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Lobeline diminishes the behavioral and neurochemical effects of nicotine and amphetamines, and is considered a potential pharmacotherapy for drug abuse and addiction. Lobeline has high affinity for nicotinic acetylcholine receptors and inhibits the function of vesicular monoamine and dopamine transporters. The present study investigated the less-explored interaction of lobeline and the endogenous opioid system. In guinea pig brain homogenates, lobeline displaced (K(i)=0.74 microM) the binding of [(3)H]DAMGO [(D-Ala(2), N-ME-Phe(4), Gly(5)-ol)-enkephalin]. In a functional assay system comprised of MOR-1 mu opioid receptors and GIRK2 potassium channels expressed in Xenopus oocytes, lobeline had no effect on the resting current, but maximally inhibited (IC(50)=1.1 microM) morphine- and DAMGO-activated potassium current in a concentration-dependent manner. In a second functional assay, lobeline-evoked [(3)H]overflow from rat striatal slices preloaded with [(3)H]dopamine was not blocked by naltrexone. Importantly, concentrations of lobeline (0.1-0.3 microM) that did not have intrinsic activity attenuated ( approximately 50%) morphine-evoked [(3)H]overflow. Overall, the results suggest that lobeline functions as a mu opioid receptor antagonist. The ability of lobeline to block psychostimulant effects may be mediated by opioid receptor antagonism, and lobeline could be investigated as a treatment for opiate addiction. [ABSTRACT FROM AUTHOR]

While many environmental factors are known to play a factor in the recovery and risk of relapse for individuals with opioid use disorder (OUD), the role of diet has been relatively unexplored. Individuals with OUD demonstrate unhealthy diet choices with an exaggerated craving for palatable "junk food," yet this relationship has not been well characterized. The present study begins to examine this relationship by first determining the influence of palatable food access on the expression of conditioned rewarding properties of acute morphine exposure in male and female rats. Following the establishment of morphine conditioned place preference (CPP) in all rats, morphine CPP expression was assessed following intra-accumbens (Acb) administration of the µ-opioid receptor agonist D-Ala2,NMe-Phe4,Glyol5-enkephalin (DAMGO) + 20 min access to no diet (ND) or high-fat (HF), in counter-balanced order. Next, all rats received 12 sessions of extinction training before CPP expression was first assessed following no treatment, then again following counter-balanced ND and HF treatments. The results showed that both male and female rats expressed similar levels of morphine CPP. Subsequent examination of morphine CPP expression revealed that HF treatment significantly reduced morphine CPP expression in males, but not females, compared to ND treatment. Neither HF or ND treatment produced morphine CPP reinstatement in either males or females following extinction. In summary, the impact of palatable feeding on the expression of conditioned drug seeking may be sex-specific and more sensitive prior to extinction., Competing Interests: Conflict of Interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Melanin-concentrating hormone (MCH) activity in the nucleus accumbens (Acb) has been shown to influence feeding behavior, yet this has not been characterized in terms of homeostatic vs. hedonic feeding processes. Hedonic feeding, driven by palatability rather than energy deficit, can be modeled through intra-Acb administration of the selective μ-opioid receptor agonist d-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO), which preferentially increases consumption and incentive motivation to obtain preferred palatable food. Pharmacological activation of MCH 1 receptors (MCHR1) within Acb has been shown to promote general feeding of chow in males, but not females. However, the effects of MCH on the incentive motivation to obtain preferred palatable food have not been explored. Here, we investigated the role of MCHR1 within the Acb in DAMGO-induced incentive motivation to obtain a sucrose pellet reward. Female Sprague Dawley rats were trained and tested for operant responding under a progressive ratio (PR) breakpoint in response to concurrent intra-Acb administration of DAMGO (0 μg and 0.025 μg/.5 μl/side) immediately following intra-Acb administration of the MCHR1 antagonist (N-(3-{1-[4-(3,4-difluoro-phenoxy)-benzyl]-piperdin-4-yl}-4-methyl-phenyl)-isobutyramide (SNAP-94847; 0 μg, 1.5 μg, and 15 μg/.5 μl/side), in a counterbalanced fashion. As expected, DAMGO significantly increased PR breakpoint and overall active lever presses. SNAP-94847 did not influence PR breakpoint by itself, compared to vehicle; however, both 1.5 and 15 μg doses of SNAP-94847 significantly blocked the increased PR breakpoint produced by intra-Acb DAMGO. The results of the study demonstrate that Acb MCHR1 may play a specific role in the hedonically-driven motivation for palatable food in females., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The relationship between physical activity levels and feeding behaviors has been a focus of preclinical research for decades, yet this interaction has only recently been explored for potential sex differences. The aim of the present study was to isolate sex-dependent effects of voluntary wheel running (RUN) vs. sedentary locked wheel (SED) home cage conditions on palatability-driven feeding behavior using a 2-diet choice task between standard chow and a high-fat diet. The sex-dependent effects of physical activity on feeding behavior were examined following a within-subject novel reversal design of physical activity conditions (i.e., RUN > SED > RUN), to assess temporal sensitivity of the interaction. Following the final 2 weeks of reestablished and sustained RUN vs. SED conditions in separate groups of both males and females, reward-related opioid and dopamine gene expression within the nucleus accumbens (Acb) brain region were analyzed. Results demonstrated that the initial RUN > SED transition led to sex-dependent effects of SED condition, as males increased, and females decreased their high fat consumption, compared to their respective high fat consumption during previous RUN condition phase. Following reintroduction to the RUN condition, males decreased, and females increased their high fat consumption, compared to their separate SED control group. Last, sex-dependent shifts in ventral striatal opioid- and dopamine-related gene expression were observed to parallel the behavioral effects. The major findings of the study reveal that SED and RUN home cage conditions shift palatability-driven feeding in the opposite direction for males and females, these effects are sensitive to reversal, and these sex-dependent feeding behaviors track sex-dependent changes to critical reward-related gene expression patterns in the Acb. Considering the present high rates of sedentary behavior and obesity, furthering our understanding of the interaction between physical activity (or lack thereof) and feeding behavior should be a priority, especially in the context of these divergent sex-dependent outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kocum, Cam, Shay, Schweizer, Konrad, Houska, Sardina, Schachtman, Vieira-Potter and Will.)

Autism Spectrum Disorder (ASD) has been associated with a complex interplay between genetic and environmental factors. Prenatal stress exposure has been identified as a possible risk factor, although most stress-exposed pregnancies do not result in ASD. The serotonin transporter (SERT) gene has been linked to stress reactivity, and the presence of the SERT short (S)-allele has been shown to mediate the association between maternal stress exposure and ASD. In a mouse model, we investigated the effects of prenatal stress exposure and maternal SERT genotype on offspring behavior and explored its association with maternal microRNA (miRNA) expression during pregnancy. Pregnant female mice were divided into four groups based on genotype (wildtype or SERT heterozygous knockout (Sert-het)) and the presence or absence of chronic variable stress (CVS) during pregnancy. Offspring behavior was assessed at 60 days old (PD60) using the three-chamber test, open field test, elevated plus-maze test, and marble-burying test. We found that the social preference index (SPI) of SERT-het/stress offspring was significantly lower than that of wildtype control offspring, indicating a reduced preference for social interaction on social approach, specifically for males. SERT-het/stress offspring also showed significantly more frequent grooming behavior compared to wildtype controls, specifically for males, suggesting elevated repetitive behavior. We profiled miRNA expression in maternal blood samples collected at embryonic day 21 (E21) and identified three miRNAs (mmu-miR-7684-3p, mmu-miR-5622-3p, mmu-miR-6900-3p) that were differentially expressed in the SERT-het/stress group compared to all other groups. These findings suggest that maternal SERT genotype and prenatal stress exposure interact to influence offspring behavior, and that maternal miRNA expression late in pregnancy may serve as a potential marker of a particular subtype of ASD pathogenesis.

Purpose: Innovations in macroimplant design, specifically ultrawide implants 7.0 mm or greater in diameter, have allowed immediate molar replacement. This is a retrospective study assessing the survival rates of ultrawide diameter implants (7.0, 8.0, 9.0 mm) immediately placed into molar extraction sockets. Implants were followed up to 144 months postplacement., Materials and Methods: A retrospective study was conducted of all patients treated in a private surgical practice between January 1, 2008 and December 31, 2020, who received ultrawide dental implants (7.0, 8,0, 9.0 mm.) placed immediately into molar extraction sockets. Wide diameter healing abutments were placed on all implants at the time of surgery. Abutments and crown restorations were fabricated after at least 4 months of unloaded healing. Patient age, sex, implant location and implant diameters were examined for survival. Insertion torque values at the time of placement and time in function were also evaluated. Biometric statistics were computed with p-values (<0.05. Descriptive and bivariate statistics were computed; p-values were set at 0.05., Results: Five hundred forty-four patients (225 males; 319 females) average age 62.5 years (range 27 to 95) had 563 implants placed. Five hundred thirty-five of five hundred sixty-three (535/563) implants survived; 28 failed [clinical survival rate (CSR) 95.03%]. Number and time in function were: 0 to 12 years 100%; 0 to 9 years 85%; 0 to 6 years 69%; 0 to 3 years 35% or 10 to 12 years 16%; 7 to 9 years 16%; 4 to 6 years 34%; 0 to 3 years 35%. No significant differences were found between sex and implant failures (p = 0.22). Maxillary (266/285; 93.3%) and mandibular (269/278; 96.8%) implant CSRs were not significantly different. Three implant diameters were used: 7.0 mm (206/563) [36.6%]; 8.0 mm (267/563) [47.4%]; 9.0 mm (90/563) [15.9%]. Clinical survival rates were: 7.0 mm (201/206) [97.6%]; 8.0 mm (252/267) [94.4%]; 9.0 mm (82/90) [91.1%]. Mean age for patients with failed implants did not show any significant differences (p = 0.1398). Fifteen of the 28 failed implants failed within 120 days of surgical placement (prior to definitive restoration; [53.6%]; 4 implants failed between 4 and 12 months [14.3%]; 9 implants failed at least 1-year postloading [32.1%]., Conclusions: The results of this long-term retrospective study regarding ultrawide diameter implants suggested that these implants were viable treatment options for immediate molar replacement following tooth extraction in either jaw with an unloaded healing protocol. High clinical survival rates were reported over a 144-month (12-year) timeframe., (© 2022 by the American College of Prosthodontists.)

The use of rodents to acquire understanding of the function of neural circuits and of the physiological, genetic and developmental underpinnings of behaviour has been constrained by limitations in the scalability, automation and high-throughput operation of implanted wireless neural devices. Here we report scalable and modular hardware and software infrastructure for setting up and operating remotely programmable miniaturized wireless networks leveraging Bluetooth Low Energy for the study of the long-term behaviour of large groups of rodents. The integrated system allows for automated, scheduled and real-time experimentation via the simultaneous and independent use of multiple neural devices and equipment within and across laboratories. By measuring the locomotion, feeding, arousal and social behaviours of groups of mice or rats, we show that the system allows for bidirectional data transfer from readily available hardware, and that it can be used with programmable pharmacological or optogenetic stimulation. Scalable and modular wireless-network infrastructure should facilitate the remote operation of fully automated large-scale and long-term closed-loop experiments for the study of neural circuits and animal behaviour., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Rationale: The N-phenylpropyl-N'-substituted piperazines SA-4503 (N-phenylpropyl-N'-(3,4-dimethoxyphenethyl)piperazine) and YZ-185 (N-phenylpropyl-N'-(3-methoxyphenethyl)piperazine) bind to sigma (σ) receptors and block the development of cocaine-induced conditioned place preference at concentrations that inhibit cocaine-induced hyperactivity. YZ-067 (N-phenylpropyl-N'-(4-methoxyphenethyl)piperazine) also binds to sigma receptors and attenuates cocaine-induced hyperactivity in mice., Objectives: The present study determined the effect of YZ-067 on the development and expression of cocaine (66 μmol/kg or 33 μmol/kg) conditioned place preference (CPP) and locomotor sensitization in mice., Results: YZ-067 (10 or 31.6 μmol/kg) did not have intrinsic effects on place preference or place aversion. Interestingly, the 31.6 μmol/kg YZ-067 dose enhanced the development of cocaine place preference, while 10 μmol/kg YZ-067 attenuated the development of cocaine-induced locomotor sensitization. However, YZ-067 did not alter the expression of cocaine place preference nor cocaine-induced locomotor sensitization. In follow-up studies, YZ-067 did not affect performance in the zero maze or rotarod, indicating that sigma receptors probed by this ligand do not regulate anxiety-like or coordinated motor skill behaviors, respectively., Conclusion: Overall, these results are consistent with previous studies demonstrating a role for sigma receptors in the behavioral effects of cocaine. However, the present findings also indicate that N-phenylpropyl-N'-substituted piperazines do not strictly block cocaine's behavioral effects and that sigma receptor may differentially mediate cocaine-induced hyperactivity and place conditioning.

Sigma-1 (σ 1 ) receptors have been investigated for their involvement in learning, rewarding and motivational processes. PD144418, a σ 1 receptor antagonist, has been found to produce a dose-dependent attenuation of locomotor activity induced by cocaine, and by itself, does not suppress basal locomotor activity in mice. Moreover, PD144418 decreases the motivational effort of a food-reinforced behavior in male rats, without altering appetite or food palatability. It remains unknown whether the PD144418 can alter the motivational effort of a food-reinforced behavior in response to altered energy homeostasis, as is the case under 24 -h food deprivation. Additionally, while the previous experiments indicate effects in male rats, there has been no research examining the effects of PD144418, or any other σ 1 receptor antagonist, on motivational aspects of feeding in females. The present study examined the effects of PD144418 on motivational aspects of feeding in male and female rats using an operant task under sated or food deprived conditions. Results indicated that when animals are sated, at the highest dose (10 μmol/kg), under a progressive ratio (PR) reinforcement schedule, PD144418 significantly attenuated the breakpoint and the number of active lever responses for sucrose pellets in both males and females. When animals are in a state of energy deficit, as is the case following 24-hr food deprivation, PD144418 does not alter motivationally driven operant responding as measured by the breakpoint in either sex but does alter the number of earned reinforcers responses in females., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Rationale: Previous research indicates that the selective sigma-1 receptor ligand PD144418 and the selective sigma-2 ligands YUN-252 can inhibit cocaine-induced hyperactivity. The effects of these ligands on other stimulants, such as methamphetamine, have not been reported., Objectives: The present study examined the effects of PD144418 and YUN-252 pretreatment on methamphetamine-induced hyperactivity after acute treatment., Methods: Mice (n = 8-14/group) were injected with PD144418 (3.16, 10, or 31.6 μmol/kg), YUN-252 (0.316, 3.16, 31.6 μmol/kg), or saline. After 15 min, mice injected with 2.69 μmol/kg methamphetamine or saline vehicle, where distance traveled during a 60-min period was recorded. Additionally, the effect of PD144418 on the initiation and expression of methamphetamine sensitization was determined by treating mice (n = 8-14/group) with PD144418, methamphetamine or saline repeatedly over a 5-day period, and testing said mice with a challenge dose after a 7-day withdrawal period., Results: Results indicate that both PD144418 and YUN-252, in a dose-dependent manner, attenuated hyperactivity induced by an acute methamphetamine injection. Specifically, 10 μmol/kg or 31.6 μmol/kg of PD144418 and 31 μmol/kg of YUN-252 suppressed methamphetamine-induced hyperactivity. In regard to methamphetamine sensitization, while 10 μmol/kg PD144418 prevented the initiation of methamphetamine sensitization, it did not have an effect on the expression., Conclusions: Overall, the current results suggest an intriguing potential for this novel sigma receptor ligand as a treatment for the addictive properties of methamphetamine. Future analysis of this novel sigma receptor ligand in assays directly measuring reinforcement properties will be critical.

Palatability driven feeding and voluntary physical activity are mediated by and influence similar neural mechanisms, notably through the actions of opioids within the nucleus accumbens. Recent studies suggest that access to a voluntary running wheel results in sex dependent behavioral and physiological adaptations related to opioid mediated palatability-driven feeding. To explore this relationship, male and female Wistar rats were given either access to a voluntary running wheel (RUN group) or no access (SED group) for one week prior to being stereotaxically implanted with bilateral cannulae targeting the nucleus accumbens. Following 7 days of recovery, with RUN or SED conditions continuing the duration of the experiment, all rats were assessed daily (2 h/day) for feeding behavior of concurrently accessible high-carbohydrate and high-fat diet for one week. Following this week, all rats were administered the μ-opioid receptor agonist D-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO) (0.0025  μg, 0.025  μg, or 0.25 μg/0.5 μl/side) or the opioid antagonist naloxone (20 μg/0.5 μl/side) into the nucleus accumbens and given concurrent access (2 h) to both diets. All groups expressed a significant baseline preference for the high-carbohydrate diet. DAMGO administration, compared to saline treatment, led to significant increased consumption of the high-carbohydrate diet in all treatment groups. While high-fat diet consumption also increased following DAMGO administration, the influence of DAMGO was much more robust for the preferred high-carbohydrate diet in all groups. Compared to males, females consumed significantly more of both diets at baseline and following DAMGO treatment. Both male and female rats in the RUN condition consumed more high-carbohydrate diet compared to rats in the SED condition. While males exhibited similar increased consumption of both diets regardless of RUN or SED condition, females in the RUN condition displayed a greater sensitivity to DAMGO-driven consumption of the preferred high-carbohydrate, compared to SED females., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The present study examined the influence of physical activity vs. sedentary home cage conditions on baseline and opioid-driven high-fat feeding behaviors in two common strains of laboratory rats. Sprague-Dawley and Wistar rats were singly housed with either access to a voluntary running wheel (RUN) or locked-wheel (SED) for 5 weeks, before being stereotaxically implanted with bilateral cannulae targeting the nucleus accumbens. Following recovery, with RUN or SED conditions continuing the duration of the experiment, all rats were given 2 h daily access to a high-fat diet for 6 consecutive days to establish a stable baseline intake. Over the next 2 weeks, all subjects were administered the μ-opioid agonist D-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO) (multiple dose range) or saline into the nucleus accumbens, immediately followed by 2 h access to a high-fat diet. Drug treatments were separated by at least 1 day and treatment order was counterbalanced. Baseline consumption of the high-fat diet during the 1-week baseline acclimation period did not differ between RUN and SED groups in either rat strain. Higher doses of DAMGO produced increased fat consumption in both strains of rats, yet no differences were observed between RUN vs. SED treated groups. However, SED treatment produced a greater locomotor response following intra-accumbens DAMGO administration, compared to the RUN condition, during the 2 h feeding session. The data suggest that the animals housed in sedentary versus voluntary wheel running conditions may differ in behavioral tolerance to the locomotor but not the orexigenic activating properties of intra-accumbens DAMGO treatment., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Sigma-1 (σ 1 ) receptors have been investigated for their involvement in learning, rewarding and motivational processes, particularly as it relates to substances of abuse. Few studies have examined the effects of σ 1 receptor agonists and antagonists on the rewarding and motivational properties of natural reinforcers, such as food. Studies that have investigated σ 1 receptor agonists and antagonists has produced conflicting results. σ 1 receptor antagonist PD144418 has been found to produce a dose-dependent attenuation of locomotor activity induced by cocaine, and by itself, does not suppress basal locomotor activity in mice. However, its effects on reward and motivation as it relates to food are unknown. The present study examined the involvement of σ 1 receptors in mediating the rewarding and motivational properties of food using an operant task. The results indicated that at the highest dose (10 μmol/kg), PD144418 significantly attenuated the number of active lever responses for chow pellets but did not decrease the number of active lever responses for sucrose pellets under a fixed ratio (FR2) schedule of reinforcement. However, under a progressive ratio (PR) reinforcement schedule, 10 μmol/kg of PD14418 significantly reduced the breakpoint, a measure indicative of effort or motivation, for both chow and sucrose pellets. When ad libitum chow or sucrose pellets were made freely available (i.e. no lever press required) inside the operant chamber, 10 μmol/kg, PD144418 did not have an effect on number of pellets consumed. These findings indicate that PD144418 reduces the motivational effort of a food reinforced behavior., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Considering the current obesity epidemic is due in large part to an energy imbalance, it is crucial to explore biological mechanisms that mediate palatable high energy food intake and physical activity behavior levels. Previous research demonstrates a unique sex dependent influence of physical activity on diet preference, specifically changes in palatable high-fat diet intake. Therefore, factors of motivation may be underlying the differential effect of physical activity in male and female rats on their diet preference. The present study extends this hypothesis by assessing diet preference in male and female Wistar rats selectively bred for high (HVR) and low (LVR) levels of voluntary wheel running distances. HVR and LVR rats were housed under either sedentary (SED) or voluntary wheel running access (RUN) conditions for the duration of the study. Following a 1 week acclimation period to these conditions, standard chow was replaced with concurrent ad libitum access to a choice of 3 pelleted diets (high-fat, high-sucrose, and high-corn starch); all 3 were provided in the home cage. Body weight, running distance, and intake of each diet was measured daily. At the conclusion of the 4 week diet preference test, animals were sacrificed and ventral striatum tissue was collected for later analysis. Results demonstrated intake patterns of diets were uniquely influenced by physical activity dependent on both the sex and the selectively bred line of rat. In addition, reward related ventral striatal mRNA expression was also dependent on both the sex and the selectively bred line of rat. Overall, the pattern of both behavioral and mRNA results suggest that voluntary wheel running behavior differentially mediates palatable diet consumption in males and females. Considering the pervasive abundance of both physical inactivity, combined with over-consumption of energy dense palatable diets, it is vital to understand the nature of these behavioral interactions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Feeding behaviors can be modified via homeostatic and hedonic mechanisms. Homeostasis, while primarily concerned with maintaining energy balance via food consumption and energy expenditure, can alter food reward and motivation in response to food deprivation. Alternatively, reward and motivation of food is also driven by its palatability or hedonic nature, and this process can be augmented by opioid receptor activation. The present study examined sex differences in the motivational properties of sucrose pellets through manipulation of homeostatic and hedonic processes via acute food deprivation and acute systemic administration of morphine, respectively. The results showed that regardless of sex, systemic injections of morphine did not alter the motivation to obtain a sucrose pellet on a progressive ratio schedule of reinforcement but does significantly increase consumption of sucrose pellets when freely available. Male and female rats demonstrated similar increased consumption of sucrose pellets under free feeding conditions following acute (24-hours) food deprivation, compared to the non-deprived conditions. Overall, the findings from these experiments indicate that female rats work harder in order to obtain a sucrose pellet (under a Progressive Ratio (PR) schedule of reinforcement) and consume more sucrose pellets than males. However, while acute morphine administration causes similar increases on feeding in males and females, it does not alter motivation as measured by breakpoint on a PR schedule of reinforcement., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Previous studies suggest an interaction between the level of physical activity and diet preference. However, this relationship has not been well characterized for sex differences that may exist. The present study examined the influence of sex on diet preference in male and female Wistar rats that were housed under either sedentary (no wheel access) (SED) or voluntary wheel running access (RUN) conditions. Following a 1 week acclimation period to these conditions, standard chow was replaced with concurrent ad libitum access to a choice of 3 pelleted diets (high-fat, high-sucrose, and high-corn starch) in the home cage. SED and RUN conditions remained throughout the next 4 week diet preference assessment period. Body weight, running distance, and intake of each diet were measured daily. At the conclusion of the 4 week diet preference test, animals were sacrificed and brains were collected for mRNA analysis. Fecal samples were also collected before and after the 4 week diet preference phase to characterize microbiota composition. Results indicate sex dependent interactions between physical activity and both behavioral and physiological measures. Females in both RUN and SED conditions preferred the high-fat diet, consuming significantly more high-fat diet than either of the other two diets. While male SED rats also preferred the high-fat diet, male RUN rats consumed significantly less high-fat diet than the other groups, instead preferring all three diets equally. There was also a sex dependent influence of physical activity on both reward related opioid mRNA expression in the ventral striatum and the characterization of gut microbiota. The significant sex differences in response to physical activity observed through both behavioral and physiological measures suggest potential motivational or metabolic difference between males and females. The findings highlight the necessity for further exploration between male and female response to physical activity and feeding behavior., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The low activity allele of the maternal polymorphism, 5HTTLPR, in the serotonin transporter, SLC6A4, coupled with prenatal stress is reported to increase the risk for children to develop autism spectrum disorder (ASD). Similarly, maternal Slc6a4 knock-out and prenatal stress in rodents results in offspring demonstrating ASD-like characteristics. The present study uses an integrative genomics approach to explore mechanistic changes in early brain development in mouse embryos exposed to this maternal gene-environment phenomenon. Restraint stress was applied to pregnant Slc6a4 +/+ and Slc6a4 +/- mice and post-stress embryonic brains were assessed for whole genome level profiling of methylome, transcriptome and miRNA using Next Generation Sequencing. Embryos of stressed Slc6a4 +/+ dams exhibited significantly altered methylation profiles and differential expression of 157 miRNAs and 1009 genes affecting neuron development and cellular adhesion pathways, which may function as a coping mechanism to prenatal stress. In striking contrast, the response of embryos of stressed Slc6a4 +/- dams was found to be attenuated, shown by significantly reduced numbers of differentially expressed genes (458) and miRNA (0) and genome hypermethylation. This attenuated response may pose increased risks on typical brain development resulting in development of ASD-like characteristics in offspring of mothers with deficits in serotonin related pathways during stressful pregnancies.

Dietary supplementation with the long-chain omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) has been shown to have a beneficial effect on reducing the symptoms associated with several neuropsychiatric conditions including anxiety and depression. However, the mechanisms underlying this effect remain largely unknown. Increasing evidence suggests that the vast repertoire of commensal bacteria within the gut plays a critical role in regulating various biological processes in the brain and may contribute to neuropsychiatric disease risk. The present study determined the contribution of DHA on anxiety and depressive-like behaviors through modulation of the gut microbiota in a paradigm of social isolation. Adult male and female mice were subjected to social isolation for 28days and then placed either on a control diet or a diet supplemented with 0.1% or 1.0% DHA. Fecal pellets were collected both 24h and 7days following the introduction of the new diets. Behavioral testing revealed that male mice fed a DHA diet, regardless of dose, exhibited reduced anxiety and depressive-like behaviors compared to control fed mice while no differences were observed in female mice. As the microbiota-brain-axis has been recently implicated in behavior, composition of microbial communities were analyzed to examine if these sex-specific effects of DHA may be associated with changes in the gut microbiota (GM). Clear sex differences were observed with males and females showing distinct microbial compositions prior to DHA supplementation. The introduction of DHA into the diet also induced sex-specific interactions on the GM with the fatty acid producing a significant effect on the microbial profiles in males but not in females. Interestingly, levels of Allobaculum and Ruminococcus were found to significantly correlate with the behavioral changes observed in the male mice. Predictive metagenome analysis using PICRUSt was performed on the fecal samples collected from males and identified enrichment in functional KEGG pathway terms relevant to processes such as the biosynthesis of unsaturated fatty acids and antioxidant metabolism. These results indicate that DHA alters commensal community composition and produces beneficial effects on anxiety and depressive-like behaviors in a sex-specific manner. The present study provides insight into the mechanistic role that gut microbes may play in the regulation of anxiety and depressive-like behaviors and how dietary intervention can modulate these effects., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Previous research has found that rats behaviorally screened for high (vs. low) wheel running were more vulnerable to cocaine abuse. To assess the extent to which a genetic component is involved in this drug-abuse vulnerability, rats selectively bred for high or low voluntary running (HVR or LVR, respectively) were examined for differences in cocaine seeking in the present study., Methods: Female rats were trained to lever press for food and then were assessed for differences in acquisition of cocaine (0.4mg/kg; i.v.) self-administration across 10 sessions. Once acquired, rats self-administered cocaine for a 14-day maintenance phase, followed by a 14-day extinction phase when cocaine was no longer available. Subsequently, reinstatement of cocaine seeking was examined with priming injections of cocaine (5, 10 & 15mg/kg), caffeine (30mg/kg), yohimbine (2.5mg/kg) and cocaine-paired cues., Results: A greater percentage of LVR rats met the acquisition criteria for cocaine self-administration and in fewer sessions than HVR rats. No differences in responding for cocaine were observed between phenotypes during maintenance. However, during extinction LVR rats initially responded at higher rates and persisted in cocaine seeking for a greater number of sessions. No phenotype differences were observed following drug and cue-primed reinstatement of cocaine seeking., Conclusions: In general, LVR rats were more sensitive to the reinforcing effects of cocaine than HVR rats during periods of transition into and out of cocaine self-administration. Thus, LVR rats sometimes showed a greater vulnerability cocaine seeking than HVR rats., Competing Interests: Declaration of Interest Conflict of Interest No conflict declared., (Published by Elsevier Ireland Ltd.)

Unlabelled: Rats selectively bred for high (HCR) and low (LCR) aerobic capacity show a stark divergence in wheel running behavior, which may be associated with the dopamine (DA) system in the brain. HCR possess greater motivation for voluntary running along with greater brain DA activity compared to LCR. We recently demonstrated that HCR are not immune to ovariectomy (OVX)-associated reductions in spontaneous cage (i.e. locomotor) activity. Whether HCR and LCR rats differ in their OVX-mediated voluntary wheel running response is unknown., Purpose: To determine whether HCR are protected from OVX-associated reduction in voluntary wheel running., Methods: Forty female HCR and LCR rats (age ~27weeks) had either SHM or OVX operations, and given access to a running wheel for 11weeks. Weekly wheel running distance was monitored throughout the intervention. Nucleus accumbens (NAc) was assessed for mRNA expression of DA receptors at sacrifice., Results: Compared to LCR, HCR ran greater distance and had greater ratio of excitatory/inhibitory DA mRNA expression (both line main effects, P<0.05). Wheel running distance was significantly, positively correlated with the ratio of excitatory/inhibitory DA mRNA expression across animals. In both lines, OVX reduced wheel running (P<0.05). Unexpectedly, although HCR started with significantly greater voluntary wheel running, they had greater OVX-induced reduction in wheel running than LCR such that no differences were found 11weeks after OVX between HCROVX and LCROVX (interaction, P<0.05). This significant reduction in wheel running in HCR was associated with an OVX-mediated reduction in the ratio of excitatory/inhibitory DA mRNA expression., Conclusion: The DA system in the NAc region may play a significant role in motivation to run in female rats. Compared to LCR, HCR rats run significantly more, which associates with greater ratio of excitatory/inhibitory DA mRNA expression. However, despite greater inherent motivation to run and an associated brain DA mRNA expression profile, HCR rats are not protected against OVX-induced reduction in wheel running or OVX-mediated reduction in the ratio of excitatory/inhibitory DA receptor mRNA expression. OVX-mediated reduction in motivated physical activity may be partially explained by a reduced ratio of excitatory/inhibitory DA receptor mRNA expression for which intrinsic fitness does not confer protection., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The present study explored the role of the amygdala in mediating a unique pattern of feeding behavior driven by intra-accumbens (intra-Acb) opioid activation in the rat. Temporary inactivation of the basolateral amygdala (BLA), via GABAA agonist muscimol administration prevents increased consumption following intra-Acb opioid administration of the selective μ-opioid agonist D-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO), yet leaves food approach behaviors intact, particularly after consumption has ended. One interpretation is that inactivation of the BLA selectively blocks neural activity underlying DAMGO-driven consummatory (consumption) but not appetitive (approach) behaviors. The present experiments take advantage of this temporal dissociation of consumption and approach behaviors to investigate their associated neural activity. Following either intra-Acb saline or DAMGO administration, with or without BLA muscimol administration, rats were given 2-hr access to a limited amount of high-fat diet. Immediately following the feeding session, rats were sacrificed and brains assayed for neural activity patterns across critical brain regions known to regulate both appetitive and consummatory feeding behaviors. The results show that intra-Acb DAMGO administration increased c-Fos activation in orexin neurons within the perifornical area of the hypothalamus and that this increase in activation is blocked by BLA muscimol inactivation. Intra-Acb DAMGO administration significantly increased c-Fos activation within dopaminergic neurons of the ventral tegmental area, compared to saline controls, and BLA inactivation had no effect on this increase. Overall, these data provide underlying circuitry that may mediate the selective influence of the BLA on driving consummatory, but not appetitive, feeding behaviors in a model of hedonically driven feeding behavior., ((c) 2015 APA, all rights reserved).)

The exact role of opioid receptor signaling in mediating voluntary wheel running is unclear. To provide additional understanding, female rats selectively bred for motivation of low (LVR) versus high voluntary running (HVR) behaviors were used. Aims of this study were 1) to identify intrinsic differences in nucleus accumbens (NAc) mRNA expression of opioid-related transcripts and 2) to determine if nightly wheel running is differently influenced by bilateral NAc injections of either the mu-opioid receptor agonist D-Ala2, NMe-Phe4, Glyo5-enkephalin (DAMGO) (0.25, 2.5 μg/side), or its antagonist, naltrexone (5, 10, 20 μg/side). In Experiment 1, intrinsic expression of Oprm1 and Pdyn mRNAs were higher in HVR compared to LVR. Thus, the data imply that line differences in opioidergic mRNA in the NAc could partially contribute to differences in wheel running behavior. In Experiment 2, a significant decrease in running distance was present in HVR rats treated with 2.5 μg DAMGO, or with 10 μg and 20 μg naltrexone between hours 0-1 of the dark cycle. Neither DAMGO nor naltrexone had a significant effect on running distance in LVR rats. Taken together, the data suggest that the high nightly voluntary running distance expressed by HVR rats is mediated by increased endogenous mu-opioid receptor signaling in the NAc, that is disturbed by either agonism or antagonism. In summary, our findings on NAc opioidergic mRNA expression and mu-opioid receptor modulations suggest HVR rats, compared to LVR rats, express higher running levels mediated by an increase in motivation driven, in part, by elevated NAc opioidergic signaling., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Previous research has demonstrated that the nucleus accumbens is a site where opioids and cannabinoids interact to alter feeding behavior. However, the influence of the endocannabinoid 2-arachidonylglycerol (2-AG) on the well-characterized model of intra-accumbens opioid driven high-fat feeding behavior has not been explored. The present experiments examined high-fat feeding associated behaviors produced by the interaction of 2-AG and the μ-opioid receptor agonist DAla(2),N,Me-Phe(4),Gly-ol(5)-enkaphalin (DAMGO) administered into the nucleus accumbens. Sprague-Dawley rats were implanted with bilateral cannulae aimed at the nucleus accumbens and were co-administered both a sub-threshold dose of 2-AG (0 or 0.25 μg/0.5 μl/side) and DAMGO (0, 0.025 μg or 0.25 μg/0.5 μl/side) in all dose combinations, and in a counterbalanced order. Animals were then immediately allowed a 2h-unrestricted access period to a palatable high-fat diet. Consumption, number and duration of food hopper entries, and locomotor activity were all monitored. DAMGO treatment led to an increase in multiple behaviors, including consumption, duration of food hopper entry, and locomotor activity. However, combined intra-accumbens administration of DAMGO and a subthreshold dose of 2-AG led to a significant increase in number of food hopper entries and locomotor activity, compared to DAMGO by itself. The results confirm that intra-accumbens administration of subthreshold dose of the endogenous cannabinoid 2-AG increases the DAMGO-induced approach and locomotor behaviors associated with high-fat feeding., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: This pilot study examined whether the addition of a normal protein (NP) vs. high protein (HP) breakfast leads to alterations in food cravings and plasma homovanillic acid (HVA), which is an index of central dopamine production, in overweight/obese 'breakfast skipping' late-adolescent young women., Methods: A randomized crossover design was incorporated in which 20 girls (age 19 ± 1 y; BMI 28.6 ± 0.7 kg/m2) consumed 350 kcal NP (13 g protein) breakfast meals, 350 kcal HP (35 g protein) breakfast meals, or continued breakfast skipping (BS) for 6 consecutive days/pattern. On day 7 of each pattern, a 4 h testing day was completed including the consumption of breakfast (or no breakfast) followed by food craving questionnaires and blood sampling for HVA concentrations throughout the morning., Results: Both breakfast meals reduced post-meal cravings for sweet and savory foods and increased HVA concentrations vs. BS (all, p < 0.05). Between breakfast meals, the HP breakfast tended to elicit greater reductions in post-meal savory cravings vs. NP (p = 0.08) and tended to elicit sustained increases in HVA concentrations prior to lunch vs. NP (p = 0.09). Lastly, HVA concentrations were positively correlated with the protein content at breakfast (r: 0.340; p < 0.03)., Conclusions: Collectively, these findings suggest that the addition of breakfast reduces post-meal food cravings and increases homovanillic acid concentrations in overweight/obese young people with higher protein versions eliciting greater responses.

Previous work examining animal models of cognitive flexibility have focused on tasks where animals are required to shift between cues in order to reach a food reward from among a limited set of choices. Performance by nonhuman animals on these tasks, including reversal learning, intradimensional set-shifting, and extradimensional set-shifting, are affected by pharmacological action on serotonergic, dopaminergic, and alpha-adrenergic, but not beta-adrenergic receptors. However, beta-adrenergic antagonists, such as propranolol, are widely utilized for conditions such as test anxiety. Propranolol improves performance in humans during cognitive flexibility tasks where there is a broad set of potential solutions. The current investigation utilized a digging task where the rodent must develop a novel solution in order to obtain a reward. Similar to the effects observed in humans, propranolol improved performance on this task, while not affecting performance on set-shifting tasks, as with previous animal studies. This may allow future investigation of the neurobiological mechanism by which propranolol affects context-specific anxiety, and could provide insight into the neurobiology of creativity., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Previous research has demonstrated a dissociation of certain neural mediators that contribute to the increased consumption of a high-fat diet that follows intra-accumbens (Acb) administration of μ-opioid receptor agonists vs. 24-h food deprivation. These two models, both which induce rapid consumption of the diet, have been shown to involve a distributed corticolimbic circuitry, including the amygdala. Specifically, the central amygdala (CeA) has been shown to be involved in high-fat feeding within both opioid and food-deprivation driven models. The present experiments were conducted to examine the more specific role of CeA opioid transmission in mediating high-fat feeding driven by either intra-Acb administration of the μ-opioid agonist d-Ala2-NMe-Phe4-Glyol5-enkephalin (DAMGO) or 24-h home cage food deprivation. Injection of DAMGO into the Acb (0.25 μg/0.5 μl/side) increased consumption of the high-fat diet, but this feeding was unaffected by administration of opioid antagonist, naltrexone (5 μg/0.25 μl/side) administered into the CeA. In contrast, intra-CeA naltrexone administration attenuated high-fat intake driven by 24-h food deprivation, demonstrating a specific role for CeA opioid transmission in high-fat consumption. Intra-CeA naltrexone administration alone had no effect on baseline feeding levels within either feeding model. These findings suggest that CeA opioid transmission mediates consumption of a palatable high-fat diet driven by short-term negative-energy balance (24-h food deprivation), but not intra-Acb opioid receptor activation., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Circuits that participate in specific subcomponents of feeding (e.g., gustatory perception, peripheral feedback relevant to satiety and energy balance, reward coding, etc.) are found at all levels of the neural axis. Further complexity is conferred by the wide variety of feeding-modulatory neurotransmitters and neuropeptides that act within these circuits. An ongoing challenge has been to refine the understanding of the functional specificity of these neurotransmitters and circuits, and there have been exciting advances in recent years. We focus here on foundational work of Dr. Ann Kelley that identified distinguishable actions of striatal opioid peptide modulation and dopamine transmission in subcomponents of reward processing. We also discuss her work in overlaying these neuropharmacological effects upon anatomical pathways that link the telencephalon (cortex and basal ganglia) with feeding-control circuits in the hypothalamus. Using these seminal contributions as a starting point, we will discuss new findings that expand our understanding of (1) the specific, differentiable motivational processes that are governed by central dopamine and opioid transmission, (2) the manner in which other striatal neuromodulators, specifically acetylcholine, endocannabinoids and adenosine, modulate these motivational processes (including via interactions with opioid systems), and (3) the organization of the cortical-subcortical network that subserves opioid-driven feeding. The findings discussed here strengthen the view that incentive-motivational properties of food are coded by substrates and neural circuits that are distinguishable from those that mediate the acute hedonic experience of food reward. Striatal opioid transmission modulates reward processing by engaging frontotemporal circuits, possibly via a hypothalamic-thalamic axis, that ultimately impinges upon hypothalamic modules dedicated to autonomic function and motor pattern control. We will conclude by discussing implications for understanding disorders of "non-homeostatic" feeding., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Sigma receptor antagonists diminish the effects of cocaine in behavioral assays, including conditioned place preference. Previous locomotor activity experiments in mice determined that the sigma receptor ligand YZ-185 (N-phenylpropyl-N'-(3-methoxyphenethyl)piperazine) enhanced cocaine-induced hyperactivity at a lower (0.1  μ mol/kg) dose and dose-dependently attenuated cocaine-induced hyperactivity at higher (3.16-31.6  μ mol/kg) doses. The present study investigated the effect of YZ-185 on cocaine's conditioned-rewarding properties in mice. YZ-185 (0.1, 0.316, 3.16, and 31.6  μ mol/kg) did not have intrinsic activity to produce conditioned place preference or aversion. A higher (31.6  μ mol/kg) YZ-185 dose, but not lower (0.1-3.16  μ mol/kg) YZ-185 doses, prevented the development of place preference to cocaine (66  μ mol/kg). YZ-185 did not alter the expression of cocaine place preference. To further characterize YZ-185's behavioral profile, its effects in the elevated zero maze and rotarod procedures were also determined; YZ-185 produced no significant change from baseline in either assay, indicating that the sigma receptors probed by YZ-185 do not regulate anxiety-like or coordinated motor skill behaviors. Overall, these results suggest that YZ-185 is a sigma receptor antagonist at the 31.6  μ mol/kg dose and demonstrate that sigma receptors can mediate the development of the conditioned-rewarding properties of cocaine.

Multiple studies have reported prenatal stress as a potential risk factor for the development of autism spectrum disorder (ASD). In rodents, a significant reduction in sociability is seen in prenatally stressed offspring of genetically stress-susceptible dams. Certain dietary factors that contribute to stress reactivity may, therefore, exacerbate prenatal stress-mediated behavioral changes in adult offspring. Adults with a diet rich in omega-6 polyunsaturated fatty acids (PUFAs) display increased stress reactivity. In the current study, the effects of prenatal diet and prenatal stress on social behavior in adult offspring mice were examined. Pregnant C57BL/6J dams received either chronic variable stress or no stress, and were also placed on a control diet or a diet rich in omega-6 PUFAs, in a 2×2 design. We subsequently tested the adult offspring for sociability, anxiety, and locomotor behaviors using a 3-chambered social approach task, an elevated-plus maze, an open field task and a rotarod task. Results indicated that a maternal diet rich in omega-6 PUFAs during gestation and lactation produce changes in sociability consistent with those observed in ASD. Additionally, offspring exposed to a diet rich in omega-6 PUFAs during gestation and lactation had increased levels of anxiety in the elevated-plus maze. Prenatal stress had no effect on offspring behavior. These findings provide evidence for a possible environmental risk factor that contributes to the production of autistic-like behavior in mice., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Metabotropic glutamate receptor 5 (mGlu5) has been implicated in a variety of learning and memory processes and is important for avoidance learning. The present studies used an mGlu5 receptor positive allosteric modulator, 3-cyano-N-(1,3 diphenyl-1H-hyrazol-5-yl)benzamide (CDPPB), to characterize the importance of mGlu5 receptors in aversively- and appetitively-motivated spatial learning tasks (tasks in which the instrumental contingency involves discriminative cues that differ in spatial location). C57Bl/6 male mice were initially trained in the Barnes maze in the absence of drug. Subsequently, CDPPB (30mg/kg, i.p.), administered 20min prior to each of 3 daily reversal learning training sessions in the Barnes maze, significantly enhanced performance compared to vehicle-treated controls and had a significant effect on search strategy. Mice treated with CDPPB also displayed significantly less perseverative behavior than control-treated animals. In a second experiment, male Sprague-Dawley rats were trained in an appetitively-motivated, delayed alternation version of a T-maze. 30mg/kg CDPPB (s.c.), delivered 20min prior to each of 5 daily training sessions, enhanced the delay rats were able to withstand between the sample and choice portions of each T-maze trial. The present results emphasize the role of mGlu5 receptors in spatial learning tasks and support previous studies which report mGlu5 positive allosteric modulators can enhance learning in some tasks and may have potential as nootropic drugs., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Dopamine signaling in the nucleus accumbens (NAc) has been postulated to influence reward development towards drugs of abuse and exercise. Herein, we used generation 4-5 rats that were selectively bred to voluntary run high (HVR) versus low (LVR) distances in order to examine if dopamine-like 1 (D1) receptor modulation in the NAc differentially affects nightly voluntary wheel running between these lines. A subset of generation 5-6 HVR and LVR rats were also used to study the mRNA expression of key genes related to reward and addiction in the NAc (i.e., DRD1, DRD5, DRD2, Nr4a2, FosB, and BDNF). In a crossover fashion, a D1-like agonist SKF 82958 (2 μg per side) or D1-like full antagonist SCH 23390 (4 μg per side) was bilaterally injected into the NAc of HVR and LVR female Wistar rats prior to their high running nights. Notably, during hours 2-4 (between 2000 and 2300) of the dark cycle there was a significant decrement in running distances in the HVR rats treated with the D1 agonist (p=0.025) and antagonist (p=0.017) whereas the running distances in LVR rats were not affected. Interestingly, HVR and LVR rats possessed similar NAc concentrations of the studied mRNAs. These data suggest that: a) animals predisposed to run high distances on a nightly basis may quickly develop a rewarding response to exercise due to an optimal D1-like receptor signaling pathway in the NAc that can be perturbed by either activation or blocking, b) D1-like agonist or antagonist injections do not increase running distances in rats that are bred to run low nightly distances, and c) running differences between HVR and LVR animals are seemingly not due to the expression of the studied mRNAs. Given the societal prevalence of obesity and extraneous physical inactivity, future studies should be performed in order to further determine the culprit for the low running phenotype observed in LVR animals., (Copyright © 2011. Published by Elsevier Inc.)

Previous research has demonstrated that administration of μ-opioid receptor agonists into the nucleus accumbens increases high-fat diet consumption in sated rats and has shown a role of basolateral amygdala (BLA) activity in mediating this response. The present experiments were conducted to examine the role of BLA opioid transmission in mediating high-fat feeding driven by either intra-accumbens opioid activation or 24-h home cage food deprivation. Injection of the μ-opioid agonist, d-Ala2-NMe-Phe4-Glyol5-enkephalin (DAMGO) into the nucleus accumbens (0.25μg/0.5μl/side) increased consumption of a high-fat diet, and this effect was attenuated by pre-treatment with the opioid antagonist, naltrexone (5μg/0.25μl/side) administered into the BLA. In contrast, intra-BLA naltrexone administration had no influence on the increase in high-fat intake following 24-h food deprivation. These findings suggest that BLA opioid transmission is an important mediator of palatability-driven feeding as modeled by intra-accumbens opioid activation, while BLA opioid transmission has no significant influence on the increase in high-fat feeding driven by short-term negative-energy balance., (Copyright © 2010. Published by Elsevier Inc.)

Nucleus accumbens micro-opioid stimulation leads to robust increases in the intake of highly palatable foods, such as a high-fat diet. While interactions between opioids and certain striatal neurotransmitters underlying this phenomenon have been explored, many potential interactions have not. Striatal adenosine has been shown to have a significant influence on striatal neurotransmission and locomotor activity behavior, however the interaction between opioids and adenosine on feeding behaviors has received less attention. The present study explored this interaction within the context of opioid-driven consumption of a high-fat diet. Specifically, intra-accumbens administration of selective A1 and A2(A) adenosine receptor ligands, with or without concurrent administration of the micro-opioid agonist (D)-Ala(2),N,Me-Phe(4),Gly-ol(5)-enkaphalin (DAMGO), on high-fat consumption and associated locomotor activity was examined. The A1 receptor agonist 2-Chloro-N6-cyclopentyladenosine (CCPA) had no effect on either baseline or DAMGO-induced locomotor or consumption behaviors associated with the high-fat diet. However, the A2(A) receptor agonist 2-p-(2 carboxyethyl)-phenethylamino-5'-N-ethylcarboxamido adenosine hydrochloride (CGS 21680) and the prodrug of the A2(A) receptor antagonist MSX-2, 3-(3-hydroxypropyl)-8-(m-methoxystyryl)-7-methyl-1-propargylxanthine phosphate disodium salt (MSX-3) produced the expected decrease and increase in locomotor activity, respectively. CGS 21680 had no effect on baseline or DAMGO-driven consumption of the high-fat diet. MSX-3 had no effect on DAMGO-induced locomotor activity but increased DAMGO-induced consumption. Lastly, the increased activity and consumption produced by MSX-3 alone was blocked by prior administration of the opioid antagonist naltrexone. In summary, these results suggest a potential role of striatal adenosine A2(A) receptors in mediating baseline and striatal opioid-mediated intake of a high-fat diet.

The present experiments were conducted to provide a more detailed behavioral analysis of the dissociable roles of the basolateral (BLA) and central nucleus (CeA) of the amygdala in mediating intra-accumbens (Acb) opioid-induced feeding of a high-fat diet. Confirming previous findings, temporary inactivation of the CeA with the GABAA agonist muscimol reduced DAMGO (D-Ala2-NMe-Phe4-Glyol5-enkephalin)-induced and baseline food intake, whereas intra-BLA muscimol selectively blocked only DAMGO-induced food intake, leaving baseline feeding intact. However, although inactivation of the BLA reduced DAMGO-induced food intake to control levels, this treatment led to exaggerated number and duration of food hopper entries after food intake had ended. A subsequent experiment under conditions of limited access to the diet found the identical pattern of behavior following intra-Acb administration of DAMGO, regardless of whether the BLA was inactivated. Last, BLA inactivation was shown to have no influence on feeding driven by a state of negative-energy balance (24-hr food deprivation), demonstrating a specific influence of the BLA on opioid-driven feeding. These findings suggest that BLA mediates palatability-driven feeding and that this influence is particular to the consummatory act of ingestion., (2009 APA, all rights reserved)

There have been many trials describing the effects of polyunsaturated fatty acids (PUFA) on fecundity, neonatal development, and maternal behavior in humans, but few controlled studies in rodents. We examined the effects of a maternal diet high in omega 3 (N-3) or omega 6 (N-6) PUFA on NIH Swiss mice. Female mice were ad libitum fed one of three complete and balanced diets (N-3, enriched in menhaden oil; N-6, enriched in corn oil; C, control diet, Purina 5015) from age 4 wk until the end of the study. Mice were bred at approximately 19 wk and 27 wk of age, providing a total of 838 pups from 129 litters in two experiments. After weaning their pups from parity 1, behavior of dams was assessed on elevated-plus and open-field mazes. Although the fraction of male pups from the N-3 and C groups was not different from 0.5, dams on the N-6 diet birthed more daughters than sons (213 vs. 133; P < 0.001). Although maternal stress has been reported to favor birth of daughters, the behavior of N-6 dams was not different from controls. By contrast, the N-3 dams displayed greater anxiety, spending less time in the open arms and more time in the closed arms of the elevated maze and traveling less distance and exhibiting less exploratory behavior in the open field (P < 0.05). N-3 dams tended to produce smaller litters than C dams, and N-3-suckled pups gained less weight (P < 0.05). In conclusion, the N-3 diet had negative effects on murine fecundity and maternal behavior, whereas the N-6 diet favored birth of daughters.

It has long been known that central opioid systems play an important role in certain aspects of appetite and food intake, particularly with regard to the hedonic or rewarding impact of calorically dense food, such as fat and sugar. Ventral striatal enkephalin may be a key component of this system, as infusions of mu-opiate agonists into this region strongly increase feeding, whereas infusions of opiate antagonists decrease food intake. While pharmacological analysis has consistently supported such a role, direct measurement of enkephalin gene expression in relation to differing food motivational conditions has not been examined. In this study, the effects of a restricted laboratory chow diet (resulting in negative energy balance) as well has recent consumption of chow (short-term satiety) on striatal preproenkephalin (PPE) and prodynorphin (PD) mRNA expression were measured in rats, using both Northern blot analysis and in situ hybridization methods. As a comparison, hypothalamic (arcuate nucleus) neuropeptide Y (NPY) was also measured in these conditions. PPE expression was broadly downregulated throughout the striatum in animals that had recently consumed a meal, whereas it was unaffected by negative energy balance. Expression of an additional striatal peptide gene, PD, did not follow this pattern, although diet restriction caused a decrease in accumbens core dynorphin mRNA. Conversely, as expected, arcuate nucleus NPY mRNA expression was markedly upregulated by negative energy balance, but was unchanged by recent food consumption. This double dissociation between striatal and hypothalamic peptide systems suggests a specific role for striatal PPE in relatively short-term food motivational states, but not in long-term metabolic responses to diet restriction.

Nucleus accumbens mu-opioid stimulation causes marked increases in the intake of highly palatable foods, such as a high-fat diet. However, to date there has been little examination of how other striatal neurotransmitters may mediate opioid-driven feeding of palatable foodstuffs. In the current study, free feeding rats with bilateral cannulae aimed at the nucleus accumbens received intra-accumbens pretreatment with antagonists for dopamine D-1 (SCH23390; 0 microg or 1 microg/0.5 microl/side), dopamine D-2 (raclopride; 0 microg or 2.0 microg/0.5 microl/side), AMPA (LY293558; 0 microg, 0.01 microg or 0.10 microg/0.5 microl/side), muscarinic (scopolamine 0 microg, 0.1, 1.0, or 10 microg/0.5 microl/side) or nicotinic (mecamylamine; 0 microg, 10 microg/0.5 microl/side) receptors, immediately prior to infusions of the mu-receptor agonist D-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO; 0.25 microg/0.5 microl) or vehicle. The effects of these pretreatments on 2 hr fat intake was compared to pretreatment with a general opioid antagonist (naltrexone; 0 microg or 20 microg/0.5 microl/side). DAMGO-induced feeding was unaffected by prior antagonism of dopamine, glutamate, or nicotinic receptors. As expected, naltrexone infusions blocked DAMGO-elicited fat intake. Antagonism of muscarinic acetylcholine receptors reduced feeding in both the DAMGO and vehicle-treated conditions. In an additional experiment, cholinergic receptor stimulation alone did not affect intake of the fat diet, suggesting that nucleus accumbens cholinergic stimulation is insufficient to alter feeding of a highly palatable food. These data suggest that the feeding effects caused by striatal opioid stimulation are independent from or downstream to the actions of dopamine and glutamate signaling, and provide novel insight into the role of striatal acetylcholine on feeding behaviors.

Work over the past decade has supported the idea that discrete aspects of appetitive motivation are differentially mediated by separate but interacting neurochemical systems within the nucleus accumbens (Acb). We review herein a series of studies in rats comparing the effects of manipulating Acb amino acid, opioid, acetylcholine, and dopamine systems on tests of free-feeding and food-reinforced operant responding. Results from our laboratory and in the literature support three general conclusions: (1) GABA output neurons localized exclusively within the Acb shell directly influence hypothalamic effector mechanisms for feeding motor patterns, but do not participate in the execution of more complex food-seeking strategies; (2) enkephalinergic neurons distributed throughout the Acb and caudate-putamen mediate the hedonic impact of palatable (high sugar/fat) foods, and these neurons are under modulatory control by striatal cholinergic interneurons; and (3) dopamine transmission in the Acb governs general motoric and arousal processes related to response selection and invigoration, as well as motor learning-related plasticity. These dissociations may reflect the manner in which these neurochemical systems differentially access pallido-thalamo-cortical loops reaching the voluntary motor system (in the case of opioids and dopamine), versus more restricted efferent connections to hypothalamic motor/autonomic control columns (in the case of Acb shell GABA and glutamate systems). Moreover, we hypothesize that while these systems work in tandem to coordinate the anticipatory and consummatory phases of feeding with hypothalamic energy-sensing substrates, the striatal opioid network evolved a specialized capacity to promote overeating of energy-dense foods beyond acute homeostatic needs, to ensure an energy reserve for potential future famine.

Penetrating, perforating, and avulsive fragmentation injuries present a unique surgical challenge for oral and maxillofacial surgeons in the Iraqi theater of operation. Maxillofacial injuries encountered in Operation Iraqi Freedom I and Operation Iraqi Freedom II have presented injury patterns not encountered previously in other large-scale armed conflicts. Current literature in the field of oral and maxillofacial surgery does not cover adequately the concerns that are inherent to care and treatment planning at an echelon III facility. This article addresses clinical and surgical practice guidelines that were developed by oral surgeons in theater and from feedback they received from higher echelons of care.

The management of complex maxillofacial injuries sustained in modern warfare or terrorist attack has presented military surgeons with a new form of injury pattern previously not discussed in the medical literature. The unique wounding characteristics of the IED, the portability of the weapon platform, and the relative low cost of development make it an ideal weapon for potential terrorist attacks. If potential future terrorist attacks in the United States follow the same pattern as the incidents currently unfolding in the Middle East, civilian practitioners will be required to manage these wounds early for primary surgical intervention and late for secondary and tertiary reconstructive efforts.

Rationale: Stress and one of the physiological components of most stress responses, glucocorticoid hormones (CORT), are known to influence the rewarding effects of a number of drugs of abuse. We have previously shown that an acute uncontrollable stressor (inescapable shock, IS) potentiates the rewarding effects of morphine using conditioned place preference (CPP)., Objectives: The following experiments were conducted to determine the role of CORT in this process., Methods: First, the CORT response to 3.0 mg/kg morphine was measured in male Sprague-Dawley rats 24 h following exposure to IS. Second, we determined the effect of adrenalectomy (ADX) on the IS-potentiated CPP to morphine. Finally, we used the temporary CORT synthesis inhibitors metyrapone and aminoglutethimide to determine the necessity of CORT rises during either IS or morphine administration on the potentiated CPP response., Results: Prior IS significantly potentiated the CORT response to morphine. ADX significantly blocked the potentiated CPP to morphine produced by previous IS. However, CORT inhibition during IS had no effect on the IS potentiation of morphine CPP, whereas inhibition during morphine administration completely blocked this potentiation., Conclusions: The results indicate that the CORT response to morphine is enhanced in rats that were previously exposed to an uncontrollable stressor, and that this response to the drug, not the stressor, is necessary for the stress-enhanced potentiation of morphine CPP.

Endogenous opioid peptides within the nucleus accumbens are thought to mediate the hedonic aspects of food intake, particularly foods such as fat and sugar. In view of evidence that the amygdala also regulates positive affect, we hypothesized this brain region participates in the control of opioid-mediated food intake. The robust increase in the intake of fat following intra-accumbens administration of the mu-opioid agonist D-Ala2,Nme-Phe4,Glyol5-enkephalin (DAMGO) was completely blocked by concurrent temporary inactivation (muscimol, GABA(A) agonist) of either the basolateral or central nucleus of the amygdala. In summary, we demonstrate that amygdala inactivation prevents the intra-accumbens opioid induced "binge" eating of fat, possibly through reducing the hedonic properties of high-fat palatable food.

Rationale: Exposure to a single session of uncontrollable inescapable shock (IS), but not to identical controllable escapable shock, produces a potentiation of morphine's rewarding properties that is unusual in that the stressor can be given a number of days before the drug administration in an environment quite different from the drug context. Many other behavioral outcomes of stressors that depend on the uncontrollability of the stressor are mediated by alterations in serotonergic (5-HT) neurons within the dorsal raphe nucleus (DRN)., Objectives: The present experiments examined the role of the DRN and 5-HT in mediating the effect of IS on the rewarding properties of morphine as assessed by conditioned place preference (CPP)., Methods: In experiment 1, subjects received small electrolytic lesions of the DRN and were tested for morphine (3.0 mg/kg, SC) CPP after IS or control treatment. In experiment 2, subjects received an intra-DRN microinjection of the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 1.0 microg/0.5 microl) either before IS or before morphine (3.0 mg/kg, SC) injections during CPP testing., Results: IS potentiated morphine CPP in controls, but both DRN lesion and intra-DRN 8-OH-DPAT, either before IS or before morphine administration, completely blocked this effect., Conclusions: These data implicate alterations in DRN 5-HT neurons in the potentiation of morphine reward produced by uncontrollable stress.

Brain opioid peptide systems are known to play an important role in motivation, emotion, attachment behaviour, the response to stress and pain, and the control of food intake. Opioid peptides within the ventral striatum are thought to play a key role in the latter function, regulating the affective response to highly palatable, energy-dense foods such as those containing fat and sugar. It has been shown previously that stimulation of mu opiate receptors within the ventral striatum increases intake of palatable food. In the present study, we examined enkephalin peptide gene expression within the striatum in rats that had been given restricted daily access to an energy-dense, palatable liquid food, chocolate Ensure(R). Rats maintained on an ad libitum diet of rat chow and water were given 3-h access to Ensure(R) daily for two weeks. One day following the end of this period, preproenkephalin gene expression was measured with quantitative in situ hybridization. Compared with control animals, rats that had been exposed to Ensure(R) had significantly reduced enkephalin gene expression in several striatal regions including the ventral striatum (nucleus accumbens), a finding that was confirmed in a different group with Northern blot analysis. Rats fed this regimen of Ensure(R) did not differ in weight from controls. In contrast to chronic Ensure(R), acute ingestion of Ensure(R) did not appear to affect enkephalin peptide gene expression. These results suggest that repeated consumption of a highly rewarding, energy-dense food induces neuroadaptations in cognitive-motivational circuits.

Endogenous opioid peptides within the nucleus accumbens, a forebrain site critical for the regulation of reward-related behavior, are believed to play an important role in the control of appetite. In particular, this system is thought to mediate the hedonic aspects of food intake, governing the positive emotional response to highly palatable food such as fat and sugar. Previous work has shown that intra-accumbens administration of the mu-opioid agonist D-Ala2,Nme-Phe4,Glyol5-enkephalin (DAMGO) markedly increases food intake and preferentially enhances the intake of palatable foods such as fat, sucrose, and salt. Using information from recently performed c-fos mapping experiments, we sought to explore the involvement of structures efferent to the nucleus accumbens in this feeding response. Free-feeding rats with dual sets of bilateral cannulas aimed at the nucleus accumbens and one of several output structures were infused with DAMGO (0, 0.25 microg/0.5 microl) in the accumbens, and fat intake was measured over a 2 hr period. Concurrent temporary inactivation with the GABA(A) agonist muscimol (5-20 ng/0.25 microl) of the dorsomedial hypothalamic nucleus, lateral hypothalamus, ventral tegmental area, or the intermediate region of the nucleus of the solitary tract blocked the robust increase in fat intake induced by intra-accumbens DAMGO at doses of muscimol that did not affect general motor activity. Muscimol alone also inhibited and augmented baseline fat intake in the lateral and dorsomedial hypothalamic nuclei, respectively. These results suggest that intake of energy-dense palatable food is controlled by activity in a neural network linking ventral striatal opioids with diencephalic and brainstem structures.

Previous research has shown that the effect of exposure to uncontrollable stressors on conditioned fear responding and escape behavior in rats is dependent on serotonergic neural activity in the dorsal raphe nucleus (DRN). The role that norepinephrine released in the DRN plays in producing the behavioral consequences of exposure to inescapable tail shock in rats was investigated in the present study. The selective alpha1 adrenoreceptor antagonist benoxathian was injected into the DRN before exposure to inescapable tail shock or before behavioral testing conducted 24 h later. Benoxathian prevented the impairment of escape responding produced by inescapable shock, but did not reverse this effect when given before testing. The enhancement of conditioned fear produced by prior inescapable shock was attenuated by benoxathian administered before inescapable shock or before behavioral testing. These results support the view that noradrenergic input to the DRN is necessary to produce the behavioral effects of inescapable tail shock., (Copyright 2002 Elsevier Science B.V.)

There is a long-standing interest in the role of endogenous opioid peptides in feeding behavior and, in particular, in the modulation of food reward and palatability. Since drugs such as heroin, morphine, alcohol, and cannabinoids, interact with this system, there may be important common neural substrates between food and drug reward with regard to the brain's opioid systems. In this paper, we review the proposed functional role of opioid neurotransmission and mu opiate receptors within the nucleus accumbens and surrounding ventral striatum. Opioid compounds, particularly those selective for the mu receptor, induce a potent increase in food intake, sucrose, salt, saccharin, and ethanol intake. We have explored this phenomenon with regard to macronutrient selection, regional specificity, role of output structures, Fos mapping, analysis of motivational state, and enkephalin gene expression. We hypothesize that opioid-mediated mechanisms within ventral striatal medium spiny neurons mediate the affective or hedonic response to food ('liking' or food 'pleasure'). A further refinement of this hypothesis is that activation of ventral striatal opioids specifically encodes positive affect induced by tasty and/or calorically dense foods (such as sugar and fat), and promotes behaviors associated with this enhanced palatability. It is proposed that this brain mechanism was beneficial in evolutionary development for ensuring the consumption of relatively scarce, high-energy food sources. However, in modern times, with unlimited supplies of high-calorie food, it has contributed to the present epidemic of obesity.

We have recently demonstrated that exposure to a single session of inescapable shock (IS), but not to identical amounts and distributions of escapable shock (ES), increases the rewarding properties of morphine, as measured by conditioned place preference (CPP). Interestingly, we also found that exposure to IS has no effect, or even interferes with amphetamine CPP. The present study explored whether the potentiating effect of IS on morphine reward, but not amphetamine reward, would generalize to the locomotor properties of these drugs. The locomotor response to morphine and amphetamine was measured 120 h following exposure to either IS or home cage control (HCC) treatment. On test day, the activity of all subjects was measured for 1 h before and 3 h after drug administration. The results demonstrated that exposure to IS potentiated the locomotor response to morphine, while having no effect on the response to amphetamine. An additional study investigated whether the effects of IS on the locomotor properties of morphine were sensitive to stressor controllability, by comparing the influence of IS, ES, or control treatment. Again, IS potentiated the locomotor properties of morphine, while exposure to ES and control treatment had no effect.