Environmental and climate variability drive population size of annual penaeid shrimp in a large lagoonal estuary.

Species with short life spans frequently show a close relationship between population abundance and environmental variation making these organisms potential indicator species of climatic variability. White (Penaeus setiferus), brown (P. aztecus), and pink (P. duorarum) penaeid shrimp typically have an annual life history and are of enormous ecological, cultural, and economic value to the southeastern United States and Gulf of Mexico. Within North Carolina, all three species rely on the Pamlico Sound, a large estuarine system that straddles Cape Hatteras, one of the most significant climate and biogeographic breaks in the world, as a nursery area. These characteristics make penaeid species within the Pamlico Sound a critical species-habitat complex for assessing climate impacts on fisheries. However, a comprehensive analysis of the influence of the environmental conditions that influence penaeid shrimp populations has been lacking in North Carolina. In this study, we used more than 30 years of data from two fishery-independent trawl surveys in the Pamlico Sound to examine the spatial distribution and abundance of adult brown, white, and pink shrimp and the environmental drivers associated with adult shrimp abundance and juvenile brown shrimp recruitment using numerical models. Brown shrimp recruitment models demonstrate that years with higher temperature, salinity, offshore windstress, and North Atlantic Oscillation phase predict increased abundance of juveniles. Additionally, models predicting adult brown, white, and pink shrimp abundance illustrate the importance of winter temperatures, windstress, salinity, the North Atlantic Oscillation index, and the abundance of spawning adult populations from the previous year on shrimp abundance. Our findings show a high degree of variability in shrimp abundance is explained by climate and environmental variation and indicate the importance of understanding these relationships in order to predict the impact of climate variability within ecosystems and develop climate-based adaptive management strategies for marine populations.

Brief Oil Exposure Reduces Fitness in Wild Gulf of Mexico Mahi-Mahi (Coryphaena hippurus).

The Deepwater Horizon (DWH) disaster released 3.19 million barrels of crude oil into the Gulf of Mexico (GOM) in 2010, overlapping the habitat of pelagic fish populations. Using mahi-mahi (Coryphaena hippurus)─a highly migratory marine teleost present in the GOM during the spill─as a model species, laboratory experiments demonstrate injuries to physiology and behavior following oil exposure. However, more than a decade postspill, impacts on wild populations remain unknown. To address this gap, we exposed wild mahi-mahi to crude oil or control conditions onboard a research vessel, collected fin clip samples, and tagged them with electronic tags prior to release into the GOM. We demonstrate profound effects on survival and reproduction in the wild. In addition to significant changes in gene expression profiles and predation mortality, we documented altered acceleration and habitat use in the first 8 days oil-exposed individuals were at liberty as well as a cessation of apparent spawning activity for at least 37 days. These data reveal that even a brief and low-dose exposure to crude oil impairs fitness in wild mahi-mahi. These findings offer new perspectives on the lasting impacts of the DWH blowout and provide insight about the impacts of future deep-sea oil spills.

Magnesium transport in the aglomerular kidney of the Gulf toadfish (Opsanus beta).

Despite having an aglomerular kidney, Gulf toadfish can survive in water ranging from nearly fresh up to 70 parts per thousand salinity. In hyperosmotic environments, the major renal function is to balance the passive Mg2+ load from the environment with an equal excretion. However, the molecular transporters involved in Mg2+ secretion are poorly understood. We investigated whether environmental MgCl2 alone or in combination with elevated salinity affected transcriptional regulation of genes classically involved in renal Mg2+ secretion (slc41a1, slc41a3, cnnm3) together with three novel genes (trpm6, trpm7, claudin-19) and two isoforms of the Na+/K+-ATPase α-subunit (nka-α1a, nka-α1b). First, toadfish were acclimated to 5, 9, 35, or 60 ppt water (corresponding to ~ 7, 13, 50 and 108 mmol L-1 ambient [Mg2+], respectively) and sampled at 24 h or 9 days. Next, the impact of elevated ambient [Mg2+] was explored by exposing toadfish to control (50 mmol L-1 Mg2+), or elevated [Mg2+] (100 mmol L-1) at a constant salinity for 7 days. Mg2+ levels in this experiment corresponded with levels in control and hypersaline conditions in the first experiment. A salinity increase from 5 to 60 ppt stimulated the level of all investigated transcripts in the kidney. In Mg2+-exposed fish, we observed a 14-fold increase in the volume of intestinal fluids and elevated plasma osmolality and [Mg2+], suggesting osmoregulatory challenges. However, none of the renal gene targets changed expression compared with the control group. We conclude that transcriptional regulation of renal Mg2+ transporters is induced by elevated [Mg2+] in combination with salinity rather than elevated ambient [Mg2+] alone.

Detection of dengue virus serotype 2 (DENV-2) in population of Aedes mosquitoes from Sibu and Miri divisions of Sarawak using reverse transcription polymerase chain reaction (RT-PCR) and semi-nested PCR.

Dengue has been a public health concern for many years in Malaysia. Having knowledge on the current circulating dengue serotypes and population of vector mosquitoes is key in controlling outbreaks and future outbreak predictions. The current study reports the first study on detecting dengue virus serotypes in the Aedes mosquito population in Sibu and Miri divisions of Sarawak. Mosquito samples were collected at selected localities from September 2016 to December 2017. Localities were selected mainly focussing on urban residential areas. The mosquitoes collected comprises of the field-caught adults and immatures collected from artificial and natural water containers. Collected mosquitoes were identified to species level and screened for the presence of dengue virus using conventional reverse transcription polymerase chain reaction (RT-PCR). Dengue virus serotype 2 (DENV-2) was identified in 3 pools of field-caught female Aedes albopictus adults collected from Jalan Tong Sang, Sibu, Sibu Lake Garden, and Taman Ceria, Permyjaya, Miri, respectively. DENV-2 was also detected in one pool of adult male Ae. albopictus emerged from immatures collected from Taman Ceria, Permyjaya, Miri. The findings in this study revealed that Ae. albopictus was the main species colonizing the study areas, and the current circulating dengue virus serotype was DENV-2. This study also reports the first natural evidence of transovarial transmission of dengue in the natural population of Ae. albopictus within the study area and provides information as reference for further vector-pathogen studies.

Detection of dengue virus serotype 2 (DENV-2) in population of Aedes mosquitoes from Sibu and Miri divisions of Sarawak using reverse transcription polymerase chain reaction (RT-PCR) and semi-nested PCR

@#Dengue has been a public health concern for many years in Malaysia. Having knowledge on the current circulating dengue serotypes and population of vector mosquitoes is key in controlling outbreaks and future outbreak predictions. The current study reports the first study on detecting dengue virus serotypes in the Aedes mosquito population in Sibu and Miri divisions of Sarawak. Mosquito samples were collected at selected localities from September 2016 to December 2017. Localities were selected mainly focussing on urban residential areas. The mosquitoes collected comprises of the field-caught adults and immatures collected from artificial and natural water containers. Collected mosquitoes were identified to species level and screened for the presence of dengue virus using conventional reverse transcription polymerase chain reaction (RT-PCR). Dengue virus serotype 2 (DENV-2) was identified in 3 pools of field-caught female Aedes albopictus adults collected from Jalan Tong Sang, Sibu, Sibu Lake Garden, and Taman Ceria, Permyjaya, Miri, respectively. DENV-2 was also detected in one pool of adult male Ae. albopictus emerged from immatures collected from Taman Ceria, Permyjaya, Miri. The findings in this study revealed that Ae. albopictus was the main species colonizing the study areas, and the current circulating dengue virus serotype was DENV-2. This study also reports the first natural evidence of transovarial transmission of dengue in the natural population of Ae. albopictus within the study area and provides information as reference for further vector-pathogen studies.

Exposure to Crude Oil from the Deepwater Horizon Oil Spill Impairs Oil Avoidance Behavior without Affecting Olfactory Physiology in Juvenile Mahi-Mahi (Coryphaena hippurus).

The understanding of the detection threshold and behavioral response of fishes in response to crude oil is critical to predicting the effects of oil spills on wild fish populations. The Deepwater Horizon oil spill released approximately 4.9 million barrels of crude oil into the northern Gulf of Mexico in 2010, overlapping spatially and temporally with the habitat of many pelagic fish species. Yet, it is unknown whether highly migratory species, such as mahi-mahi (Coryphaena hippurus), might detect and avoid oil contaminated waters. We tested the ability of control and oil-exposed juvenile mahi-mahi (15-45 mm) to avoid two dilutions of crude oil in a two-channel flume. Control fish avoided the higher concentration (27.1 µg/L Σ50PAH), while oil-exposed (24 h, 18.0 µg/L Σ50PAH) conspecifics did not. Electro-olfactogram (EOG) data demonstrated that both control and oil-exposed (24 h, 14.5 µg/L Σ50PAH) juvenile mahi-mahi (27-85 mm) could detect crude oil as an olfactory cue and that oil-exposure did not affect the EOG amplitude or duration in response to oil or other cues. These results show that a brief oil exposure impairs the ability of mahi-mahi to avoid oil and suggests that this alteration likely results from injury to higher order central nervous system processing rather than impaired olfactory physiology.

Damsels in Distress: Oil Exposure Modifies Behavior and Olfaction in Bicolor Damselfish (Stegastes partitus).

In fishes, olfactory cues evoke behavioral responses that are crucial to survival; however, the receptors, olfactory sensory neurons, are directly exposed to the environment and are susceptible to damage from aquatic contaminants. In 2010, 4.9 million barrels of crude oil were released into the northern Gulf of Mexico from the Deepwater Horizon disaster, exposing marine organisms to this environmental contaminant. We examined the ability of bicolor damselfish (Stegastes partitus), exposed to the water accommodated fraction (WAF) of crude oil, to respond to chemical alarm cue (CAC) using a two-channel flume. Control bicolor damselfish avoided CAC in the flume choice test, whereas WAF-exposed conspecifics did not. This lack of avoidance persisted following 8 days of control water conditions. We then examined the physiological response to CAC, brine shrimp rinse, bile salt, and amino acid cues using the electro-olfactogram (EOG) technique and found that WAF-exposed bicolor damselfish were less likely to detect CAC as an olfactory cue but showed no difference in EOG amplitude or duration compared to controls. These data indicate that a sublethal WAF exposure directly modifies detection and avoidance of CAC beyond the exposure period and may suggest reduced predator avoidance behavior in oil-exposed fish in the wild.

Assessment of early life stage mahi-mahi windows of sensitivity during acute exposures to Deepwater Horizon crude oil.

Windows of exposure to a weathered Deepwater Horizon oil sample (slick A) were examined for early life stage mahi-mahi (Coryphaena hippurus) to determine whether there are developmental periods of enhanced sensitivity during the course of a standard 96-h bioassay. Survival was assessed at 96 h following oil exposures ranging from 2 h to 96 h and targeting 3 general periods of development, namely the prehatch phase, the period surrounding hatch, and the posthatch phase. In addition, 3 different oil preparations were used: high- and low-energy water accommodated fractions of oil and very thin surface slicks of oil (∼1 µm). The latter 2 were used to distinguish between effects due to direct contact with the slick itself and the water underlying the slick. Considering the data from all 3 exposure regimes, it was determined that the period near or including hatch was likely the most sensitive. Furthermore, toxicity was not enhanced by direct contact with slick oil. These findings are environmentally relevant given that the concentrations of polycyclic aromatic hydrocarbons eliciting mortality from exposures during the sensitive periods of development were below or near concentrations measured during the active spill phase. Environ Toxicol Chem 2017;36:1887-1895. © 2016 SETAC.

Physiological stress and post-release mortality of white marlin (Kajikia albida) caught in the United States recreational fishery.

White marlin, a highly migratory pelagic marine fish, support important commercial and recreational fisheries throughout their range in the tropical and subtropical Atlantic Ocean. More than 10 000 individuals can be caught annually in the United States recreational fishery, of which the vast majority are captured on circle hooks and released alive. The probability of post-release mortality of white marlin released from circle hooks has been documented to be <0.02, but the associated physiological stress resulting from capture and handling techniques has not been characterized despite its importance for understanding the health of released fish. We examined the physiological response of 68 white marlin caught on circle hooks in the recreational fishery and followed the fate of 22 of these fish with pop-up satellite archival tags programmed to release after 30 days. Measures of plasma sodium, chloride, glucose and lactate concentrations taken from fish that were briefly and consistently (mean = 120 s, standard deviation = 40 s) removed from the water increased with angling time, but post-release mortality was inversely related to angling time. The probability of post-release mortality was predicted by elevated plasma potassium concentrations and was more than 10 times greater than has been previously reported for white marlin caught on circle hooks that were not removed from the water. This disparity in estimates of post-release mortality suggests that removal of fish from the water for physiological sampling greatly heightens stress, disrupts homeostasis and thus increases the probability of post-release mortality. Our results demonstrate that elevated concentrations of plasma potassium predict mortality in white marlin and that the probability of post-release mortality is highly dependent on post-capture handling procedures.

Time- and Oil-Dependent Transcriptomic and Physiological Responses to Deepwater Horizon Oil in Mahi-Mahi (Coryphaena hippurus) Embryos and Larvae.

The Deepwater Horizon (DWH) oil spill contaminated the spawning habitats for numerous commercially and ecologically important fishes. Exposure to the water accommodated fraction (WAF) of oil from the spill has been shown to cause cardiac toxicity during early developmental stages across fishes. To better understand the molecular events and explore new pathways responsible for toxicity, RNA sequencing was performed in conjunction with physiological and morphological assessments to analyze the time-course (24, 48, and 96 h post fertilization (hpf)) of transcriptional and developmental responses in embryos/larvae of mahi-mahi exposed to WAF of weathered (slick) and source DWH oils. Slick oil exposure induced more pronounced changes in gene expression over time than source oil exposure. Predominant transcriptomic responses included alteration of EIF2 signaling, steroid biosynthesis, ribosome biogenesis and activation of the cytochrome P450 pathway. At 96 hpf, slick oil exposure resulted in significant perturbations in eye development and peripheral nervous system, suggesting novel targets in addition to the heart may be involved in the developmental toxicity of DHW oil. Comparisons of changes of cardiac genes with phenotypic responses were consistent with reduced heart rate and increased pericardial edema in larvae exposed to slick oil but not source oil.

Factors associated with adolescents' propensity to drive with multiple passengers and to engage in risky driving behaviors.

PURPOSE: Research shows that parenting factors and individual difference variables, such as sensation seeking (SS) and risk perceptions (RPs), are associated with increased motor vehicle crash risk for young drivers. The presence of peer passengers is also known to be associated with increased crash risk. However, as previous studies did not study these factors concurrently, less is known about the factors that are associated with driving with peer passengers and if peer passengers may mediate the effect of parenting and individual difference variables on adolescents' engagement in risky driving behavior. METHODS: We examined predictors of driving with multiple passengers (DWMPs) and explored it as a potential mediator of pathways from three factors: (1) SS, (2) RPs, and (3) Parental monitoring and rule-setting to risky driving behaviors in a convenience sample of 198 adolescent drivers using a cross-sectional Web-based survey. RESULTS: Findings indicate that both stronger RPs and perceiving parents as strong monitors and rule setters were associated with less engagement in risky driving, whereas greater SS was associated with more engagement in risky driving; RPs, monitoring, and SS were also significantly associated with DWMPs in these same directions. DWMPs partially mediated the effect of these risk factors on risky driving behavior. CONCLUSIONS: Results inform theory and policy by examining factors associated with risk taking in the context of adolescent driving. Interventions can be developed to complement graduated driver licensing laws by targeting individual difference variables and decreasing opportunities for peer passenger carriage.

Seasonal variations in the physiological stress response to discrete bouts of aerial exposure in the little skate, Leucoraja erinacea.

Aerial exposure and acute thermal stress have been shown to elicit profound physiological disruptions in obligate water-breathing teleosts. However, no study has investigated these responses in an elasmobranch. To address this, venous blood samples were collected and evaluated from little skates (Leucoraja erinacea) subjected to discrete aerial exposure durations (0, 15, and 50 min) coupled with differing abrupt thermal changes (gradient between seawater and air; winter: ΔT=-3 °C; summer: ΔT=+9 °C) in two distinct laboratory studies. In general, blood acid-base properties (e.g. decline in pH; elevation in PCO(2)) and select metabolites (elevated whole-blood lactate) and electrolytes (elevated plasma K(+)) were significantly disrupted by aerial exposure, and were most disturbed after skates were exposed to air for 50 min. However, the magnitude of the blood acid-base perturbations, metabolic contribution to the resulting blood acidosis, elevations to ionic and metabolic parameters, and delayed mortality were more extreme during the summer study, suggesting that acute thermal stress exacerbates the physiological impairments associated with aerial exposure in little skates. Conversely, a reduced thermal gradient (from seawater to air) may attenuate the magnitude of metabolic and ionic perturbations, resulting in a high physiological threshold for coping with extended aerial exposure.

Adolescent drivers' perceptions of the advantages and disadvantages of abstention from in-vehicle cell phone use.

Driver in-vehicle cell phone use presents a dangerous distraction for adolescent drivers for whom motor vehicle crashes represents the leading cause of death. We used the National Young Driver Survey (NYDS), a nationally representative (N=5665) cross-sectional study of adolescent driving behavior, to examine potential psychosocial correlates of cell phone use while driving (CPWD). Results indicated that stronger beliefs about the advantages of abstention from CPWD were associated with less frequent CPWD, adjusted OR: 0.46 95% [CI: 0.40-0.53]), while stronger beliefs about the disadvantages of abstention were associated with more frequent CPWD, adjusted OR: 1.41 95% CI: [1.21-1.64]. In the absence of strong advantage beliefs, disadvantage beliefs did not have a meaningful association with less frequent CPWD. Almost 30% of adolescents held weaker advantage beliefs coupled with stronger disadvantage beliefs, placing them most at risk. These findings offer guidance for a wide range of intervention and health promotion efforts.

Bisphosphonate treatment in polyostotic fibrous dysplasia of the cranium: case report and literature review.

OBJECTIVE: To report the case of a patient with polyostotic fibrous dysplasia of the cranium who showed dramatic improvement after treatment with intravenous zoledronic acid. METHODS: We present the clinical findings, laboratory test results, surgical pathology report, and imaging studies of a man with extensive fibrous dysplasia of the cranium and review the literature regarding the use of bisphosphonates in patients with this debilitating skeletal disorder. RESULTS: A 32-year-old man presented with chronic occipital headache, and computed tomography of the head revealed extensive bony lesions of the middle and posterior cranial fossa. Bone biopsy confirmed the diagnosis of fibrous dysplasia. Laboratory blood test results revealed elevated serum alkaline phosphatase (140 U/L [reference range, 39-117 U/L]) and elevated serum bone-specific alkaline phosphatase (30.6 µg/L [reference range, 6-20 µg/L]). The patient was treated with intravenous pamidronate without improvement, and therapy was switched to zoledronic acid, which resulted in rapid resolution of headache symptoms, decrease in bone-specific alkaline phosphatase levels to 24.9 µg/L, and dramatic radiologic improvement on repeated computed tomography of the head. CONCLUSIONS: The treatment options for fibrous dysplasia of the cranium have been limited to conservative follow-up or surgery, and the use of zoledronic acid in this condition has not been previously reported. Intravenous bisphosphonate therapy is suggested to be a useful option in the treatment of cranial fibrous dysplasia.

Effects of age and weight-based dosing of enoxaparin on anti-factor xa levels in pediatric patients.

OBJECTIVE: The objective of this dose range study is to expand on the relationship between age and weight-based doses of enoxaparin and resulting levels of anti-factor Xa (anti-Xa) in pediatric patients. The primary outcome of this study is to determine the average dose of enoxaparin required to produce a therapeutic effect. Secondary outcomes include the number of enoxaparin dose changes required to achieve a therapeutic level of anti-Xa in each age group, the success rates of achieving and maintaining therapeutic anti-Xa levels, and the effect of serum antithrombin concentrations on anti-Xa levels. The study will also determine whether different dispensed concentrations of enoxaparin play a role in achieving therapeutic levels of anti-Xa. METHODS: Single center, retrospective chart review. Patients were excluded from the study if they were older than 18 years of age, were receiving enoxaparin for prophylactic purposes, had a creatinine clearance < 30 ml/min/1.73m(2), and if no anti-factor Xa levels were drawn. RESULTS: Average enoxaparin doses required for therapeutic levels of anti-factor Xa were 1.8 mg/kg for patients <1 month, 1.64 mg/kg (1 month to 1 year), 1.45 mg/kg (1 to 6 years), and 1.05 mg/kg (>6 years of age). An average of 3.24 dose changes was required for neonates to achieve therapeutic levels anti-factor Xa. The success rates for achieving and maintaining therapeutic levels were both 41%. Patients with low serum antithrombin levels were more likely to have low anti-Xa levels than those with normal or high values, 52% vs 40% vs 18%, respectively. Patients receiving diluted concentrations, 10 or 20 mg/mL, experienced lower anti-Xa levels than patients who received the standard manufactured concentration of 100 mg/mL, 61% vs 33%. CONCLUSION: Based on this dose-range study, enoxaparin should be initiated at larger doses than recommended by the current guidelines to promptly achieve therapeutic anti-Xa levels. Doses should be divided into three age groups instead of two as currently suggested in the guidelines. To increase the likelihood of achieving therapeutic levels, the commercially available enoxaparin product should not be diluted if possible.

Isobolographic analysis of chlordiazepoxide and triazolam combinations in squirrel monkeys discriminating triazolam.

RATIONALE: The discriminative stimulus (DS) effects of chlordiazepoxide (CDP) differ from those of other typical benzodiazepine (BZ) agonists in that CDP does not always occasion full substitution for a BZ agonist DS. OBJECTIVES: The present study tested the hypothesis that the unusual DS effects of CDP may result from its relatively low intrinsic efficacy by examining the combinations of CDP and triazolam using isobolographic analysis in squirrel monkeys discriminating triazolam. METHODS AND RESULTS: Squirrel monkeys were previously trained to discriminate triazolam (0.03 mg/kg, i.v.) from vehicle under a fixed-ratio 10 (FR 10) schedule of food reinforcement. CDP occasioned partial substitution for triazolam and did not alter the DS effects of triazolam, whereas single doses of triazolam enhanced the DS effects of triazolam, and bretazenil antagonized the triazolam DS. The isobolographic analysis showed that CDP and triazolam combinations resulted in additive effects in animals in which CDP substituted for triazolam, whereas infra-additive effects were obtained in animals in which CDP did not substitute for triazolam. CONCLUSIONS: The partial substitution of CDP for triazolam and the infra-additive effects obtained in animals in which CDP did not substitute for triazolam suggest that CDP may have lower intrinsic efficacy than triazolam. However, the lack of overall effect of CDP pretreatment and the lack of shift in animals in which CDP substituted for triazolam suggest that other factors, such as differential activity at BZ receptor subtypes, may play a role in the effects of CDP.

Triazolam discrimination in squirrel monkeys distinguishes high-efficacy agonists from other benzodiazepines and non-benzodiazepine drugs.

RATIONALE: Triazolam is a high-efficacy benzodiazepine (BZ) agonist, which might be hypothesized to engender highly pharmacologically specific discriminative stimulus (DS) effects and distinguish among BZ agonists with different intrinsic efficacy. OBJECTIVES: The pharmacological specificity of the triazolam stimulus was determined by examining the effects of conventional and atypical BZ agonists, and other ligands active at the gamma-aminobutyric acidA (GABAA) receptor complex. Receptor mechanisms underlying the DS effects of triazolam were examined further using the BZ receptor antagonist flumazenil. METHODS AND RESULTS: Squirrel monkeys were trained to discriminate triazolam (0.03 mg/kg, i.v.) from vehicle under a fixed-ratio 10 (FR 10) schedule of food reinforcement. While the BZ agonists midazolam, diazepam, and lorazepam substituted fully for triazolam, chlordiazepoxide, oxazepam and nordiazepam produced only partial substitution, suggesting these latter compounds may have reduced intrinsic efficacy. The BZ/alpha1-preferring agonist zolpidem substituted fully for triazolam, and potencies for triazolam-like effects of BZ agonists were significantly correlated with potencies for their zolpidem-like effects (Rowlett et al. 1999). Flumazenil antagonized the DS effects of triazolam, but the slope of the Schild plot was significantly different from unity, suggesting multiple receptors may be involved in the DS effects of triazolam. CONCLUSIONS: BZ agonists can be distinguished on the basis of substitution for triazolam and, thus, the triazolam discrimination may be a useful tool for identifying compounds of different efficacy at BZ receptors. BZ/alpha1 receptors appear to play a prominent role in the DS effects of triazolam, but the contribution of other subtypes of BZ receptors cannot be ruled out.

Using behavior to elucidate receptor mechanisms: a review of the discriminative stimulus effects of benzodiazepines.

Drug discrimination procedures have been used to study receptor mechanisms of benzodiazepine (BZ) agonists with the goal of developing new therapeutic agents that retain positive effects of conventional BZ ligands yet have reduced side effects. The present review provides a synthesis of existing literature on discriminative stimulus effects of BZ agonists in order to elucidate their underlying receptor mechanisms, specifically in terms of intrinsic efficacy and receptor selectivity. The available evidence suggests that receptor selectivity is a critical determinant of the discriminative stimulus effects of BZ agonists. In particular, BZ-1 receptors appear to play a fundamental role, whereas the role of BZ-2 receptors remains elusive. In addition, data from many drug discrimination studies suggest that the conventional BZ agonist chlordiazepoxide may have reduced intrinsic efficacy compared with other BZ agonists.

Transduction of the discriminative stimulus effects of zolpidem by GABA(A)/alpha1 receptors.

Zolpidem is an imidazopyridine with high affinity at gamma-aminobutyric acid(A) (GABA(A)) receptors expressing alpha1 subunits. In squirrel monkeys trained to discriminate a high dose of zolpidem (> or =3.0 mg/kg) from saline, zolpidem and another GABA(A)/alpha1 receptor-preferring agonist, zaleplon, substituted dose-dependently for zolpidem, whereas the non-selective agonists diazepam and triazolam were did not substitute at any dose tested. These findings offer the first evidence for a selective role of GABA(A)/alpha1 receptors in the interoceptive effects of high doses of zolpidem.