Artificial intelligence large language model scores highly on focused practice designation in metabolic and bariatric surgery board practice questions.

BACKGROUND: Artificial intelligence models such as ChatGPT (Open AI) have performed well on the exams of various medical and surgical fields. It is not yet known how ChatGPT performs on similar metabolic and bariatric surgery (MBS) questions. OBJECTIVE: Assess the performance of ChatGPT on Focused Practice Designation in Metabolic and Bariatric Surgery board-style questions. SETTING: United States. METHODS: Questions obtained from the largest commercially available bank of FPD-MBS practice questions were entered into ChatGPT-4, as is, without prior training. We assessed the overall percentage correct as well as the percentage correct within each of the five American Board of Surgery (ABS) question categories. One-way ANOVA was used to determine if the frequency of correct answers differed between categories. RESULTS: Out of 255 questions, ChatGPT-4 correctly answered 189 (74.1%). Between the five question categories there was no difference between the frequency of correct answers (p = 0.22). It did not matter if questions were entered individually or in groups of up to 10. CONCLUSION: Without prior training, ChatGPT-4 scored highly when evaluated on the largest practice question bank for the FPD-MBS exam.

Non-pharmaceutical interventions to reduce COVID-19 transmission in the UK: a rapid mapping review and interactive evidence gap map.

BACKGROUND: Non-pharmaceutical interventions (NPIs) were crucial in the response to the COVID-19 pandemic, although uncertainties about their effectiveness remain. This work aimed to better understand the evidence generated during the pandemic on the effectiveness of NPIs implemented in the UK. METHODS: We conducted a rapid mapping review (search date: 1 March 2023) to identify primary studies reporting on the effectiveness of NPIs to reduce COVID-19 transmission. Included studies were displayed in an interactive evidence gap map. RESULTS: After removal of duplicates, 11 752 records were screened. Of these, 151 were included, including 100 modelling studies but only 2 randomized controlled trials and 10 longitudinal observational studies.Most studies reported on NPIs to identify and isolate those who are or may become infectious, and on NPIs to reduce the number of contacts. There was an evidence gap for hand and respiratory hygiene, ventilation and cleaning. CONCLUSIONS: Our findings show that despite the large number of studies published, there is still a lack of robust evaluations of the NPIs implemented in the UK. There is a need to build evaluation into the design and implementation of public health interventions and policies from the start of any future pandemic or other public health emergency.

Age-dependent effects of dopamine receptor inactivation on cocaine-induced behaviors in male rats: Evidence of dorsal striatal D2 receptor supersensitivity.

N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), which irreversibly inactivates dopamine (DA) receptors, causes pronounced age-dependent behavioral effects in rats. For example, EEDQ either augments or does not affect the DA agonist-induced locomotor activity of preweanling rats while attenuating the locomotion of adolescent and adult rats. The twofold purpose of this study was to determine whether EEDQ would: (a) potentiate or attenuate the cocaine-induced locomotor activity of preweanling, adolescent, and adult rats; and (b) alter the sensitivity of surviving D2 receptors. Rats were treated with vehicle or EEDQ (2.5 or 7.5 mg/kg) on postnatal day (PD) 17, PD 39, and PD 84. In the behavioral experiments, saline- or cocaine-induced locomotion was assessed 24 hr later. In the biochemical experiments, dorsal striatal samples were taken 24 hr after vehicle or EEDQ treatment and later assayed for NPA-stimulated GTPγS receptor binding, G protein-coupled receptor kinase 6 (GRK6), and ß-arrestin-2 (ARRB2). GTPγS binding is a direct measure of ligand-induced G protein activation, while GRK6 and ARRB2 modulate the internalization and desensitization of D2 receptors. Results showed that EEDQ potentiated the locomotor activity of preweanling rats, while attenuating the locomotion of older rats. NPA-stimulated GTPγS binding was elevated in EEDQ-treated preweanling rats, relative to adults, indicating enhanced functional coupling between the G protein and receptor. EEDQ also reduced ARRB2 levels in all age groups, which is indicative of increased D2 receptor sensitivity. In sum, the present results support the hypothesis that D2 receptor supersensitivity is a critical factor mediating the locomotor potentiating effects of EEDQ in cocaine-treated preweanling rats.

Development and validation of a gene expression test to identify hard-to-heal chronic venous leg ulcers.

BACKGROUND: Chronic venous leg ulcers pose a significant burden to healthcare systems, and predicting wound healing is challenging. The aim of this study was to develop a genetic test to evaluate the propensity of a chronic ulcer to heal. METHODS: Sequential refinement and testing of a gene expression signature was conducted using three distinct cohorts of human wound tissue. The expression of candidate genes was screened using a cohort of acute and chronic wound tissue and normal skin with quantitative transcript analysis. Genes showing significant expression differences were combined and examined, using receiver operating characteristic (ROC) curve analysis, in a controlled prospective study of patients with venous leg ulcers. A refined gene signature was evaluated using a prospective, blinded study of consecutive patients with venous ulcers. RESULTS: The initial gene signature, comprising 25 genes, could identify the outcome (healing versus non-healing) of chronic venous leg ulcers (area under the curve (AUC) 0·84, 95 per cent c.i. 0·73 to 0·94). Subsequent refinement resulted in a final 14-gene signature (WD14), which performed equally well (AUC 0·88, 0·80 to 0·97). When examined in a prospective blinded study, the WD14 signature could also identify wounds likely to demonstrate signs of healing (AUC 0·73, 0·62 to 0·84). CONCLUSION: A gene signature can identify people with chronic venous leg ulcers that are unlikely to heal.

Dopamine D2 Receptor Supersensitivity as a Spectrum of Neurotoxicity and Status in Psychiatric Disorders.

Abnormality of dopamine D2 receptor (D2R) function, often observed as D2R supersensitivity (D2RSS), is a commonality of schizophrenia and related psychiatric disorders in humans. Moreover, virtually all psychotherapeutic agents for schizophrenia target D2R in brain. Permanent D2RSS as a feature of a new animal model of schizophrenia was first reported in 1991, and then behaviorally and biochemically characterized over the next 15-20 years. In this model of schizophrenia characterized by production of D2RSS in ontogeny, there are demonstrated alterations of signaling processes, as well as functional links between the biologic template of the animal model and ability of pharmacotherapeutics to modulate or reverse biologic and behavioral modalities toward normality. Another such animal model, featuring knockout of trace amine-associated receptor 1 (TAAR1), demonstrates D2RSS with an increase in the proportion of D2R in the high-affinity state. Currently, TAAR1 agonists are being explored as a therapeutic option for schizophrenia. There is likewise an overlay of D2RSS with substance use disorder. The aspect of adenosine A2A-D2 heteroreceptor complexes in substance use disorder is highlighted, and the association of adenosine A2A receptor antagonists in discriminative and rewarding effects of psychostimulants is outlined. In summary, these new animal models of schizophrenia have face, construct, and predictive validity, and distinct advantages over earlier models. While the review summarizes elements of D2RSS in schizophrenia per se, and its interplay with substance use disorder, a major focus is on presumed new molecular targets attending D2RSS in schizophrenia and related clinical entities.

Tissue invasion and metastasis: Molecular, biological and clinical perspectives.

Cancer is a key health issue across the world, causing substantial patient morbidity and mortality. Patient prognosis is tightly linked with metastatic dissemination of the disease to distant sites, with metastatic diseases accounting for a vast percentage of cancer patient mortality. While advances in this area have been made, the process of cancer metastasis and the factors governing cancer spread and establishment at secondary locations is still poorly understood. The current article summarizes recent progress in this area of research, both in the understanding of the underlying biological processes and in the therapeutic strategies for the management of metastasis. This review lists the disruption of E-cadherin and tight junctions, key signaling pathways, including urokinase type plasminogen activator (uPA), phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene (PI3K/AKT), focal adhesion kinase (FAK), ß-catenin/zinc finger E-box binding homeobox 1 (ZEB-1) and transforming growth factor beta (TGF-ß), together with inactivation of activator protein-1 (AP-1) and suppression of matrix metalloproteinase-9 (MMP-9) activity as key targets and the use of phytochemicals, or natural products, such as those from Agaricus blazei, Albatrellus confluens, Cordyceps militaris, Ganoderma lucidum, Poria cocos and Silybum marianum, together with diet derived fatty acids gamma linolenic acid (GLA) and eicosapentanoic acid (EPA) and inhibitory compounds as useful approaches to target tissue invasion and metastasis as well as other hallmark areas of cancer. Together, these strategies could represent new, inexpensive, low toxicity strategies to aid in the management of cancer metastasis as well as having holistic effects against other cancer hallmarks.

Genome-wide scan demonstrates significant linkage for male sexual orientation.

BACKGROUND: Findings from family and twin studies support a genetic contribution to the development of sexual orientation in men. However, previous studies have yielded conflicting evidence for linkage to chromosome Xq28. METHOD: We conducted a genome-wide linkage scan on 409 independent pairs of homosexual brothers (908 analyzed individuals in 384 families), by far the largest study of its kind to date. RESULTS: We identified two regions of linkage: the pericentromeric region on chromosome 8 (maximum two-point LOD = 4.08, maximum multipoint LOD = 2.59), which overlaps with the second strongest region from a previous separate linkage scan of 155 brother pairs; and Xq28 (maximum two-point LOD = 2.99, maximum multipoint LOD = 2.76), which was also implicated in prior research. CONCLUSIONS: Results, especially in the context of past studies, support the existence of genes on pericentromeric chromosome 8 and chromosome Xq28 influencing development of male sexual orientation.

Evidence that duplications of 22q11.2 protect against schizophrenia.

A number of large, rare copy number variants (CNVs) are deleterious for neurodevelopmental disorders, but large, rare, protective CNVs have not been reported for such phenotypes. Here we show in a CNV analysis of 47 005 individuals, the largest CNV analysis of schizophrenia to date, that large duplications (1.5-3.0 Mb) at 22q11.2--the reciprocal of the well-known, risk-inducing deletion of this locus--are substantially less common in schizophrenia cases than in the general population (0.014% vs 0.085%, OR=0.17, P=0.00086). 22q11.2 duplications represent the first putative protective mutation for schizophrenia.

Age-dependent differences in the strength and persistence of psychostimulant-induced conditioned activity in rats: effects of a single environment-cocaine pairing.

The aim of the present study was to determine the strength and persistence of cocaine-induced conditioned activity in young and adult rats. A one-trial protocol has proven useful for studying the ontogeny of psychostimulant-induced behavioral sensitization; therefore, a similar procedure was used to examine conditioned activity. On postnatal day (PD) 19 or PD 80, rats were injected with saline or cocaine in either a novel test chamber or the home cage. After various drug abstinence intervals (1-21 days), rats were injected with saline and returned to the test chamber, where conditioned activity was assessed. In a separate experiment, we examined whether cocaine-induced conditioned activity was a consequence of Pavlovian conditioning or a failure to habituate to the test environment. The results indicated that adult rats showed strong one-trial conditioned activity that persisted for at least 21 days, whereas young rats did not show a conditioned locomotor response. The conditioned activity shown by adult rats did not result from a failure to habituate to the cocaine-paired environment. These results indicate that cocaine-paired contextual stimuli differentially affect behavior depending on the age of the animal. The data obtained from adult rats have potential translational relevance for humans because a single environment-drug pairing caused long-term alterations in behavior.

Schizophrenia susceptibility alleles are enriched for alleles that affect gene expression in adult human brain.

It is widely thought that alleles that influence susceptibility to common diseases, including schizophrenia, will frequently do so through effects on gene expression. As only a small proportion of the genetic variance for schizophrenia has been attributed to specific loci, this remains an unproven hypothesis. The International Schizophrenia Consortium (ISC) recently reported a substantial polygenic contribution to that disorder, and that schizophrenia risk alleles are enriched among single-nucleotide polymorphisms (SNPs) selected for marginal evidence for association (P<0.5) from genome-wide association studies (GWAS). It follows that if schizophrenia susceptibility alleles are enriched for those that affect gene expression, those marginally associated SNPs, which are also expression quantitative trait loci (eQTLs), should carry more true association signals compared with SNPs that are not marginally associated. To test this, we identified marginally associated (P<0.5) SNPs from two of the largest available schizophrenia GWAS data sets. We assigned eQTL status to those SNPs based upon an eQTL data set derived from adult human brain. Using the polygenic score method of analysis reported by the ISC, we observed and replicated the observation that higher probability cis-eQTLs predicted schizophrenia better than those with a lower probability for being a cis-eQTL. Our data support the hypothesis that alleles conferring risk of schizophrenia are enriched among those that affect gene expression. Moreover, our data show that notwithstanding the likely developmental origin of schizophrenia, studies of adult brain tissue can, in principle, allow relevant susceptibility eQTLs to be identified.

The School of Hard Talks: A telehealth parent training group for caregivers of adolescents and young adults.

AIM: A large body of evidence demonstrates the importance of the family environment in the developmental trajectory of mental illness in young people. Caregiver communication skills training represents a potential model for influencing the outcomes of adolescents and young adults struggling with emerging mental health and behavioural difficulties. The aim of the current study is to describe the development of a telehealth group training intervention for caregivers of adolescents and young adults, and to report the results of a pilot feasibility-effectiveness study that took place in 2020-2021. METHODS: The "School of Hard Talks" intervention consisted of 8 h of training in communication skills consistent with motivational interviewing techniques. All pilot study participants were assigned to receive the intervention. Outcomes of interest were family conflict, caregiver stress, caregiver self-efficacy and expressed emotion (EE). Participants were assessed three times: prior to the intervention, after the intervention and 12 weeks later. RESULTS: A total of 62 participants enrolled in the study, of whom 49 completed the intervention. Large, significant improvements were observed over time in all four domains of interest. Qualitative feedback from parents was very positive and added context to quantitative observations. CONCLUSIONS: The School of Hard Talks was a feasible and effective intervention targeting both caregiver wellbeing as well as important mechanisms of risk for youth psychopathology, namely family conflict and EE. Further research involving a larger sample and a control condition are needed to confirm these findings.

Novel loci for major depression identified by genome-wide association study of Sequenced Treatment Alternatives to Relieve Depression and meta-analysis of three studies.

We report a genome-wide association study (GWAS) of major depressive disorder (MDD) in 1221 cases from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study and 1636 screened controls. No genome-wide evidence for association was detected. We also carried out a meta-analysis of three European-ancestry MDD GWAS data sets: STAR*D, Genetics of Recurrent Early-onset Depression and the publicly available Genetic Association Information Network-MDD data set. These data sets, totaling 3957 cases and 3428 controls, were genotyped using four different platforms (Affymetrix 6.0, 5.0 and 500 K, and Perlegen). For each of 2.4 million HapMap II single-nucleotide polymorphisms (SNPs), using genotyped data where available and imputed data otherwise, single-SNP association tests were carried out in each sample with correction for ancestry-informative principal components. The strongest evidence for association in the meta-analysis was observed for intronic SNPs in ATP6V1B2 (P=6.78 x 10⁻7), SP4 (P=7.68 x 10⁻7) and GRM7 (P=1.11 x 10⁻6). Additional exploratory analyses were carried out for a narrower phenotype (recurrent MDD with onset before age 31, N=2191 cases), and separately for males and females. Several of the best findings were supported primarily by evidence from narrow cases or from either males or females. On the basis of previous biological evidence, we consider GRM7 a strong MDD candidate gene. Larger samples will be required to determine whether any common SNPs are significantly associated with MDD.

Genome-wide association study of recurrent early-onset major depressive disorder.

A genome-wide association study was carried out in 1020 case subjects with recurrent early-onset major depressive disorder (MDD) (onset before age 31) and 1636 control subjects screened to exclude lifetime MDD. Subjects were genotyped with the Affymetrix 6.0 platform. After extensive quality control procedures, 671 424 autosomal single nucleotide polymorphisms (SNPs) and 25 068 X chromosome SNPs with minor allele frequency greater than 1% were available for analysis. An additional 1 892 186 HapMap II SNPs were analyzed based on imputed genotypic data. Single-SNP logistic regression trend tests were computed, with correction for ancestry-informative principal component scores. No genome-wide significant evidence for association was observed, assuming that nominal P<5 × 10(-8) approximates a 5% genome-wide significance threshold. The strongest evidence for association was observed on chromosome 18q22.1 (rs17077540, P=1.83 × 10(-7)) in a region that has produced some evidence for linkage to bipolar-I or -II disorder in several studies, within an mRNA detected in human brain tissue (BC053410) and approximately 75 kb upstream of DSEL. Comparing these results with those of a meta-analysis of three MDD GWAS data sets reported in a companion article, we note that among the strongest signals observed in the GenRED sample, the meta-analysis provided the greatest support (although not at a genome-wide significant level) for association of MDD to SNPs within SP4, a brain-specific transcription factor. Larger samples will be required to confirm the hypothesis of association between MDD (and particularly the recurrent early-onset subtype) and common SNPs.

GWA study data mining and independent replication identify cardiomyopathy-associated 5 (CMYA5) as a risk gene for schizophrenia.

We conducted data-mining analyses using the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and molecular genetics of schizophrenia genome-wide association study supported by the genetic association information network (MGS-GAIN) schizophrenia data sets and performed bioinformatic prioritization for all the markers with P-values ≤0.05 in both data sets. In this process, we found that in the CMYA5 gene, there were two non-synonymous markers, rs3828611 and rs10043986, showing nominal significance in both the CATIE and MGS-GAIN samples. In a combined analysis of both the CATIE and MGS-GAIN samples, rs4704591 was identified as the most significant marker in the gene. Linkage disequilibrium analyses indicated that these markers were in low LD (3 828 611-rs10043986, r(2)=0.008; rs10043986-rs4704591, r(2)=0.204). In addition, CMYA5 was reported to be physically interacting with the DTNBP1 gene, a promising candidate for schizophrenia, suggesting that CMYA5 may be involved in the same biological pathway and process. On the basis of this information, we performed replication studies for these three single-nucleotide polymorphisms. The rs3828611 was found to have conflicting results in our Irish samples and was dropped out without further investigation. The other two markers were verified in 23 other independent data sets. In a meta-analysis of all 23 replication samples (family samples, 912 families with 4160 subjects; case-control samples, 11 380 cases and 15 021 controls), we found that both markers are significantly associated with schizophrenia (rs10043986, odds ratio (OR)=1.11, 95% confidence interval (CI)=1.04-1.18, P=8.2 × 10(-4) and rs4704591, OR=1.07, 95% CI=1.03-1.11, P=3.0 × 10(-4)). The results were also significant for the 22 Caucasian replication samples (rs10043986, OR=1.11, 95% CI=1.03-1.17, P=0.0026 and rs4704591, OR=1.07, 95% CI=1.02-1.11, P=0.0015). Furthermore, haplotype conditioned analyses indicated that the association signals observed at these two markers are independent. On the basis of these results, we concluded that CMYA5 is associated with schizophrenia and further investigation of the gene is warranted.

Ontogeny of methamphetamine-induced and cocaine-induced one-trial behavioral sensitization in preweanling and adolescent rats.

The ontogenetic profile of psychostimulant-induced one-trial behavioral sensitization has not been determined. The purpose of this study was to systematically assess the ontogeny of methamphetamine-induced and cocaine-induced behavioral sensitization across the preweanling and adolescent periods. To this end, rats were injected with methamphetamine, cocaine, or saline in either an activity chamber or home cage during the preweanling [postnatal day (PD) 12, PD 16, or PD 20], preadolescent (PD 24), or adolescent (PD 34) periods. One day later, rats were challenged with the same psychostimulant and locomotion was measured in an activity chamber. The results showed that methamphetamine produced one-trial locomotor sensitization on PD 13 and PD 17; whereas, cocaine-induced behavioral sensitization was only evident on PD 21. The sensitized responding of preweanling rats was not influenced by environmental context. Interestingly, preadolescent and adolescent rats did not exhibit locomotor sensitization. The latter result is generally consistent with past studies showing that rats from the middle and late adolescent periods do not exhibit cocaine-induced one-trial behavioral sensitization. The present results show that methamphetamine, as well as cocaine, can produce one-trial context-independent behavioral sensitization during early ontogeny, but sensitized responding is only apparent within a narrow developmental window.

National prevalence of oral HPV infection and related risk factors in the U.S. adult population.

This article reviews the rapidly growing evidence that oral human papilloma viruses (HPV) infection contributes to the risk of oral squamous cell carcinoma. It also reports the first nationally representative estimates of oral HPV prevalence in the United States adult population. An estimated 7.3% (95% CI: 6.0, 8.9) of the U.S. population had one or more oral HPV types detected in oral rinse; 3.1% (95%CI: 2.4, 3.9) of the U.S. population had one or more oncogenic HPV types. A substantial excess risk of HPV infection in men is not explained by education, smoking, age of sexual debut, or number of lifetime sex partners. Based on the published finding from a case-control study, where there was an odds ratio of 2.6 (95% CI: 1.5, 4.2) for the association of head and neck cancer oncogenic oral HPV infection, the estimated population attributable risk for head and neck cancer in the U.S. population was 4.7%. In other words, there would be a 4.7% reduction in incidence rate of head and neck cancer in the United States if oncogenic HPV infection could be prevented. The results also provide population data that help evaluate the likely public health benefits of prophylactic vaccination against oral HPV acquisition.

Effects of repeated treatment with the 5-HT1A and 5-HT1B agonists (R)-( +)-8-hydroxy-DPAT and CP-94253 on the locomotor activity and axillary temperatures of preweanling rats: evidence of tolerance and behavioral sensitization.

RATIONALE: Drugs that stimulate 5-HT1A/1B receptors produce both tolerance and behavioral sensitization in adult rats and mice, yet it is unknown whether the same types of plasticity are evident during earlier ontogenetic periods. OBJECTIVE: The purpose of this study was to determine whether repeated treatment with selective 5-HT1A and/or 5-HT1B agonists cause tolerance and/or sensitization in preweanling rats. METHODS: In Experiments 1 and 2, male and female preweanling rats were given a single pretreatment injection of saline, the 5-HT1A agonist (R)-( +)-8-hydroxy-DPAT (8-OH-DPAT), or the 5-HT1B agonist CP-94253 on PD 20. After 48 h, rats received a challenge injection of 8-OH-DPAT or CP-94253, respectively. In Experiment 3, rats were pretreated with saline or DPAT + CP on PD 20 and challenged with the same drug cocktail on PD 22. In Experiment 4, the tolerance- or sensitization-inducing properties of 8-OH-DPAT, CP-94253, or DPAT + CP were tested after a 4-day pretreatment regimen on PD 17-20. RESULTS: On the first pretreatment day, 8-OH-DPAT, CP-94253, and DPAT + CP increased locomotion and caused hypothermia. Repeated treatment with 8-OH-DPAT (2 or 8 mg/kg) or DPAT + CP caused locomotor sensitization in preweanling rats. In contrast, tolerance to the hypothermic effects of 8-OH-DPAT (8 mg/kg), CP-94253 (5-20 mg/kg), or DPAT + CP was evident after repeated drug treatment. CONCLUSIONS: During the preweanling period, a single injection of a selective 5-HT1A or 5-HT1B agonist is capable of producing drug-induced plasticity. A pretreatment administration of 8-OH-DPAT causes both tolerance (hypothermia) and behavioral sensitization (locomotor activity) in preweanling rats, whereas repeated CP-94253 treatment results in tolerance.

Changes in community providers' screening behaviours, referral practices, and clinical confidence following participation in an early psychosis educational campaign.

AIM: Successful delivery of care to individuals with early psychosis depends on the ability of community providers to identify and refer appropriate candidates for services. Although specialty centres commonly rely upon education and outreach campaigns to building bridges with community providers, few studies have examined the effectiveness of these campaigns or the mechanisms by which they may achieve their intended effects. METHODS: We surveyed community clinicians (N = 39) about their screening behaviours, referral practices, and confidence in managing early psychosis just before and 3-6 months after attending an educational event designed to promote recognition and quality treatment of early psychosis. RESULTS: Three to six months following attendance, providers reported screening a greater proportion of clients for early psychosis, referring a greater number of clients to specialty services, and feeling more confident in their ability to respond to clients with early psychosis. Increases in confidence following attendance were associated with corresponding increases in screening behaviour. CONCLUSIONS: The results suggest that outreach campaigns designed to enhance community providers' knowledge about early psychosis assessment and resources may be effective in promoting screening, referrals, and confidence in managing psychosis. Gains in provider confidence may contribute to increases in screening. Given the lack of control group and relatively short follow-up period, more research is needed to determine the effects of early psychosis educational events and the mechanisms by which they may promote successful treatment delivery for young people in need.

Effects of the serotonin 5-HT1B receptor agonist CP 94253 on the locomotor activity and body temperature of preweanling and adult male and female rats.

Serotonin 5-HT1A receptor agonists increase locomotor activity of both preweanling and adult rodents. The part played by the 5-HT1B receptor in locomotion is less certain, with preliminary evidence suggesting that the actions of 5-HT1B receptor agonists are not uniform across ontogeny. To more fully examine the role of 5-HT1B receptors, locomotor activity and axillary temperatures of preweanling and adult male and female rats was assessed. In the first experiment, adult (PD 70) and preweanling (PD 10 and PD 15) male and female rats were injected with the 5-HT1B agonist CP 94253 (2.5-10 mg/kg) immediately before locomotor activity testing and 60 min before axillary temperatures were recorded. In the second experiment, specificity of drug action was determined in PD 10 rats by administering saline, WAY 100635 (a 5-HT1A antagonist), or GR 127935 (a 5-HT1B antagonist) 30 min before CP 94253 (10 mg/kg) treatment. CP 94253 significantly increased the locomotor activity of preweanling rats on PD 10, an effect that was fully attenuated by GR 127935. Conversely, CP 94253 significantly decreased the locomotor activity of male and female adult rats, while CP 94253 did not affect the locomotor activity of PD 15 rats. Regardless of age, CP 94253 (2.5-10 mg/kg) significantly reduced the axillary temperatures of preweanling and adult rats. When considered together, these results show that 5-HT1B receptor stimulation activates motor circuits in PD 10 rats; whereas, 5-HT1B receptor agonism reduces the overall locomotor activity of adult rats, perhaps by blunting exploratory tendencies.

Postnatal manganese exposure alters the expression of D2L and D2S receptor isoforms: relationship to PKA activity and Akt levels.

Postnatal manganese chloride (Mn) exposure causes persistent changes in presynaptic dopamine (DA) functioning (e.g., Mn reduces DA transporter levels and DA uptake), but evidence that Mn affects postsynaptic DA receptors and their associated second messenger systems is equivocal. Therefore, a goal of the present study was to determine whether exposing rats to Mn on postnatal days (PD) 1-21 would cause long-term alterations in D2 long (D2L) and D2 short (D2S) receptors that were detectible in adulthood (i.e., on PD 90). Signaling systems associated with D2 receptors were also assessed. Specifically, we measured protein kinase A (PKA) activity in the dorsal striatum and prefrontal cortex (PFC), whereas immunoblotting was used to quantify phosphorylated Akt (p-Akt) and phosphorylated ERK. Results showed that early Mn exposure caused a persistent elevation of D2L and D2S protein expression in the dorsal striatum, as well as an increase in the number of D2 binding sites. Conversely, Mn reduced D2 specific binding in the PFC on PD 90. PKA activity of Mn-treated rats was enhanced in both the dorsal striatum and PFC, whereas p-Akt levels were elevated in the dorsal striatum. When considered together, these results suggest that postnatal Mn exposure either directly or indirectly alters the functioning of postsynaptic DA receptors. One possibility is that early Mn exposure depresses presynaptic dopaminergic functioning and reduces DA levels, thereby causing an up-regulation of D2 receptors and a dysregulation of DA-associated signaling pathways. An alternative explanation is that early Mn exposure affects D2 receptors and PKA/p-Akt levels via independent mechanisms.