Lower Lip Retraction Research Articles

Soft-tissue profile changes in adult patients treated with premolar extractions

The objective of this study was to identify the soft-tissue profile changes and the potential pretreatment cephalometric parameters that clinicians could use to predict the lip response after premolar extraction treatment in adult patients. Pretreatment and posttreatment lateral cephalograms of 75 white patients treated with premolar extractions were analyzed. The following initial cephalometric measurements were recorded: upper and lower lip to E-plane, vermilion thickness, lip length, maxillary and mandibular incisor inclination, and mentolabial and nasolabial angle. Pretreatment and posttreatment radiographs were superimposed using the Björk structural method to record lip retraction and incisor/lip retraction ratio. Pearson correlation and Kruskal-Wallis tests were used to compare lip retraction and incisor/lip retraction ratio with the cephalometric variables. The sample was divided according to different extraction patterns. The mean upper and lower lip retraction values were 1.4 mm and 1.7 mm, respectively. Vermilion thickness showed a negative and statistically significant correlation (P<0.05) with lip retraction and incisor/lip retraction ratio. In addition, the mean incisor/lip retraction ratio was 61% and 98% for the upper and lower thin lip, respectively, whereas the mean incisor/lip retraction ratio was 17% and 44% for the upper and lower thick lip, respectively. The comparison among extraction patterns did not highlight any noticeable difference. The choice of a specific extraction pattern did not impact lip response. The vermilion thickness was the key factor influencing lip retraction: an increase in this parameter was related to a decrease in lip retraction and vice versa.

Cannabidiol exhibits anxiolytic-like effects and antipsychotic-like effects in mice models

Cannabidiol (CBD), a non-psychoactive compound derived from the cannabis plant, has been confirmed to induce anxiolytic-like and antipsychotic-like effects. However, the exact mechanisms remain unclear. This study substantiated CBD's interaction with the 5-HT1A receptor (5-HT1AR) in vitro (CHO cells expressing human 5-HT1AR) and in vivo (rat lower lip retraction test, LLR test). We then assessed the impact of CBD in mice using the stress-induced hyperthermia (SIH) model and the phencyclidine (PCP)-induced negative symptoms of schizophrenia model, respectively. Concurrently, we investigated whether WAY-100635, a typical 5-HT1AR antagonist, could attenuate these effects. Furthermore, the neurotransmitter changes through high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) were studied. Results revealed that CBD exhibits selective 5-HT1AR agonists-mediated effects in the rat lower lip retraction test, aligning with the robust agonistic (EC50 = 1.75 μM) profile observed in CHO cells. CBD at 3 mg/kg significantly reduced SIH (ΔT), a response that WAY-100635 abolished. Chronic administration of CBD at 100 mg/kg mitigated the increase in PCP-induced immobility time in the forced swim test (FST) and tail suspension test (TST). Moreover, it induced significant alterations in gamma-aminobutyric acid (GABA) and norepinephrine (NE) levels within the hippocampus (HPC). Thus, we concluded that the 5-HT1AR mediates CBD's anxiolytic-like effects. Additionally, CBD's effects on the negative symptoms of schizophrenia may be linked to changes in GABA and NE levels in the hippocampus. These findings offer novel insights for advancing the exploration of CBD's anxiolytic-like and antipsychotic-like effects.

Changes in Soft Tissue Variable of Lips Following Retraction of Anterioir Teeth- A Cephalometric Study.

The purpose of this study was to assess the short-term perioral soft tissue variations of the lips before and after treatment cases in 15 patients with bi-maxillary protrusion using treated lateral cephalograms who had already achieved active growth. Fifteen pre-treatment and post-treatment lateral cephalometric radiographs of 18-25-year-old individuals with bimaxillary protrusion treated with all four 1st premolar extractions were accessed from the records. From the reference planes and landmarks, 13 horizontal, 10 vertical, and 2 angular measurements were noted. Statistical comparisons between pre-treatment and post-treatment measurements were measured by a paired t-test to assess the importance of the mean variations at the predetermined significance level. Pearson's correlation coefficient (R) was utilized to assess the strength and significance of the linear relationship between the mean differences for paired (dependent and independent) variables. Pearson's correlation exhibited a noteworthy positive association between the horizontal changes in upper lip position and the horizontal changes of the upper incisor tip point (H-tU1) (R = 0.748), the upper incisor cervical point (H-cU1) (R = 0.707), the lower incisor tip point (H-tL1) (R = 0.839), and the lower incisor cervical point (H-cL1) (R = 0.767). This indicated that upper lip changes are the aftermath of the retraction of the upper and lower incisors in class I bi-maxillary protrusion malocclusion. Thick upper lips showed more retraction of the upper lip in correlation with retraction of the incisors as compared with thin lips. The lower incisor cervical point displayed the strongest association with lower lip retraction.

Eating a High Fat Diet Enhances Sensitivity of Rats to 5‐HT1A Receptor‐Mediated Behavioral Effects of Serotonergic Drugs

Diet (e.g., type and amount of food consumed) has been shown to impact drug sensitivity, in ways that might be relevant for the therapeutic effects and side effects of medications. For example, previous studies have demonstrated that rats eating a high fat diet are more sensitive to some of the effects of dopaminergic drugs. Considerably less is known about how eating a high fat diet might impact sensitivity to drugs that act on serotonin (5‐HT) systems, many of which might be beneficial for the treatment of obesity, since they can decrease feeding. Drugs with agonist effects at 5‐HT receptors can produce a collection of adverse effects, known as 5‐HT syndrome. Animal models of 5‐HT syndrome include lower lip retraction, flat body posture, penile erections, and forepaw treading. To test the hypothesis that eating a high fat diet enhances sensitivity of rats to 5‐HT syndrome, male (n=16) and female (n=16) rats eating high fat (60% kcal from fat) or standard (17% kcal from fat) laboratory chow were tested once weekly with cumulative doses of 5‐HT receptor agonists, including 8‐OH‐DPAT (0.01‐1.0 mg/kg, s.c.), lorcaserin (1.0‐32.0 mg/kg, i.p.) and WAY 163909 (1.0‐32.0 mg/kg, i.p.). Agonists were also studied in combination with antagonists selective for 5‐HT1A (WAY 100635; 0.178 mg/kg, s.c.), or 5‐HT2C (SB 242084; 1.0 mg/kg; i.p.) receptors. Food consumption and body weight were measured throughout the study. Results were analyzed using either two‐way or three‐way mixed model ANOVAs with diet and dose, diet and day, or diet, sex, and drug as factors, and Bonferroni post hoc comparisons where appropriate. Effects mediated by the 5‐HT2C receptor (e.g, penile erections as well as decreased food consumption), were only observed following injections of lorcaserin and WAY 163909 (but not 8‐OH‐DPAT), and were not different between rats eating standard or high fat chow. Regarding 5‐HT1A receptor‐mediated effects, all three 5‐HT receptor agonists induced forepaw treading in rats; however, flat body posture and lower lip retraction were only induced by 8‐OH‐DPAT. Rats eating high fat chow were more sensitive to forepaw treading, regardless of which drug induced this behavior; however, WAY 163909 induced less forepaw treading as compared to the other two drugs, regardless of diet. Rats eating high fat chow were also more sensitive to 8‐OH‐DPAT‐induced lower lip retraction, but not flat body posture. These results suggest that eating a high fat diet can impact sensitivity of rats to some of the effects of serotonergic drugs. Additionally, these results demonstrate that while both lorcaserin and WAY 163909 decrease feeding, WAY 163909 produces less 5‐HT1A‐mediated forepaw treading than lorcaserin, which might indicate that it will produce fewer side effects in humans as well. Finally, these results suggest that dietary history could influence sensitivity of individuals to the adverse effects of serotonergic drugs, such as 5‐HT syndrome.

Activity of Mitragyna speciosa ("Kratom") Alkaloids at Serotonin Receptors.

Kratom alkaloids have mostly been evaluated for their opioid activity but less at other targets that could contribute to their physiological effects. Here, we investigated the in vitro and in vivo activity of kratom alkaloids at serotonin receptors (5-HTRs). Paynantheine and speciogynine exhibited high affinity for 5-HT1ARs and 5-HT2BRs, unlike the principal kratom alkaloid mitragynine. Both alkaloids produced antinociceptive properties in rats via an opioid receptor-independent mechanism, and neither activated 5-HT2BRs in vitro. Paynantheine, speciogynine, and mitragynine induced lower lip retraction and antinociception in rats, effects blocked by a selective 5-HT1AR antagonist. In vitro functional assays revealed that the in vivo 5-HT1AR agonistic effects may be due to the metabolites 9-O-desmethylspeciogynine and 9-O-desmethylpaynantheine and not the parent compounds. Both metabolites did not activate 5-HT2BR, suggesting low inherent risk of causing valvulopathy. The 5-HT1AR agonism by kratom alkaloids may contribute to the mood-enhancing effects associated with kratom use.

Eating a High Fat Diet Enhances Sensitivity of Rats to Serotonin Syndrome

Drugs that act on serotonin (5-HT) systems are important for the treatment of many conditions, including anxiety, depression, and obesity. One potential adverse effect of these drugs is the development of 5-HT syndrome. Animal models of 5-HT syndrome include lower lip retraction, flat body posture, and forepaw treading. Diet (e.g., type and amount of food consumed) has been shown to directly impact sensitivity of rats to 5-HT syndrome. For example, eating high fat chow increases sensitivity of rats to 5-HT1A receptor agonist 8-OH-DPAT-induced lower lip retraction; however, it is not known if eating high fat chow also impacts sensitivity of rats to other 5-HT syndrome behaviors, other 5-HT receptor agonists (e.g., 5-HT2C receptor agonists), or if these effects are different among females as compared to males. To test the hypothesis that eating high fat chow enhances the sensitivity of rats to 5-HT syndrome, male and female rats eating high fat (60% kcal from fat) or standard (17% kcal from fat) chow were tested once weekly with cumulative doses of 8-OH-DPAT (0.01-1.0 mg/kg, s.c.), and two different 5-HT2C receptor agonists (lorcaserin [1.0-32.0 mg/kg, i.p.], and WAY 163909 [1.0-32.0 mg/kg, i.p.]). Both lorcaserin and WAY 163909 induced forepaw treading in male and female rats. After 5 weeks, 3-way partially repeated measures ANOVAs and Bonferroni's post hoc multiple comparisons tests revealed that forepaw treading induced by both drugs was enhanced among rats eating high fat chow. Eating high fat chow enhanced sensitivity of male rats to lorcaserin-induced forepaw treading to a greater extent than in females. However, eating high fat chow enhanced sensitivity of females to WAY 163909-induced forepaw treading to a greater extent than in males. 8-OH-DPAT-induced lower lip retraction, flat body posture, and forepaw treading in male and female rats. 8-OH-DPAT induced more lower lip retraction among male rats than female rats, and more lower lip retraction among rats eating high fat chow (in both sexes) than rats eating standard chow. Additionally, 8-OH-DPAT induced more flat body posture among male rats than female rats. These results suggest that sex and dietary history (e.g., patients diagnosed with obesity) could influence sensitivity to therapeutic and adverse effects of serotonergic drugs.

What is the best soft-tissue reference plane to quantify lip change in bimaxillary protrusion cases? A retrospective cohort study

Objectives: The objective of the study was to evaluate the validity of five soft-tissue profile planes to actual horizontal lower lip changes following treatment of severe bimaxillary protrusion patients with vertical maxillary excess using extra-alveolar miniscrews. The null hypothesis was no differences in the incremental changes of horizontal lower lip changes from pre-treatment to post-treatment of the five methods compared to actual changes. Materials and Methods: Seventy adults were treated orthodontically with extractions for bimaxillary protrusion and “gummy” smile using extra-alveolar miniscrews. Lower lip horizontal position was assessed with pre- and post-treatment lateral cephalograms and five commonly used soft-tissue reference lines were used to measure horizontal lower lip treatment change. Results: Compared to actual therapeutic lower lip horizontal retraction (4.38 mm), soft-tissue references Ricketts’ E-line (3.89 mm) and Steiner’s S-line (3.88 mm) demonstrated no statistical difference (P &gt; 0.05) from actual change. The five profile plane measures showed moderately high to high intercorrelations among themselves, but none of them were related to the actual amount of anteroposterior lip change that occurred. None of the five soft-tissue measurements showed a statistically significant difference (P &gt; 0.05) between subgroups with least and greatest lower lip retraction. Conclusion: Under conditions of maximum lower lip retraction, Rickett’s E-line and Steiner’s S-line were fair measures of horizontal lower lip change. Although actual lower lip change and soft-tissue reference plane changes were correlated poorly, intercorrelations among the five soft-tissue references planes were moderately high. None of the five soft-tissue measurements was able to discriminate (P &gt; 0.05) between treatments with least and greatest lower lip retraction. It may be concluded that Rickett’s E-line and Steiner’s S-line soft-tissue profile references are valid when there is considerable therapeutic retraction (4+ mm) of the lower lip.

Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT1A Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile.

Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT1A receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and β-arrestin recruitment. Compounds 44 and 56 (2-methylaminophenoxyethyl and 2-(1H-indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential “signaling fingerprints” that translated into distinct in vivo profiles. In vitro, 44 showed biased agonism for ERK1/2 phosphorylation and, in vivo, it preferentially exerted an antidepressant-like effect in the Porsolt forced swimming test in rats. In contrast, compound 56 exhibited a first-in-class profile: it preferentially and potently activated β-arrestin recruitment in vitro and potently elicited lower lip retraction in vivo, a component of “serotonergic syndrome”. Both compounds showed promising developability properties. The presented 5-HT1A receptor-biased agonists, preferentially targeting various signaling pathways, have the potential to become drug candidates for distinct central nervous system pathologies and possessing accentuated therapeutic activity and reduced side effects.

Eating a high fat diet enhances sensitivity of rats to serotonin syndrome

Eating a high fat diet can lead to obesity, type 2 diabetes, and dysfunction to neurotransmitter systems. For example, eating high fat chow enhances sensitivity of rats to unconditioned behavioral effects (e.g., lower lip retraction) induced by 8‐OH‐DPAT, a serotonin (5‐HT)1A receptor agonist. It is not known if eating high fat chow also impacts sensitivity of rats to other types of 5‐HT receptor agonists, or other behaviors induced by these drugs, collectively referred to as animal models of 5‐HT syndrome (e.g., flat body posture and forepaw treading). Recently, the FDA approved lorcaserin, a 5‐HT2C receptor agonist for the treatment of obesity. Lorcaserin induces some 5‐HT syndrome behaviors in rats including forepaw treading; however, it is not known if diet impacts sensitivity of rats to these lorcaserin‐induced behaviors. Further, previous research suggests that females might be more sensitive to the effects of 5‐HT receptor agonists, and to the effects of eating a high fat diet. To test the hypothesis that eating high fat chow will enhance the sensitivity of rats to the behavioral effects of 5‐HT2C and 5‐HT1A receptor agonists, 16 male and 16 female rats eating high fat chow (60% kcal from fat) or standard chow (17% kcal from fat) were tested once weekly with cumulative doses of 8‐OH‐DPAT (0.01–1.0 mg/kg, s.c.), WAY 163909 (1.0–32.0 mg/kg, i.p.), or lorcaserin (1.0–32.0 mg/kg, i.p.). 8‐OH‐DPAT induced lower lip retraction, flat body posture, and forepaw treading, while WAY 163909 and lorcaserin only induced forepaw treading. Rats eating high fat chow were more sensitive to lower lip retraction (induced by 8‐OH‐DPAT) and forepaw treading (induced by all three serotonergic drugs), as compared to male rats eating standard chow. These experiments are still ongoing; however, preliminary data and previous reports suggest that female rats will be more sensitive than males to diet‐induced enhancements in 5‐HT syndrome behaviors. Future directions will use selective 5‐HT receptor antagonists to examine the specific receptor subtypes mediating these behavioral effects in male and female rats eating different diets.Support or Funding InformationThe authors have no conflicts to disclose. N.M.B. was awarded summer funding through the American Society for Pharmacology and Experimental Therapeutics (ASPET) Summer Undergraduate Research Fellowship (SURF). N.M.B is also supported by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) under R25GM069621.

Lower facial height and soft tissue changes in bimaxillary protrusion cases

Background: Bimaxillary protrusion is frequently treated by extracting the four first premolars and retracting the incisor with maximum anchorage. This treatment may result in soft tissue changes, particularly in lip retraction, lip thickness, upper lip angle and nasolabial angle. However, the changes in facial height after orthodontic treatment often trigger controversies. Objectives: To determine the effects of incisor retraction on lower facial height and soft tissue changes in Class I malocclusion with bimaxillary protrusion treated by the extraction of the four first premolars. Methods: Pre-treatment and post-treatment lateral cephalometric radiograph samples of 25 patients treated with the standard Edgewise fixed appliance were collected. Each sample was traced and a reference line perpendicular to Sella-Nasion minus 7o through the true vertical line (TVL) was established. Arnett analysis was applied to calculate incisor retraction, lower facial height, lip retraction, lip thickness, upper lip angle and nasolabial angle changes. The results of the measurements were statistically analyzed using a paired T-test and Pearson correlation. Results: No statistically significant changes were found between upper incisor retraction and lower facial height ( p > 0.05) and upper lip thickness ( p > 0.05). The same lower incisor retraction occurred with lower facial height ( p > 0.05) and lower lip thickness ( p > 0.05). Significant positive correlation was found between upper incisor retraction and the changes in the upper lip retraction (r = 0.959, p < 0.05), upper lip angle (r = 0.775, p < 0.05) and nasolabial angle (r = 0.647, p < 0.05), while the lower incisor retraction had a positive correlation with the changes in lower lip retraction (r = 0.902, p < 0.05). Conclusion: The extraction of the four first premolars followed by the retraction of the incisor can cause changes in lip retraction, upper lip angle and nasolabial angle but not in lower facial height and lip thickness.

Cannabinoid-induced lower lip retraction in rats.

Lower lip retraction (LLR) in rats has been described as a distinctive effect of 5-HT1A agonists. In the course of evaluating behavioral effects of cannabinoid agonists in rats, LLR effects were evident following injection of several cannabinoid agonists. To pharmacologically characterize cannabinoid-induced LLR in rats. Lower lip retraction was scored using a 3-point scale for up to 6h after injection of the cannabinoid agonists Δ9-tetrahydrocannabinol (Δ9-THC, 1-10mg/kg), AM7499 (0.01-1.0mg/kg), or AM2389 (0.003-0.1mg/kg), or, for comparison, the 5-HT1A agonist 8-OH-DPAT (0.01-0.3mg/kg). Next, antagonist effects of rimonabant (1-10mg/kg) and WAY100635 (0.3mg/kg) on LLR produced by cannabinoid or 5-HT1A agonists were evaluated. Lastly, effects of 8-OH-DPAT were determined following pretreatment with AM2389 (0.003-0.01mg/kg) or Δ9-THC (1mg/kg). All three cannabinoid agonists produced LLR. Effects of AM2389 were attenuated by both rimonabant and WAY100635 whereas effects of 8-OH-DPAT were antagonized by WAY 100635 but not by rimonabant. Pretreatment with 1mg/kg Δ9-THC or 0.01mg/kgAM2389 shifted the 8-OH-DPAT dose-effect function for LLR to the left and isobolographic analysis of the data indicates CB1 and 5-HT1A interactions can be supraadditive. Cannabinoid agonists produce LLR in rats, an effect heretofore ascribed only to activity at 5-HT1A receptors, via CB1 receptor-mediated actions. Co-administration of a cannabinoid agonist and the 5-HT1A agonist 8-OH-DPAT results in a synergistic effect on LLR.

Soft tissue changes following extraction vs. nonextraction orthodontic fixed appliance treatment: a systematic review and meta‐analysis

The aim of this systematic review was to assess the effect of systematic extraction protocols during orthodontic fixed appliance treatment on the soft tissue profile of human patients. Nine databases were searched until December 2016 for controlled clinical studies including premolar extraction or nonextraction treatment. After elimination of duplicate studies, data extraction, and risk-of-bias assessment according to the Cochrane guidelines, random-effects meta-analyses of mean differences (MD) or standardized mean differences (SMD) and their 95% CIs were performed, followed by subgroup, meta-regression, and sensitivity analyses. Extraction treatment was associated with increased lower lip retraction (24 studies; 1,456 patients; MD = 1.96 mm), upper lip retraction (21 studies; 1,149 patients; MD = 1.26 mm), nasolabial angle (21 studies; 1,089 patients; MD = 4.21°), soft-tissue profile convexity (six studies; 408 patients; MD = 1.24°), and profile pleasantness (three studies; 249 patients; SMD = 0.41). Patient age, extraction protocol, and amount of upper incisor retraction during treatment were significantly associated with the observed extraction effects, while the quality of evidence was very low in all cases due to risk of bias, baseline confounding, inconsistency, and imprecision. Although tooth extractions seem to affect patient profile, existing studies are heterogenous and no consistent predictions of profile response can be made.

Evaluation of Treatment Outcomes of En masse Retraction with Temporary Skeletal Anchorage Devices in Comparison with Two-step Retraction with Conventional Anchorage in Patients with Dentoalveolar Protrusion: A Systematic Review and Meta-analysis.

Objective:The main objective is to evaluate the effectiveness of en masse retraction with temporary skeletal anchorage devices (TSADs) versus two-step retraction with conventional anchorage (CA) in terms of the skeletal, dental, and soft-tissue variables, as well as the duration of retraction or overall orthodontic treatment.Materials and Methods:An electronic search of PubMed and nine other major databases for prospective, randomized controlled trials (RCTs) and clinical controlled trials (CCTs) was carried out between January 1990 and April 2018. The bibliography in each identified article was checked out. In addition, manual searching was performed in the same time frame in five major orthodontic journals. Adult patients undergoing fixed orthodontic treatment with extraction of maxillary premolars followed by an en masse retraction in the experimental group and two-step retraction of upper anterior teeth in the control group. Methodological index for nonrandomized studies for CCTs and Cochrane's risk of bias tool for RCTs were applied.Results:Four articles (two RCTs and two CCTs) were included in this review and all articles were appropriate for the quantitative synthesis. There was no significant difference between the en masse retraction and two-step retraction groups in terms of SNA, SNB, ANB, and MP-SN angles. Using TSADs gave significantly better results in terms of posterior anchorage and incisors inclination, and greater anterior teeth retraction in comparison with CA (standardized mean difference [SMD] = –3.03 mm, P < 0.001; SMD = 0.74°, P = 0.003; SMD = –0.46 mm, P = 0.03, respectively). En masse/TSAD combination caused a significantly greater increase in nasolabial angle, higher decrease in facial convexity angle, and greater lower lip retraction in comparison with two-step/CA combination (weighted mean difference = 4.73°, P = 0.007; P = 0.0435; SMD = –0.95 mm, P = 0.01, respectively).Conclusion:There is weak-to-moderate evidence that using either en masse/TSAD combination or two-step/CA combination would lead to similar skeletal improvement. There is a very weak-to-moderate evidence that using TSADs with en masse retraction would cause better posterior anchorage and incisors inclination, and greater anterior teeth retraction than using CA with two-step retraction. There is weak-to-moderate evidence that using en masse/TSAD combination would lead to a better improvement in the facial profile. According to the quality of evidence, we confirm the need for more well-conducted RCTs in the en masse retraction field.

Activity of Serotonin 5-HT1A Receptor Biased Agonists in Rat: Anxiolytic and Antidepressant-like properties.

Although serotonin 5-HT1A receptors constitute attractive therapeutic targets, there is a lack of potential clinical candidates that have a high degree of selectivity and full agonist efficacy. Recently, novel 5-HT1A receptor "biased agonists" F15599 (also known as NLX-101) and F13714 have been reported that exhibit distinctive properties for in vitro signaling, neurochemical, electrophysiological effects, and in brain imaging. The present study characterized their effects in rat models of anxiety (elevated plus-maze, EPM, and Vogel tests), in depressive-like behavior (forced swim test), and on the induction of the three serotonergic behaviors (forepaw treading, flat body posture, and lower lip retraction). The prototypical 5-HT1A receptor ligands (±)8-OH-DPAT and buspirone were tested as comparators. In the elevated plus-maze, F15599, F13714, and (±)8-OH-DPAT dose-dependently increased the amount and percentage of time spent in the open arms with minimal effective doses (MED) of 5 mg/kg p.o., 2.5 mg/kg p.o. and 1.25 mg/kg s.c., respectively. The effects of the three agonists were abolished by pretreatment with the selective 5-HT1A receptor antagonist, WAY100635 (0.63 mg/kg s.c.). Buspirone did not show significant activity in the EPM. In contrast, in the Vogel test only buspirone was active, significantly increasing the number of licks and shocks accepted (active dose: 1.25 mg/kg s.c.). However, WAY100635 failed to reverse the effects of buspirone in this test, suggesting that they were not 5-HT1A receptor-mediated. In the forced swim test, F15599, F13714, and (±)8-OH-DPAT were potently active, abolishing immobility (MED: 0.63 mg/kg p.o., 0.63 mg/kg p.o. and 0.16 mg/kg s.c., respectively). Buspirone was not active. In measures of serotonergic behavior, F13714 and (±)8-OH-DPAT robustly elicited all three signs of serotonergic behaviors, whereas F15599 and buspirone elicited only lower-lip retraction. Taken together, these observations highlight the distinct profiles of activity of 5-HT1A agonists and suggest that the novel biased agonist F15599 combines pronounced activity in a test of anxiety (elevated plus-maze) with potent antidepressant-like effects and low propensity to induce serotonergic behaviors. These data suggest that selective biased agonists could constitute promising pharmacotherapeutics for mood disorders.

NLX-112, a highly selective 5-HT1A receptor agonist: Effects on body temperature and plasma corticosterone levels in rats

NLX-112 (a.k.a. F13640 or befiradol), exhibits nanomolar affinity, exceptional selectivity and high agonist efficacy at 5-hydroxytryptamine 5-HT1A receptors. It possesses marked activity in a variety of animal models of depression, pain and L-DOPA-induced dyskinesia. However, its influence on translational biomarkers of central 5-HT1A receptor activation has not been previously described. Here, we report on the activity, in rats, of NLX-112 to increase plasma corticosterone levels and produce hypothermia, two responses which are also elicited by 5-HT1A receptor agonists in humans.NLX-112 elicited dose-dependent hypothermia (minimal effective dose, MED: 0.31mg/kg p.o.) and also increased plasma corticosterone both by oral and intraperitoneal routes (MED: 0.63mg/kg in both cases). The increase in corticosterone induced by NLX-112 (0.63mg/kg p.o.) was abolished by co-administration of the selective 5-HT1A receptor antagonist, WAY100635. Additionally, NLX-112 also dose-dependently induced flat body posture, forepaw treading and lower lip retraction (MEDs 0.31–0.63mg/kg p.o.).The doses of NLX-112 which induce hypothermia or corticosterone release were similar to those inducing serotonergic behaviors but greater than those reported previously in models of therapeutic-like activity (range 0.04 to 0.16mg/kg). Overall, the present study provides information for clinical dose estimations of NLX-112 and suggests that therapeutic effects may occur at doses below those at which biomarker responses are observed.

Unpredictability of soft tissue changes after camouflage treatment of Class II division 1 malocclusion with maximum anterior retraction using miniscrews.

To compare soft and hard tissue responses based on the degree of maxillary incisor retraction using maximum anchorage in patients with Class II division 1 malocclusion. This retrospective study sample was divided into moderate retraction (<8.0 mm; n = 28) and maximum retraction (≥8.0 mm; n = 29) groups based on the amount of maxillary incisor retraction after extraction of the maxillary and mandibular first premolars for camouflage treatment. Pre- and posttreatment lateral cephalograms were analyzed. There were 2.3 mm and 3.0 mm of upper and lower lip retraction, respectively, in the moderate group; and 4.0 mm and 5.3 mm, respectively, in the maximum group. In the moderate group, the upper lip was most influenced by posterior movement of the cervical point of the maxillary incisor (β = 0.94). The lower lip was most influenced by posterior movement of B-point (β = 0.84) and the cervical point of the mandibular incisor (β = 0.83). Prediction was difficult in the maximum group; no variable showed a significant influence on upper lip changes. The lower lip was highly influenced by posterior movement of the cervical point of the maxillary incisor (β = 0.50), but this correlation was weak in the maximum group. Posterior movement of the cervical point of the anterior teeth is necessary for increased lip retraction. However, periodic evaluation of the lip profile is needed during maximum retraction of the anterior teeth because of limitations in predicting soft tissue responses.

Synthesis and biological investigation of new equatorial (β) stereoisomers of 3-aminotropane arylamides with atypical antipsychotic profile

A series of novel 3β-aminotropane derivatives containing a 2-naphthalene or a 2-quinoline moiety was synthesised and evaluated for their affinity for 5-HT1A, 5-HT2A and D2 receptors. Their affinity for the receptors was in the nanomolar to micromolar range. p-Substitution (6c, 6f, 6i, 6l, 6o), as well as substitution with chlorine atoms (6g, 6h, 6i), led to a significant increase in binding affinity for D2 receptors with compounds 6f (Ki=0.6nM), 6c and 6i (Ki=0.4nM), having the highest binding affinities. m-Substituted derivatives were the most promising ligands in terms of 5-HT2A receptor binding affinity whereas 2-quinoline derivatives (10a, 10b) displayed the highest affinity for 5-HT1AR and were the most selective ligands with Ki=62.7nM and Ki=30.5nM, respectively. Finally, the selected ligands 6b, 6d, 6e, 6g, 6h, 6k, 6n and 6o, with triple binding activity for the D2, 5-HT1A and 5-HT2A receptors, were subjected to in vivo tests, such as those for induced hypothermia, climbing behaviour and the head twitch response, in order to determine their pharmacological profile. The tested ligands presented neither agonist nor antagonist properties for the 5-HT1A receptors in the induced hypothermia and lower lip retraction (LLR) tests. All tested compounds displayed antagonistic activity against 5-HT2A, with 6n and 6o being the most active. Four (6b, 6k, 6n and 6o) out of eight tested compounds could be classified as D2 antagonists. Additionally, evaluation of metabolic stability was performed for selected ligands, and introduction of halogen atoms into the benzene ring of 6h, 6k, 6n and 6o improved their metabolic stability. The project resulted in the selection of the lead compounds 6n and 6o, which had antipsychotic profiles, combining dopamine D2-receptor and 5-HT2A antagonism and metabolic stability.

Concentration-Dependent Dual Mode of Zn Action at Serotonin 5-HT1A Receptors: In Vitro and In Vivo Studies.

Recent data has indicated that Zn can modulate serotonergic function through the 5-HT1A receptor (5-HT1AR); however, the exact mechanisms are unknown. In the present studies, radioligand binding assays and behavioural approaches were used to characterize the pharmacological profile of Zn at 5-HT1ARs in more detail. The influence of Zn on agonist binding to 5-HT1ARs stably expressed in HEK293 cells was investigated by in vitro radioligand binding methods using the agonist [3H]-8-OH-DPAT. The in vivo effects of Zn were compared with those of 8-OH-DPAT in hypothermia, lower lip retraction (LLR), 5-HT behavioural syndrome and the forced swim (FST) tests. In the in vitro studies, biphasic effects, which involved allosteric potentiation of agonist binding at sub-micromolar Zn concentrations and inhibition at sub-millimolar Zn concentrations, were found. The in vivo studies showed that Zn did not induce LLR or elements of 5-HT behavioural syndrome but blocked such effects induced by 8-OH-DPAT. Zn decreased body temperature in rats and mice; however, Zn failed to induce hypothermia in the 5-HT1A autoreceptor knockout mice. In the FST, Zn potentiated the effect of 8-OH-DPAT. However, in the FST performed with the 5-HT1A autoreceptor knockout mice, the anti-immobility effect of Zn was partially blocked. Both the binding and behavioural studies suggest a concentration-dependent dual mechanism of Zn action at 5-HT1ARs, with potentiation at low dose and inhibition at high dose. Moreover, the in vivo studies indicate that Zn can modulate both presynaptic and postsynaptic 5-HT1ARs; however, Zn’s effects at presynaptic receptors seem to be more potent.

Maternal Protein Deficiency Causes Region‐Specific and Sex‐Dependent Changes in 5‐HT1A Receptor Function in Adult Offspring

Protein insufficiency, rather than caloric restriction, during pregnancy leads to abnormalities in emotion and cognition in adult offspring. However, the underlying neural mechanisms are unclear. In rats, we examined serotonin1A (5‐HT1A) receptor function in adult offspring of mothers that were free‐fed standard (20%) or low (10%) protein isocaloric chow during pregnancy. Importantly, the maternal low protein diet did not affect the body weight of mothers or offspring. At P110‐117, 5‐HT1A receptor agonist DPAT (0.01‐1mg/kg, ip) induced stereotypic behaviors were measured. The potency of DPAT to induce flat body posture and lower lip retraction was reduced in female offspring, as indicated by rightward shifts (~3 fold) in the dose‐response curves. In littermates, we used quantitative autoradiography to measure the capacity of 5‐HT1A receptors to activate G proteins. The maternal low protein diet resulted in a 50% decrease in DPAT (1μM)‐stimulated [35S]GTPΥS binding in hippocampus of female offspring, with no change in frontal cortex, suggesting a region‐specific down‐regulation of postsynaptic 5‐HT1A receptor function. DPAT (1μM)‐stimulated [35S]GTPΥS binding was increased (54%) in dorsal raphe of female offspring, suggesting enhanced inhibition of serotonin neuronal activity. By contrast, no significant change in 5‐HT1A receptor function was observed in male offspring. Both in vivo and ex vivo data indicate that maternal protein deficiency causes profound region‐specific and sex‐dependent changes in 5‐HT1A receptor function, which may underlie abnormal emotion and cognition in adult offspring. Supported by Morrison Trust

Three-dimensional soft-tissue and hard-tissue changes in the treatment of bimaxillary protrusion

Facial convexity related to bimaxillary protrusion is prevalent in many populations. Underlyingskeletal protrusion combined with increased dentoalveolar protrusion contributes to facial muscle imbalance and lip incompetence, which is undesirable for many patients. In this study, we evaluated the relationship between soft-tissue and hard-tissue changes in an orthodontically treated Asian population. Twenty-four consecutive adult Asian patients (mean age, 24 years), diagnosed with severe bimaxillary dentoalveolar protrusion, were evaluated using pretreatment and posttreatment cone-beam computed tomography. The patients were treated with 4 first premolar extractions followed by anterior retraction with either skeletal or intraoral anchorage. Serial cone-beam computed tomography radiographs were registered on the entire cranial base and fossa. Soft-tissue and hard-tissue changes were determined through landmark displacement and color mapping. Upper lip retraction was concentrated between the nasolabial folds and commissures. Lower lip retraction was accompanied by significant redistribution of soft tissues at pogonion. Soft-tissue changes correlated well with regional facial muscle activity. Significant retractions (2-4 mm) of the soft tissues occurred beyond the midsagittal region. Use of skeletal anchorage resulted in 1.5 mm greater lower lip retraction than intraoral anchorage, with greater retraction of the maxillary and mandibular incisor root apices. Profound soft-tissue changes accompanied retraction of the anterior dentition with both treatment modalities.