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Objective: We aimed to elucidate the pathogenic mechanisms underlying autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), and to understand the genotype/phenotype correlation of structural variants (SVs) in the LMNB1 locus., Background: Since the discovery of 3D genome architectures and topologically associating domains (TADs), new pathomechanisms have been postulated for SVs, regardless of gene dosage changes. ADLD is a rare genetic disease associated with duplications (classical ADLD) or noncoding deletions (atypical ADLD) in the LMNB1 locus., Methods: High-throughput chromosome conformation capture, RNA sequencing, histopathological analyses of postmortem brain tissues, and clinical and neuroradiological investigations were performed., Results: We collected data from >20 families worldwide carrying SVs in the LMNB1 locus and reported strong clinical variability, even among patients carrying duplications of the entire LMNB1 gene, ranging from classical and atypical ADLD to asymptomatic carriers. We showed that patients with classic ADLD always carried intra-TAD duplications, resulting in a simple gene dose gain. Atypical ADLD was caused by LMNB1 forebrain-specific misexpression due to inter-TAD deletions or duplications. The inter-TAD duplication, which extends centromerically and crosses the 2 TAD boundaries, did not cause ADLD. Our results provide evidence that astrocytes are key players in ADLD pathology., Interpretation: Our study sheds light on the 3D genome and TAD structural changes associated with SVs in the LMNB1 locus, and shows that a duplication encompassing LMNB1 is not sufficient per se to diagnose ADLD, thereby strongly affecting genetic counseling. Our study supports breaking TADs as an emerging pathogenic mechanism that should be considered when studying brain diseases. ANN NEUROL 2024;96:855-870., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Mouse models are a critical tool for studying human diseases, particularly developmental disorders 1 . However, conventional approaches for phenotyping may fail to detect subtle defects throughout the developing mouse 2 . Here we set out to establish single-cell RNA sequencing of the whole embryo as a scalable platform for the systematic phenotyping of mouse genetic models. We applied combinatorial indexing-based single-cell RNA sequencing 3 to profile 101 embryos of 22 mutant and 4 wild-type genotypes at embryonic day 13.5, altogether profiling more than 1.6 million nuclei. The 22 mutants represent a range of anticipated phenotypic severities, from established multisystem disorders to deletions of individual regulatory regions 4,5 . We developed and applied several analytical frameworks for detecting differences in composition and/or gene expression across 52 cell types or trajectories. Some mutants exhibit changes in dozens of trajectories whereas others exhibit changes in only a few cell types. We also identify differences between widely used wild-type strains, compare phenotyping of gain- versus loss-of-function mutants and characterize deletions of topological associating domain boundaries. Notably, some changes are shared among mutants, suggesting that developmental pleiotropy might be 'decomposable' through further scaling of this approach. Overall, our findings show how single-cell profiling of whole embryos can enable the systematic molecular and cellular phenotypic characterization of mouse mutants with unprecedented breadth and resolution., (© 2023. The Author(s).)

Thyroid hormone and its receptor TRα1 play an important role in brain development. Several animal models have been used to investigate this function, including mice heterozygous for the TRα1R384C mutation, which confers receptor-mediated hypothyroidism. These mice display abnormalities in several autonomic functions, which was partially attributed to a developmental defect in hypothalamic parvalbumin neurons. However, whether other cell types in the hypothalamus are similarly affected remains unknown. Here, we used single-nucleus RNA sequencing to obtain an unbiased view on the importance of TRα1 for hypothalamic development and cellular diversity. Our data show that defective TRα1 signaling has surprisingly little effect on the development of hypothalamic neuronal populations, but it heavily affects hypothalamic oligodendrocytes. Using selective reactivation of the mutant TRα1 during specific developmental periods, we find that early postnatal thyroid hormone action seems to be crucial for proper hypothalamic oligodendrocyte maturation. Taken together, our findings underline the well-known importance of postnatal thyroid health for brain development and provide an unbiased roadmap for the identification of cellular targets of TRα1 action in mouse hypothalamic development., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Over the last decade, single-cell sequencing has transformed many fields. It has enabled the unbiased molecular phenotyping of even whole organisms with unprecedented cellular resolution. In the field of human genetics, where the phenotypic consequences of genetic and epigenetic alterations are of central concern, this transformative technology promises to functionally annotate every region in the human genome and all possible variants within them at a massive scale. In this review aimed at the clinicians in human genetics, we describe the current status of the field of single-cell sequencing and its role for human genetics, including how the technology works as well as how it is being applied to characterize and monitor diseases, to develop human cell atlases, and to annotate the genome., Competing Interests: Competing interests: Authors state no conflict of interest., (© 2022 the author(s), published by De Gruyter.)

Idiopathic Parkinson's disease is characterized by a progressive loss of dopaminergic neurons, but the exact disease aetiology remains largely unknown. To date, Parkinson's disease research has mainly focused on nigral dopaminergic neurons, although recent studies suggest disease-related changes also in non-neuronal cells and in midbrain regions beyond the substantia nigra. While there is some evidence for glial involvement in Parkinson's disease, the molecular mechanisms remain poorly understood. The aim of this study was to characterize the contribution of all cell types of the midbrain to Parkinson's disease pathology by single-nuclei RNA sequencing and to assess the cell type-specific risk for Parkinson's disease using the latest genome-wide association study. We profiled >41 000 single-nuclei transcriptomes of post-mortem midbrain from six idiopathic Parkinson's disease patients and five age-/sex-matched controls. To validate our findings in a spatial context, we utilized immunolabelling of the same tissues. Moreover, we analysed Parkinson's disease-associated risk enrichment in genes with cell type-specific expression patterns. We discovered a neuronal cell cluster characterized by CADPS2 overexpression and low TH levels, which was exclusively present in idiopathic Parkinson's disease midbrains. Validation analyses in laser-microdissected neurons suggest that this cluster represents dysfunctional dopaminergic neurons. With regard to glial cells, we observed an increase in nigral microglia in Parkinson's disease patients. Moreover, nigral idiopathic Parkinson's disease microglia were more amoeboid, indicating an activated state. We also discovered a reduction in idiopathic Parkinson's disease oligodendrocyte numbers with the remaining cells being characterized by a stress-induced upregulation of S100B. Parkinson's disease risk variants were associated with glia- and neuron-specific gene expression patterns in idiopathic Parkinson's disease cases. Furthermore, astrocytes and microglia presented idiopathic Parkinson's disease-specific cell proliferation and dysregulation of genes related to unfolded protein response and cytokine signalling. While reactive patient astrocytes showed CD44 overexpression, idiopathic Parkinson's disease microglia revealed a pro-inflammatory trajectory characterized by elevated levels of IL1B, GPNMB and HSP90AA1. Taken together, we generated the first single-nuclei RNA sequencing dataset from the idiopathic Parkinson's disease midbrain, which highlights a disease-specific neuronal cell cluster as well as 'pan-glial' activation as a central mechanism in the pathology of the movement disorder. This finding warrants further research into inflammatory signalling and immunomodulatory treatments in Parkinson's disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Aims: LY3031207, a novel microsomal prostaglandin E synthase 1 inhibitor, was evaluated in a multiple ascending dose study after nonclinical toxicology studies and a single ascending dose study demonstrated an acceptable toxicity, safety and tolerability profile., Methods: Healthy subjects were randomized to receive LY3031207 (25, 75 and 275 mg), placebo or celecoxib (400 mg) once daily for 28 days. The safety, tolerability and pharmacokinetic and pharmacodynamic profiles of LY3031207 were evaluated., Results: The study was terminated when two subjects experienced drug-induced liver injury (DILI) after they had received 225 mg LY3031207 for 19 days. Liver biopsy from these subjects revealed acute liver injury with eosinophilic infiltration. Four additional DILI cases were identified after LY3031207 dosing had been stopped. All six DILI cases shared unique presentations of hepatocellular injury with hypersensitivity features and demonstrated a steep dose-dependent trend. Prompt discontinuation of the study drug and supportive medical care resulted in full recovery. Metabolites from metabolic activation of the imidazole ring were observed in plasma and urine samples from all subjects randomized to LY3031207 dosing., Conclusions: This study emphasized the importance of careful safety monitoring and serious adverse events management in phase I trials. Metabolic activation of the imidazole ring may be involved in the development of hepatotoxicity of LY3031207., (© 2017 The British Pharmacological Society.)

Background: Access and use of historical control data was identified as a top stakeholder concern across organizations according to results of a survey of needs and challenges related to nonclinical data conducted by the FDA/PhUSE Nonclinical Working Group in 2011. There is a perception there may be additional ways to capitalize on historical control data to enhance studies or submissions across industry, academia, and government. During the working sessions of the FDA/PhUSE Computational Sciences Symposium in March 2012, a Historical Control subgroup of the FDA/PhUSE Nonclinical Working Group was formed to investigate how the industry might more effectively harness the vast amount of data from untreated/vehicle control animals. The subgroup includes broad representation of stakeholders with interest in nonclinical data., Methods: This paper describes progress to date and includes results of a second survey to determine how organizations use and would like to use historical control data., Results: Respondents to the survey strongly support that historical control data are useful and should be in an accessible format. Four potential project options were posed in the survey, with an overall positive response; also, several write-in options were suggested by respondents., Conclusions: Community-supported projects to increase the availability of well-annotated and scientifically curated collections of historical control data appear to be of most interest.

Pregabalin, (S)-3-(aminomethyl)-5-methylhexanoic acid, binds with high affinity to the α(2)δ subunit of voltage-gated calcium channels and exerts analgesic, anxiolytic, and antiseizure activities. Two-year carcinogenicity studies were completed in B6C3F1 and CD-1 mice and two separate studies in Wistar rats. Doses in mice were 200, 1000, and 5000 mg/kg/day, with systemic exposures (AUC(0-24 h)) up to 31 times the mean exposure in humans, given the maximum recommended clinical dose. In rats, doses were 50, 150, and 450 mg/kg/day in males and 100, 300, and 900 mg/kg/day in females; systemic exposures up to 24 times were achieved in clinical trials. In both strains of mice, pregabalin treatment was associated with an increased incidence of hemangiosarcoma primarily in liver, spleen, and bone marrow. The incidence of hemangiosarcoma was higher in B6C3F1 mice than in CD-1 mice, consistent with its spontaneous incidence. Pregabalin did not increase the incidence of any other tumor type in rats and was not genotoxic, based on an extensive battery of in vivo and in vitro tests in bacterial and mammalian systems. Thus, pregabalin is a single-species, single tumor-type, nongenotoxic mouse carcinogen. Hemangiosarcomas occurring in mice treated with pregabalin were genotypically distinct from hemangiosarcomas induced by genotoxic carcinogens in humans with respect to ras and p53 mutation patterns and were similar to spontaneous tumors. Furthermore, there was a strong association between pregabalin treatment and bone marrow changes in these studies in mice, suggesting a possible link between the effects observed in bone marrow and the increase in tumor incidence in pregabalin-treated mice.

The low-melting polymorphic modification of the 1:1 complex of benzocaine (BC) and picric acid (PA) had earlier been reported to be an example of a "disappearing polymorph". The BC:PA system has been reinvestigated by thermomicroscopy, calorimetry, solid-state NMR, and X-ray crystallography. The phase diagram has been derived, and robust procedures for the crystallization of the two 1:1 complexes, a hydrate of the 1:1 complex, and a 2:1 complex have been devised. The structures of all four phases have been determined and compared using graph set analysis to characterize the hydrogen-bonding patterns. It is shown that the thorough microscopic investigation of the thermal behavior, combined with calorimetric methods, can lead to the development of strategies to crystallize metastable polymorphic forms which may be difficult to obtain once their stable congeners have been obtained.

The results of studies on tedisamil dihydrochloride in the solid state demonstrate that the compound occurs in three polymorphic forms. The three modifications have been characterized by thermomicroscopy, differential scanning calorimetry (DSC), vibrational spectroscopy, solid-state nuclear magnetic resonance (NMR), and X-ray powder diffractometry (XRPD). The thermodynamic relationships are illustrated in a semischematic energy/temperature diagram that gives information about the relative stability and physical properties of the three modifications between 0 K and the melting temperatures. The three modifications are enantiotropically related. Modification II, the material obtained during manufacturing, is the thermodynamically stable crystal form at 20 degrees C. The thermodynamic transition point of mod II with I (instant melting point: 248-250 degrees C) is between 100 and approximately 140 degrees C (DeltaH(t,II/I) = 4.4+/-0.8 kJ/mol (95% CI)). A phase transition of mod II (probably into mod III) was detected thermomicroscopically at about -180 degrees C. The thermodynamic transition point of mod III with I was determined to be at -9 to -6 degrees C. Because mods I and III are thermodynamically and kinetically unstable at ambient conditions, these crystal forms are of analytical interest.

Melt granulations of lactose and PEG 4000 were made with a fluid-bed granulator and for comparison in a high-speed mixer with scraper. Two different mechanisms of granule formation occurred, coalescence and layering. The agglomeration kinetics of layering was modeled. The granulations were compressed on an instrumented press and examined for uniformity of mass, hardness and disintegration time. Remarkable differences in tablet properties were found between the mechanisms of granule formation.

Three modifications of D-mannitol were produced and investigated: mod. I (mp 166.5 degrees C, heat of fusion 53.5 kJ mol(-1)), mod. II (mp 166 degrees C, heat of fusion 52.1 kJ mol(-1)), and mod. III (mp incongruent 150-158 degrees C, heat of transition, III to I 0.2 kJ mol(-1)). The measured densities are 1.490 +/- 0.000 g cm(-3) [95% confidence interval (CI)] for mod. I, 1.468 +/- 0.002 g cm(-3) (95% CI) for mod. II, and 1.499 +/- 0.004 g cm(-3) (95% CI) for mod. III. It was possible to relate the different modifications given in the literature to one of the three pure crystal forms or to mixtures of two or all three modifications. The thermodynamic relationship among the crystal forms is represented in a semi-schematic energy/temperature diagram. From these data we can conclude that mod. III is thermodynamically stable at absolute zero. It is enantiotropically related to mod. I and mod. II. FTIR and Raman spectra, differential scanning calorimetry curves, and X-ray powder patterns of these crystal forms are depicted for doubtless assignment in the future. The water uptake of the three modifications at 92% relative humidity and 25 degrees C is less than 1%. The differences of the heat capacities and the heats of solution between mod. II and III are not significant, whereas mod. I shows small significant differences compared with the other modifications. In addition, compaction studies of these crystal forms were performed by means of an instrumented hydraulic press. The results show that mod. III should have the best tableting behavior under these conditions., (Copyright 2000 Wiley-Liss, Inc.)

The thermodynamic terms enantiotropy and monotropy are demonstrated by means of solid-state analytical results of polymorphous flurbiprofen (FBP). Vibrational spectra, differential scanning calorimetry (DSC), and thermomicroscopy investigations as well as X-ray powder patterns for three modifications of FBP are described. The melting points are mod. I 113-114 degreesC (enthalpy of fusion 27.9 +/- 0.2 kJ mol-1) for modification I (mod. I), 92 degreesC for mod. II, and 87 degreesC for mod. III. The true densities of mod. I (1.279 +/- 0.001 g cm-3) and mod. II (1.231 +/- 0.002 g cm-3) were measured at 25 degreesC. Modification I (commercial product) is the thermodynamically stable crystal form from absolute zero to its melting point. Modification II was crystallized on a gram scale from a warm saturated solution of FBP in n-heptane and rapid cooling of the solution to -18 degreesC. Modification I is monotropically related to mod. II and mod. III, due to application of the density rule and the entropy-of-fusion rule. The thermodynamic relationships between the three modifications are demonstrated by a semischematic energy/temperature diagram. Theoretical vapor pressure/temperature diagrams and energy/temperature diagrams are compared and briefly discussed.

Misonidazole is a hypoxic cell radiosensitizer that induces a peripheral neuropathy in humans after exceeding a schedule-dependent cumulative threshold dose. Clinical studies of misonidazole have been conducted using oral administration, whereas most other radiosensitizers have been administered intravenously. Since route of exposure can potentially influence the toxicity of xenobiotics, the objective of this study was to assess the neurotoxicity of misonidazole in rats following intravenous dosing using a battery of routine clinical, neurofunctional, biochemical, and histopathologic screening methods. Male Sprague-Dawley rats were administered intravenous doses of misonidazole at 0 (vehicle control), 100, 200, 300, or 400 mg kg-1 once per day, 5 days per week, for 2 weeks. Animals were evaluated for neurofunctional and pathological changes following termination of treatment (Days 15-17) and at the end of a 4 week observation period (Days 43-45). During the dosing phase, hypoactivity, salivation, rhinorrhea, chromodacryorrhea, rough pelage and ataxia were observed at 400 mg kg-1, and body weight gain of the 300 and 400 mg kg-1 groups was significantly decreased relative to the vehicle controls by 24% and 49%, respectively. Corresponding reductions in food consumption were 8% and 23%, respectively. Although most 400 mg kg-1 animals appeared normal on Day 15 prior to the neurofunctional evaluations, rotorod testing precipitated a number of clinical signs including: ataxia, impaired righting reflex, excessive rearing, tremors, vocalization, circling, head jerking, excessive sniffing and hyperactivity. All of these animals recovered and appeared normal from Day 17 through study termination. There were no treatment-related effects on motor activity, acoustic startle response, rotorod performance, forelimb group strength, toe and tail pinch reflexes, tibial nerve beta-glucuronidase activity or tail nerve conduction velocity. Although hindlimb grip strength of the 400 mg kg-1 group was significantly decreased by 17% relative to the vehicle controls on Day 15, this finding appeared related to the reduced food consumption and body weight gain in these animals. No microscopic changes were detected in peripheral nerves. Necrosis and proliferation of fibrillary astrocytes (gliosis) were seen in the cerebellum and medulla of the 400 mg kg-1 animals on Day 16. Gliosis in these same brain regions was observed in the 300 and 400 mg kg-1 groups on Day 44. The results show that intravenous administration of misonidazole to rats causes dose-limiting central nervous system toxicity without effects on peripheral nervous tissue. The lack of peripheral neurotoxicity was most likely due to a combination of several interrelated factors including route of administration, duration and intensity of the dosing regimen, and total cumulative dose.

In recent years, concern about possible female reproductive and developmental toxicity due to environmental contaminants, such as PCBs, has been growing. Because this area of toxicology had not been emphasized prior to this time, there are many gaps in current knowledge about female developmental and reproductive toxicology and only a limited number of validated tests to assay effects of toxicants on various parts of the reproductive and developmental cycle. This article reviews the current state of knowledge on this topic and also explores a variety of techniques for assessing female reproductive and developmental toxicity. These include an assay of the state of intercellular communication among the embryo, fetus and placenta; protocols for assessing toxicity in early pregnancy; and techniques for evaluating the role of glutathione in protecting the conceptus from xenobiotics.

CI-921, an anilinoacridine compound active against leukemic and solid tumors, was evaluated for potential developmental toxicity. Intravenous injections of CI-921 in dextrose were given to female Sprague-Dawley rats (0.1, 0.5, and 1.0 mg/kg) on Gestation Days (GD) 6-15 and to female New Zealand White rabbits (0.1, 1.0 and 2.0 mg/kg) on GD 6-18. Appropriate vehicle and untreated controls were included. Maternal and fetal parameters, including external, visceral, and skeletal malformations and variations, were assessed. Treatment of rats with 1.0 mg/kg resulted in maternal toxicity, manifested as reduced body weight gain and food consumption during and after treatment. Reduced fetal body weight, an increased incidence of stunted fetuses, malformations of the axial and appendicular skeleton, microphthalmia, and an increased number of anatomical variations (including anomalies of the axial skeleton and apparent hydronephrosis) also occurred in rats at 1.0 mg/kg. Treatment of rabbits resulted in no apparent maternal toxicity. However, reduced fetal body weight, agenesis of the azygous lobe of the lung, and an increased incidence of variations of the axial skeleton occurred at 2.0 mg/kg in rabbits. These results indicate that CI-921, at the highest dose tested in each species, produced developmental toxicity in the presence of maternal toxicity in rats, but in the absence of maternal toxicity in rabbits.

Male Sprague-Dawley rats were trained to press a lever on a fixed ratio-40 (FR-40) schedule for food reinforcement. Doses ranging from 0.5 to 16 mg/kg of the mixed narcotic agonist-antagonist cyclazocine (30-min pretreatment) resulted in a dose-dependent decrease in the number of reinforcements obtained and a reciprocal increase in "pausing" (IRT's greater than 10 sec). A 5-min pretreatment with 4 mg/kg of the narcotic antagonist naloxone attenuated the cyclazocine disruption. The 5-HT antagonist metergoline (1 mg/kg; 180-min pretreatment) also blocked cyclazocine effects to approximately the same degree as did naloxone. However, the shift of the dose response pattern of cyclazocine was not parallel for either antagonist. A greater degree of attenuation of the cyclazocine effects was observed when naloxone (4 mg/kg) and metergoline (0.1 mg/kg) were given together, indicating that cyclazocine disruption may be antagonized by either a narcotic antagonist or a 5-HT antagonist, and that these antagonists may operate synergistically. Thus, the behavioral effects of cyclazocine may relate to both opioid and serotonergic components.

The embryotoxic and teratogenic potential of sulfur dioxide (SO2) was evaluated in CF-1 and New Zealand rabbits exposed to SO2 alone or in combination with carbon monoxide (CO). The animals inhaled filtered room air (controls), SO2 (mice, 25 ppm; rabbits, 70 ppm), or SO2 plus CO (250 ppm) for 7 hr/day from days 6 through 15 (mice) and from days 6 through 18 (rabbits) of gestation. In both species, inhalation of SO2 resulted in slight toxicity in the dams and an increased incidence of minor skeletal variants among their offspring; exposure to the combination did not potentiate the increased incidence of these variants. A teratogenic effect was not discerned in either mice or rabbits exposed to SO2 alone or in combination with carbon monoxide, but the fetuses of mice exposed to the combination were significantly smaller than those exposed only to SO2.

A sodium salt of ethylenediaminetetraacetate (Na3EDTA) and ethylenediamine (EDA) were subjected to a repeated insult patch test on Hartley albino guinea pigs (10 per compound). All guinea pigs (10 of 10) receiving EDA were sensitized. None of the guinea pigs (0 of 10) was sensitized to Na3 EDTA. Likewise, none of the guinea pigs sensitized to EDA reacted positively when challenged with Na3 EDTA. Based on these results, it is concluded that EDTA is not likely to be a sensitizer to humans, and would not likely cross-sensitize with EDA. In addition, the presence of very small amounts of the sodium salts of EDTA in cosmetic and pharmaceutical preparations does not represent an appreciable risk of human skin sensitization.

Administration of the indolealkylamine hallucinogen d-lysergic acid diethylamide (LSD), the phenethylamine hallucinogen 2,5-dimethoxy-4-methylamphetamine (DOM) and the putative 5-hydroxytryptamine (5-HT) agonist quipazine all produced a dose-dependent decrease in fixed ratio (FR-40) response rates and a concomitant increase in the number of 10-second pause intervals. Although naloxone (4.0 mg/kg) had no effect on FR-40 responding per se, the pause-producing effects of LSD and, to a lesser extent, DOM were potentiated by pretreatment with naloxone. The action of quipazine on reinforcers was unaffected by combination with naloxone, while the effect on pause intervals was slightly attenuated by naloxone pretreatment. These data and previous studies suggest that the pause-producing effects of indolealkylamine and phenethylamine hallucinogens reflect their activation of a selective portion of brain 5-HT receptors. The potentiation of these effects by naloxone may relate to a modulation of central 5-HT systems by endogenous opioid mechanisms tending to restore an imbalance in various 5-HT pathways caused by the hallucinogenic 5-HT agonists. The more generalized disruptive effects of quipazine on brain 5-HT systems may be less susceptible to the endogenous opioid modulation or may actually combine with it to induce a greater disruption.

The mixed narcotic agonist-antagonist cyclazocine and the 5-HT agonist quipazine disrupt food-rewarded fixed ratio-40 (FR-40) operant behavior in rats as a dose-dependent decrease in the number of reinforcers obtained and a reciprocal increase in the number of 10-second intervals between responding ("pausing"). This disruption has been shown to result in part from interaction with 5-HT neuronal systems, and may be a consequence of: (1) disruption of cognitive processes, (2) motivational impairment, or (3) motor deficits. To identify which of these components is (are) involved in the disruption of operant responding, female Sprague-Dawley rats were tested for food consumption, spontaneous locomotor activity, or rotarod performance following intraperitoneal injection of cyclazocine, quipazine, or both. Cyclazocine decreased food consumption at doses larger than those required to disrupt operant behavior, while quipazine decreased consumption at doses disruptive to operant responding. Little effect was exerted by either drug on spontaneous locomotor activity, while rotarod performance was disrupted only by very large doses of either drug relative to effects of FR-40 behavior. These data indicate that neither drug appears to disrupt operant behavior by causing gross motor deficits. Thus, cyclazocine may disrupt operant responding by impairing cognition, while quipazine may act through food satiation mechanisms.

Pregnant Sprague-Dawley rats received oral doses of 0, 0.2 or 2 mg/kg/day polybrominated biphenyls (PBB) as fireMaster BP-6 (BP-6) from day 6 of gestation through day 24 postpartum. At approximately 6 months of age male and female offspring were food-deprived to 80% of their free-feeding weights and subjected to four phases of an autoshaping paradigm. Acquisition of Phase I, a VI-90 second schedule of responding, was significantly delayed for female offspring from dams administered 2 mg/kg/day BP-6; a trend toward delayed acquisition was observed in all other PBB-exposed animals. No BP-6-related difference in latency to respond during this phase was observed. Male offspring from dams administered BP-6 appeared to acquire Phase II responding (a FI-90 second contingency) at a faster rate than did control males. In contrast, BP-6-exposed females acquired Phase II responding at a somewhat slower rate than did control females. The sex-related difference in responding may involve a rate-dependent influence, as control females acquired Phase II responding much more quickly than did control males. Control males and females acquired Phase III (FR-20 responding) at approximately the same rate. No BP-6-related deficits were observed during the initial few days of acquisition of FR-20 responding. However, BP-6-exposed male offspring tended to respond more than did control males after this time. BP-6-exposed females tended to respond less than did control females only as the responding of controls approached an asymptote. Phase IV involved FR-20 responding following challenge with d-amphetamine or chloral hydrate; no significant BP-6-related changes in disruption of this behavior were observed.