Perrie M. Adams

Acute and chronic phencyclidine effects on locomotor activity, stereotypy and ataxia in rats.

Behavioral rating scales, developed to measure phencyclidine (PCP)-induced stereotypy and ataxia in rats, were tested using acute dose-response and chronic paradigms with concomitant assessment of locomotor activity by automated counters. Also, effects of chronic PCP on apomorphine-induced stereotypy were assessed as a test of dopamine supersensitivity. A linear dose-response effect was found for measures of all three behaviors through moderate dose levels (2-6 mg/kg), but only ataxia ratings continued to increase, showing a linear relationship through the higher (8 and 10 mg/kg) doses. Chronic daily PCP administration showed progressive augmentation of stereotypy, tolerance to ataxia at 10 min post-injection, and a biphasic increase followed by decrease to day 1 levels in locomotor activity over 14 days. No significant change was found in apomorphine stereotypy following chronic PCP treatment. The chronic behavioral changes demonstrated in this study may provide a model of PCP-induced psychological and cognitive changes seen following chronic usage in man.

Effects of maternal exposure to polychlorobiphenyls (PCBs) on F1 generation behavior in the rat

The effect of Fenclor 42 (PCB) exposure of female rats (Fischer 344 strain) was studied through assessment of the behavioral development of their F1 progeny. Female rats were exposed to PCB according to the following treatment schedule: (A) (5 days) 2 weeks prior to mating, (B) during gestation (Days 6-15 of pregnancy), (C) during lactation (Days 1-21 after delivery). Behavioral endpoints of motor reflexes, motor coordination, activity (preweaning behaviors), and learning (postweaning behavior) were evaluated for PCB ip dosages of 5-10 mg/kg/day for 5 days (preconception exposure), and PCB oral dosages of 2-4 mg/kg/day for 10 days (in utero exposure) and of 1-2 mg/kg/day for 20 days (during lactation exposure). Dosage-dependent differences in the evaluated behaviors were found in the offspring of the PCB-exposed females when compared to the offspring of corn-oil (vehicle)-exposed females. Significant differences in the development of cliff avoidance reflexive behavior, swimming ability, and open field activity were particularly evident. Furthermore the PCB exposure of female rats during gestation and lactation resulted in impaired acquisition of the active avoidance behavior while preconceptional PCB exposure significantly affected active avoidance performance as reflected in increased number of avoidance responses to reach criterion for extinction. These results show that Fenclor 42 does possess a significant risk to the offspring of exposed females, and further illustrate the sensitivity of progeny behavioral assessment in detecting suspected functional teratogenesis.

A blood-based algorithm for the detection of Alzheimer's disease.

Background: We previously created a serum-based algorithm that yielded excellent diagnostic accuracy in Alzheimer’s disease. The current project was designed to refine that algorithm by reducing the number of serum proteins and by including clinical labs. The link between the biomarker risk score and neuropsychological performance was also examined. Methods: Serum-protein multiplex biomarker data from 197 patients diagnosed with Alzheimer’s disease and 203 cognitively normal controls from the Texas Alzheimer’s Research Consortium were analyzed. The 30 markers identified as the most important from our initial analyses and clinical labs were utilized to create the algorithm. Results: The 30-protein risk score yielded a sensitivity, specificity, and AUC of 0.88, 0.82, and 0.91, respectively. When combined with demographic data and clinical labs, the algorithm yielded a sensitivity, specificity, and AUC of 0.89, 0.85, and 0.94, respectively. In linear regression models, the biomarker risk score was most strongly related to neuropsychological tests of language and memory. Conclusions: Our previously published diagnostic algorithm can be restricted to only 30 serum proteins and still retain excellent diagnostic accuracy. Additionally, the revised biomarker risk score is significantly related to neuropsychological test performance.

The Effects of Thyroid Hormone Level and Action in Developing Brain: Are These Targets for the Actions of Polychlorinated Biphenyls and Dioxins?

Alterations in thyroid hormone level or responsivity to thyroid hormone have significant neurologic sequelae throughout the life cycle. Duringfetal and early neonatal periods, disorders of thyroid hormone may lead to the development of motor and cognitive disorders. During childhood and adult life, thyroid hormone is required for neuronal maintenance as well as normal metabolic function. Those with an underlying disorder of thyroid hormone homeostasis or mitochondrial function may be at greater risk for developing cognitive, motor, or metabolic dysfunction upon exposure to substances which alter thyroid hormone economy. Polychlorinated biphenyls (PCBs) and dioxins have been argued to interfere with thyroid hormone action and thus may affect the developing and mature brain. Animal models provide useful tools for studying the effects of thyroid hormone disorders and the effects of environmental endocrine disruptors. The congenitally hypothyroid, hyt/hyt, mouse exhibits abnormalities in both the cognitive and motor systems. In this mouse and other animal models of thyroid hormone disorders, delayed somatic and reflexive development are noted, as are permanent deficits in hearing and locomotor and adaptive motor behavior. This animals behavioral abnormalities are predicated on anatomic abnormalities in the nervous system. In turn, these abnormalities are correlated with differences in neuronal structural proteins. In normal mice, the expression of mRNAs coding for these proteins occurs temporally with the onset of autonomous thyroid hormone production. The hyt/hyt mouse has a mutation in the thyroid stimulating hormone receptor (TSHr) gene which renders it incapable of transducing the TSH signal in the thyrocyte to produce thyroid hormone. Some behavioral and possibly some biochemical abnormalities in mice exposed to PCBs are similar to those seen in the hyt/hyt mouse. In addition to direct effects on brain development and neuronal maintenance, thyroid hormone is necessary for maintaining metabolic functioning through its influence on mitochondria. Because the brain is particularly sensitive to inadequate energy generation, disorders of thyroid hormone economy also indirectly impair brain functioning. Alterations in thyroid hormone level result in differing expression of mitochondrial genes. Mutations in these mitochondrial genes lead to well-recognized syndromes of encephalomyopathy, myopathy, and multisystem disorder. Hence, PCBs and dioxins, by possibly altering the thyroid hormone milieu, may alter thefunctioning of mitochondria in the generation of adenosine triphosphate (ATP). The use of animal models of thyroid hormone deficiency for behavioral, anatomic, histologic, and molecular comparison will help elucidate the mechanisms of action of these putative endocrine-disrupting compounds. The study of thyroid hormone disorders provides a template for relating thyroid hormone mediated effects on the brain to these compounds.

Effects of dopaminergic drugs on phencyclidine-induced behavior in the rat

Abstract Phencyclidine-induced behavior was studied in combination with drugs which block or enhance central dopamine activity. Haloperidol inhibited phencyclidine-induced stereotyped behavior and locomotor activity, and increased ataxia at all dose levels used (2.0, 4.0 and 6.0 mg/kg). Apomorphine potentiated phencyclidine-induced stereotypy at all doses in later post-injection periods (beyond 30 min). The effects of apomorphine on phencyclidine-induced locomotor activity were dose-dependent, showing inhibition at 2.0 mg/kg and enhancement at 4.0 and 6.0 mg/kg. These findings support suggested involvement of dopamine in phencyclidine-induced behavior and indicate the value of concurrent assessment of different phencyclidine-induced behavior for evaluating neurotransmitter effects.

Evaluation and characterization of the hyt/hyt hypothyroid mouse. II. Abnormalities of TSH and the thyroid gland.

The hyt/hyt mouse (BALB/cBY-hyt, C.hytRF) provides a useful model for exploring the effect of inherited severe primary hypothyroidism. Studies were undertaken to try to define the basis of the primary hypothyroidism in mice homozygous for the autosomal recessive gene, hyt. These mice had congenital hypothyroidism of fetal onset after 15 days post conception. Through their lifetime, the hyt/hyt mice had reduced serum thyroxine (T4), triiodothyronine (T3), reduced thyroid gland intralumenal colloid on electron microscopy and a 100-fold elevation of TSH-like activity compared to hyt/+ littermates. Thyroglobulin made in hyt/hyt animals was similar in size to normal thyroglobulin which was inconsistent with a major structural thyroglobulin gene defect. The thyroglobulin was iodinated. Marked, erratic dilation of rough endoplasmic reticulum (RER) was noted in hyt/hyt mouse follicular cells. Despite these ultrastructural findings, pulse chase and immunoprecipitation studies with isolated hyt/hyt and normal thyroid glands indicated that normal thyroglobulin processing occurred in the RER and Golgi of the hyt/hyt mice. The hyt/hyt thyroid glands were hypoplastic compared to hyt/+ littermates. Histologically, the hyt/hyt thyroid glands demonstrated an increase in smaller follicular cells, and greater variability in follicular size compared to hyt/+ littermates. Histological and ultrastructural abnormalities in the gland were similar to those seen in certain cases of human congenital hypothyroidism with TSH receptor insensitivity of the thyroid gland. These findings along with the significant TSH elevation, the reduction in colloid and in serum T3 and T4, the efficacy of the hypothalamo-pituitary-thyroid feedback system, and previous observations of reduced iodine uptake and intrathyroidal T4, suggested that primary hypothyroidism in the hyt/hyt mouse might be due to a defect in TSH responsivity of the thyroid gland.

Thyroid Hormone Control of Brain and Motor Development: Molecular, Neuroanatomical, and Behavioral Studies

Thyroid hormones, T3 and T4, have been shown to play significant but poorly understood roles in development and differentiation of rodent and human brain(Lauder, 1989; Legrand, 1982–83; Stein et al, 1989a; 1991a,d; Eayrs, 1968; Morreale de Escobar et al, 1984; Garza et al, 1988; Ruiz-Marcos, 1989; Nunez et al, 1989). Hypothyroidism leads to molecular(Stein et al, 1989a,c; 1991a; Nunez et al, 1989; Hendrich et al, 1987), neuroendocrinological(Noguchi et al, 1986, Bakke et al, 1975, Stein et al, 1989b, Porterfield et al, 1981), neuroanatomical(Lauder et al, 1986; Lauder, 1989; Ruiz-Marcos, 1989; Eayrs, 1955; Garza et al, 1988; Morreale de Escobar et al, 1989; Marc et al, 1985; Legrand, 1982–83; Rami et al, 1986b; Narayanan et al, 1985; Marinesco, 1924; Lotmar, 1928; Rosman, 1975), behavioral and neuropsychological(Adams et al, 1989,1991; Anthony et al, 1991; Eayrs, 1968; Davenport et al, 1976; Klein, 1985; Rovet et al, 1987; Rovet, 1989; Man, 1971; Boyages et al, 1988; Pharoah,1984), and neurological abnormalities(Chaouki et al, 1989; Boyages et al, 1988; Delong et al, 1985; Nelson et al, 1986; Macfaul et al; 1978; Stein et al, 1991d, Rochiccioli et al, 1989) in the developing brain. Specifically, disorders of neuronal process growth and connectivity are noted neuroanatomically and motor syndromes involving motor cortex and pyramidal tracts are commonly observed in hypothyroid humans and rodents. These neurological and neuropathological abnormalities may be predicated on abnormalities in the cytoskeletal structures and in their molecular components. The cytoskeleton is a primary target for thyroid hormone in euthyroid and hypothyroid brain.

Potentiation of apomorphine and d-amphetamine effects by naloxone

Abstract The effects of naloxone, an opiate antagonist, on the stereotypic behavior and locomotor activity induced by apomorphine and d-amphetamine were studied. Groups of adult male Sprague-Dawley rats were first tested for stereotypy and locomotor activity after apomorphine (0.0 – 2.0 mg/kg) or d-amphetamine (0.0 – 10.0 mg/kg). Groups were subsequently tested with saline or naloxone (1.0 – 4.0 mg/kg) plus the previously used dosage of apomorphine or d-amphetamine. Naloxone alone did not produce stereotypy, but did significantly reduce locomotor activity. Naloxone potentiated apomorphine and d-amphetamine induced stereotypy. Apomorphine-induced activity was increased by naloxone, but d-amphetamine-induced activity at 2.5 mg/kg was reduced. The results are compatible with the suggestion that naloxone may potentiate both apomorphine and d-amphetamine by inhibiting an opiate receptor mechanism which normally interacts with catecholamine neuronal action.

The Effects of Congenital Hypothyroidism Using the hyt/hyt Mouse on Locomotor Activity and Learned Behavior

The offspring of matings between hyt/hyt male mice and hyt/+ females were examined for somatic and behavioral differences. The hyt/hyt offspring displayed delayed somatic development for eye opening and ear extension relative to their euthyroid littermates. Behavioral measurement of locomotor activity indicated hyperactivity at 14 days of age and hypoactivity at 21 and 40 days relative to the euthyroid mice. Impaired swimming escape behavior and Morris maze spatial learning were observed in the hyt/hyt animals. Comparative evaluation of +/+ progenitor strain offspring having no hypothyroidism in their genetic background indicated significant differences in somatic and behavioral endpoints between the hyt/hyt and euthyroid (hyt/+, +/+) animals. These results confirm the utility of the hyt/hyt mouse for studies of the impact of congenital hypothyroidism on the functional development of the offspring.

Biology of the congenitally hypothyroid hyt/ hyt mouse

The hyt/hyt mouse has an autosomal recessive, fetal onset, characterized by severe hypothyroidism that persists throughout life and is a reliable model of human sporadic congenital hypothyroidism. The hypothyroidism in the hyt/hyt mouse reflects the hyporesponsiveness of the thyroid gland to thyrotropin (TSH). This is attributable to a point mutation of C to T at nucleotide position 1666, resulting in the replacement of a Pro with Leu at position 556 in transmembrane domain IV of the G protein-linked TSH receptor. This mutation leads to a reduction in all cAMP-regulated events, including thyroid hormone synthesis. The diminution in T3/T4 in serum and other organs, including the brain, also leads to alterations in the level and timing of expression of critical brain molecules, i.e. selected tubulin isoforms (M beta 5, M beta 2, and M alpha 1), microtubule associated proteins (MAPs), and myelin basic protein, as well as to changes in important neuronal cytoskeletal events, i.e. microtubule assembly and SCa and SCb axonal transport. In the hyt/hyt mouse, fetal hypothyroidism leads to reductions in M beta 5, M beta 2, and M alpha 1 mRNAs, important tubulin isoforms, and M beta 5 and M beta 2 proteins, which comprise the microtubules. These molecules are localized to layer V pyramidal neurons in the sensorimotor cortex, a site of differentiating neurons, as well as a site for localization of specific thyroid hormone receptors. These molecular abnormalities in specific cells and at specific times of development or maturation may contribute to the observed neuroanatomical abnormalities, i.e. altered neuronal process growth and maintenance, synaptogenesis, and myelination, in hypothyroid brain. Abnormal neuroanatomical development in selected brain regions may be the factor underlying the abnormalities in reflexive, locomotor, and adaptive behavior seen in the hyt/hyt mouse and other hypothyroid animals.