-, but not pramipexole-induced PPI deficits. WC10, but not WC44, prevented apomorphine-induced PPI deficits; both compounds opposed pramipexole-induced PPI deficits, suggesting functional D3 and D1/D2 antagonist profiles for WC10, and functional D3 receptor antagonism for WC44. This assay may be valuable for detecting predominantly D3 vs. D2 receptor-linked mechanisms of action in vivo.

Normal human aging and early-stage schizophrenia share common molecular profiles.

We examined genome-wide expression datasets from human prefrontal cortex of normal and schizophrenic individuals ranging from 19 to 81 years of age. We found that changes in gene expression that are correlated with aging in normal subjects differ dramatically from those observed with aging in schizophrenic subjects. Only 2.5% of genes were correlated with age in both groups. Surprisingly, we also found a significant overlap (29-34%) between those genes whose expression was correlated with aging in normal subjects and those significantly altered in subjects with early-stage schizophrenia (within 4 years of diagnosis). This suggests that schizophrenia onset anticipates the normal aging process, and further, that some symptoms of aging, i.e. dementia and psychosis, might be explained by these common molecular profiles.