Perception of discrepancy in the upper midline position in conjunction with the gingival display according to various occupations in Iran.

Objective: This study evaluated the influence of various gingival displays on the esthetic perception in the presence of upper dental midline discrepancy. Methods: A smiling image of a male subject was altered digitally to produce five image series: normal smile (series A), decreased tooth show (series B), increased gingival show (series C), maxillary cant (series D), and asymmetric upper lip elevation (series E). In each image series, the midline was deviated to the right and left incrementally. A total of 210 raters (four professional groups and laypersons, n = 42 in each group) determined the midline deviation threshold and the attractiveness of midline position in each series. Results: The right and left thresholds were statistically similar for the symmetrical series (A, B, and C), while for series D, the right threshold was significantly lower. In most rater groups, the mean threshold order was: B > A > E > C > D. In all the series, the raters selected the coincident midline as the most attractive series except for series D, for which 1-2-mm deviations to the left were selected as the most attractive by almost all the groups. Conclusions: It is crucial to establish the coincident midline position in a symmetrical smile, especially when a gummy smile exists. In the asymmetrical gingival show, a coincident midline might not be the most esthetic midline position.

Novel Fat Taste Receptor Agonists Curtail Progressive Weight Gain in Obese Male Mice.

BACKGROUND & AIMS: The spontaneous preference for dietary lipids is principally regulated by 2 lingual fat taste receptors, CD36 and GPR120. Obese animals and most of human subjects exhibit low orosensory perception of dietary fat because of malfunctioning of these taste receptors. Our aim was to target the 2 fat taste receptors by newly synthesized high affinity fatty acid agonists to decrease fat-rich food intake and obesity. METHODS: We synthesized 2 fat taste receptor agonists (FTA), NKS-3 (CD36 agonist) and NKS-5 (CD36 and GPR120 agonist). We determined their molecular dynamic interactions with fat taste receptors and the effect on Ca2+ signaling in mouse and human taste bud cells (TBC). In C57Bl/6 male mice, we assessed their gustatory perception and effects of their lingual application on activation of tongue-gut loop. We elucidated their effects on obesity and its related parameters in male mice fed a high-fat diet. RESULTS: The two FTA, NKS-3 and NKS-5, triggered higher Ca2+ signaling than a dietary long-chain fatty acid in human and mouse TBC. Mice exhibited a gustatory attraction for these compounds. In conscious mice, the application of FTA onto the tongue papillae induced activation of tongue-gut loop, marked by the release of pancreato-bile juice into collecting duct and cholecystokinin and peptide YY into blood stream. Daily intake of NKS-3 or NKS-5 via feeding bottles decreased food intake and progressive weight gain in obese mice but not in control mice. CONCLUSIONS: Our results show that targeting fat sensors in the tongue by novel chemical fat taste agonists might represent a new strategy to reduce obesity.

Paternal preconception exposure to chronic morphine alters respiratory pattern in response to morphine in male offspring.

The clinical use of opioids is restricted by its deleterious impacts on respiratory system. Gaining a better understanding of an individual's susceptibility to adverse opioid effects is important to recognize patients at risk. Ancestral drug addiction has been shown to be associated with alterations in drug responsiveness in the progenies. In the current study, we sought to evaluate the effects of preconception paternal morphine consumption on respiratory parameters in response to acute morphine in male offspring during adulthood, using plethysmography technique. Male Wistar rats administered 10 days of increasing doses of morphine in the period of adolescence. Thereafter, following a 30-day abstinence time, adult males copulated with naïve females. The adult male offspring were examined for breathing response to morphine. Our results indicated that sires who introduce chronic morphine during adolescence leads to increase irregularity of respiratory pattern and asynchronization between inter-breath interval (IBI) and respiratory volume (RV) time series in male offspring. These findings provide evidence that chronic morphine use by parents even before pregnancy can affect respiratory pattern and response to morphine in the offspring.

Preconception paternal morphine exposure leads to an impulsive phenotype in male rat progeny.

RATIONALE: Identifying the long-term neurocognitive implications of opioid addiction may further our understanding of the compulsive nature of this brain disorder. The aim of this study was to examine the effects of paternal adolescent opiate exposure on cognitive performance (visual attention, impulsivity, and compulsivity) in the next generation. METHODS: Male Wistar rats received escalating doses of morphine (2.5-25 mg/kg, s.c.) or saline for 10 days during adolescence (P30-39). In adulthood (P70-80), these rats were allowed to mate with drug-naive females. Male offspring from morphine- and saline-exposed sires, once in adulthood, were trained and tested in the 5-choice serial reaction time test (5-CSRTT) to evaluate their cognitive abilities under baseline, drug-free conditions as well as following acute (1, 3, 5 mg/kg morphine) and subchronic morphine (5 mg/kg morphine for 5 days) treatment. Behavioral effects of the opioid receptor antagonist naloxone were also assessed. RESULTS: Morphine-sired offspring exhibited delayed learning when the shortest stimulus duration (1 s) was introduced, i.e., when cognitive load was highest. These subjects also exhibited a reduced ability to exert inhibitory control, as reflected by increased premature and perseverative responding under drug-free baseline conditions in comparison to saline-sired rats. These impairments could not be reversed by administration of naloxone. Moreover, impulsive behavior was further enhanced in morphine-sired rats following acute and subchronic morphine treatment. CONCLUSION: Paternal opiate exposure during adolescence was found to primarily impair inhibitory control in male progeny. These results further our understanding of the long-term costs and risk of opioid abuse, extending across generations.

Sex-specific transgenerational effects of adolescent morphine exposure on short-term memory and anxiety behavior: Male linage.

Current estimates indicate that opioid use and misuse are a rising epidemic, which presents a substantial socioeconomic burden around the world. Chronic opioid consumption, specifically during the critical period of adolescence, can lead to enduring effects not only in individuals but also in future generations. Utilizing rodent model, we have previously reported the impacts of paternal exposure to chronic morphine during adolescence on neurobehavioral features in progenies. Currently, the potential transgenerational effects of paternal morphine exposure during adolescence on anxiety-like behavior and short-term memory remains unknown. Male Wistar rats were exposed to increasing doses of morphine for ten days in adolescence (PND 30-39). Thereafter, following a 30-days drug-free period, the treated male rats mated with naïve females. The anxiety-like behavior and short-term memory performance were assessed in adult male and female offspring (PND 60) using open field and Y-maze tests. Both male and female progenies of morphine-treated sires revealed a significant reduction in the movement velocity compared to progenies of saline-treated sires as measured by open field test. Morphine-sired male but not female offspring also showed a non-significant large decreasing effect on time spent in the center and frequency of entries to the center of open field box. Moreover, a significant reduction in the number of entries and percent of time spent in the novel arm was observed in male and female morphine-sired offspring, as measured using Y-maze test. Growth outcomes also did not demonstrate any difference in the number of dam's fertility, pups birth, and death between morphine-sired and saline-sired groups in both sexes. Collectively, paternal exposure to morphine during adolescence induces sex-specific and selective disturbances in short-term memory while anxiety-like behavior was slightly disturbed.

Adolescent Substance Abuse, Transgenerational Consequences and Epigenetics.

Adolescence is the transitional period between childhood and adulthood and a critical period in brain development. Adolescence in humans is also associated with increased expression of risk-taking behaviors. Epidemiological and clinical studies, for example, show a surge of drug abuse and raise the hypothesis that the adolescent brain undergoes critical changes resulting in diminished control. Determining how substance abuse during this critical period might cause longterm neurobiological changes in cognition and behavior is therefore critically important. The present work aims to provide an evaluation of the transgenerational and multi-generational phenotypes derived from parent animals exposed to drugs of abuse only during their adolescence. Specifically, we will consider changes found following the administration of cannabinoids, nicotine, alcohol and opiates. In addition, epigenetic modifications of the genome following drug exposure will be discussed as emerging evidence of the underlying adverse transgenerational effects. Notwithstanding, much of the new data discussed here is from animal models, indicating that future clinical studies are much needed to better understand the neurobiological consequences and mechanisms of drug actions on the human brains' development and maturation.

Early life maternal deprivation attenuates morphine induced inhibition in lateral paragigantocellularis neurons in adult rats.

Early life stress can serve as one of the principle sources leading to individual differences in confronting challenges throughout the lifetime. Maternal deprivation (MD), a model of early life stress, can cause persistent alterations in brain function, and it may constitute a risk factor for later incidence of drug addiction. It is becoming more apparent that early life MD predisposes opiate abuse in adulthood. Although several behavioral and molecular studies have addressed this issue, changes in electrophysiological features of the neurons are yet to be understood. The lateral paragigantocellularis (LPGi) nucleus, which participates in the mediation of opiate dependence and withdrawal, may be susceptible to modifications following MD. This study sought to find whether early life MD can alter the discharge activity of LPGi neurons and their response to acute morphine administration in adult rats. Male Wistar rats experienced MD on postnatal days (PNDs) 1-14 for three h per day. Afterward, they were left undisturbed until PND 70, during which the extracellular activities of LPGi neurons were recorded in anesthetized animals at baseline and in response to acute morphine. In both MD and control groups, acute morphine administration induced heterogeneous (excitatory, inhibitory, and no effect) responses in LPGi neurons. At baseline recording, the interspike interval variability of the LPGi neurons was attenuated in both inhibitory and excitatory responses in animals with the history of MD. The extent of morphine-induced discharge inhibition was also lower in deprived animals compared to the control group. These findings suggest that early life MD induces long-term alterations in LPGi neuronal activity in response to acute administration of morphine. Therefore, the MD may alter the vulnerability to develop opiate abuse in adulthood.

Paternal exposure to morphine during adolescence potentiates morphine withdrawal in male offspring: Involvement of the lateral paragigantocellularis nucleus.

BACKGROUND: Opiate exposure during adolescence perturbs the brain's maturation process and potentially confers long-term adverse consequences, not only in exposed individuals but also in their posterity. Here, we investigate the outcomes of adolescent paternal morphine exposure on morphine withdrawal profile in male offspring. METHODS: Male Wistar rats were chronically subjected to 10 days of an escalating regimen of morphine during adolescence. After a 20-day washout period, adult males were allowed to copulate with naïve females. The adult male offspring were tested for somatic and affective components of naloxone-precipitated morphine withdrawal using conditioned place aversion. Moreover, electrical activity of the lateral paragigantocellularis (LPGi) nucleus, which is involved in development of opiate dependence, was recorded in response to a challenge dose of morphine via extracellular single-unit recordings. RESULTS: Morphine-sired offspring exhibited augmented expression of naloxone-induced somatic and affective signs of opiate withdrawal compared to the control saline-sired counterparts. In vivo recording revealed that LPGi neurons displayed heterogeneous responses (inhibitory, excitatory, and no change) to acute morphine administration in both morphine- and saline-sired animals. The morphine-induced discharge inhibition was potentiated in morphine-sired offspring. However, the extent of discharge excitation in response to morphine did not reach significance in these subjects. Moreover, the lack of alteration in maternal behavior toward morphine-sired offspring indicates that this is due to germline-dependent transmission of epigenetic traits across generations. CONCLUSIONS: Preconception paternal exposure to morphine during adolescence potentiates opiate withdrawal signs in male offspring which is mediated, at least in part, by epigenetic alteration of LPGi-related brain circuitry.

Maternal deprivation induces persistent adaptations in putative dopamine neurons in rat ventral tegmental area: in vivo electrophysiological study.

Early life aversive experiences can trigger persistent deficits in neuronal signaling within the mesolimbic pathway, most notably in the dopamine (DA) neurons of the ventral tegmental area (VTA). The identity of such cellular mechanisms currently appears as an important issue. To address this concern, we investigated whether early life maternal deprivation (MD) would affect the electrical activity of VTA DA neurons, via in vivo extracellular single-unit recording. Male Wistar rats were deprived of their dams for 3 h per day from postnatal days (PND) 1-14. Thereafter, the adult animals (PND 70-80) were tested for the discharge activity of putative VTA DA neurons. The VTA DA neurons displayed a decrease in firing rate and an increase in the variability of baseline discharge activity in deprived animals. MD also caused a decrease in burst firing of VTA DA neurons compared to control subjects. In summary, early life MD induces a hypoactive VTA DA system, which may contribute to lifespan psychopathologies.

Adolescent drug exposure: A review of evidence for the development of persistent changes in brain function.

Over the past decade, many studies have indicated that adolescence is a critical period of brain development and maturation. The refinement and maturation of the central nervous system over this prolonged period, however, makes the adolescent brain highly susceptible to perturbations from acute and chronic drug exposure. Here we review the preclinical literature addressing the long-term consequences of adolescent exposure to common recreational drugs and drugs-of-abuse. These studies on adolescent exposure to alcohol, nicotine, opioids, cannabinoids and psychostimulant drugs, such as cocaine and amphetamine, reveal a variety of long-lasting behavioral and neurobiological consequences. These agents can affect development of the prefrontal cortex and mesolimbic dopamine pathways and modify the reward systems, socio-emotional processing and cognition. Other consequences include disruption in working memory, anxiety disorders and an increased risk of subsequent drug abuse in adult life. Although preventive and control policies are a valuable approach to reduce the detrimental effects of drugs-of-abuse on the adolescent brain, a more profound understanding of their neurobiological impact can lead to improved strategies for the treatment and attenuation of the detrimental neuropsychiatric sequelae.

Paternal exposure to morphine during adolescence induces reward-resistant phenotype to morphine in male offspring.

The developing brain is extremely sensitive to drugs during adolescence. The devastating impacts of opioid abuse in this critical period not only do involve individuals but also are witnessed in the subsequent generations. Therefore, what is recognized as the population susceptible to the effects of opioid abuse could be much greater in number. In this study, we explored the transgenerational effects of morphine exposure in adolescent stage on morphine reward in male offspring through the patriline. Male Wistar rats underwent 10 days of incremental doses of morphine administration during adolescence; the broad spectrum of neurobehavioral alterations in rat adolescence is akin to that of human adolescence. Thereafter, following a 20-day wash-out period, adult males copulated with naïve females. The adult male offspring were examined for morphine (0, 1, 2 and 5 mg/kg)-induced conditioned place preference (CPP). Moreover, the spontaneous activity of ventral tegmental area (VTA) dopamine (DA) neurons was investigated utilizing extracellular single-unit recording technique. Our results demonstrated that paternal morphine exposure prior to conception leads to the development of a tolerance to the rewarding effects of morphine at the low dose of 1 mg/kg (rightward shift in dose-effect curve). Furthermore, morphine-sired rats elicited a decrease in spontaneous burst firing of VTA DA neurons (burst event frequency, bursting activity and burst duration) compared to saline-sired ones. Hence, our study has provided evidence that paternal morphine exposure during adolescence alters the rewarding effects of morphine in male offspring. This effect may be mediated in part by a decrease in phasic activation of VTA DA neurons.

Exposure to opiates in male adolescent rats alters pain perception in the male offspring.

During the past decades, the use/misuse of opioids has increased dramatically among adolescent population. It is now well acknowledged that various morphological and physiological changes occur in the brain during adolescence. During this critical period, brain development and maturation could be affected by several factors including stress, drug abuse, nutritional status, etc. Although studies on transgenerational effects of substances such as alcohol, nicotine, and cocaine have focused on both paternal and maternal drug exposure, most reports on transgenerational effects of morphine are restricted to maternal exposure. Thus, in this study, we aimed to investigate the transgenerational effect of paternal morphine exposure during adolescence on pain perception and antinociceptive effect of morphine in rat offspring. Male rats received escalating doses of morphine for 10 days during postnatal days 31-40. Twenty days after the last morphine injection, male rats were mated with intact female rats, and then behavioral tests were conducted on the male offspring on postnatal day 60. Pain perception and morphine antinociception were evaluated using the formalin test. Our results demonstrated that morphine-sired and saline-sired animals differed in the interphase and phase 2 of the formalin test. These findings indicate a significant transgenerational effect of paternal morphine exposure on pain-related behaviors in rat offspring.