Biomedical subjects

Gregory I Elmer

Publications and source records attributed to Gregory I Elmer.

8 recordsLinked to original sources

PubMed2005

Prenatal exposure to a repeated variable stress paradigm elicits behavioral and neuroendocrinological changes in the adult offspring: potential relevance to schizophrenia.

Exposure to stress during gestation induces marked changes in the behavior of the affected offspring. Examining the consequences of prenatal stress may prove useful in understanding more about the origins of schizophrenia because a number of clinical investigations have suggested that developmental insults are associated with an increased incidence of schizophrenia. The purpose of these studies is to investigate the effects of stress during gestation on the behaviors of the adult male rat offspring with an emphasis on developing a heuristic animal model of schizophrenia. Pregnant female Sprague-Dawley rats were exposed to a novel variable stress paradigm during either the second or third week of gestation. Behavioral and neuroendocrinological consequences of prenatal stress exposure were evaluated in the male offspring on postnatal day 35 or 56. Prenatal stress exposure during the third week of pregnancy caused adult male rats to exhibit prolonged elevation in plasma glucocorticoid levels following acute exposure to restraint stress indicative of diminished glucocorticoid negative feedback. Similarly, exposure to stress during the third week of pregnancy elicited an enhanced locomotor response to the psychomotor stimulant amphetamine on postnatal day 56 but not on postnatal day 35. In addition, prepulse inhibition of the acoustic startle response was diminished across a range of prepulse stimulus intensities in prenatally stressed adult male rats. Similarly, prenatally stressed rats showed evidence of a disruption in auditory sensory gating as measured by the N40 response. Taken together, these findings suggest that prenatal stress exposure significantly changed many facets of adult rat behavior. Interestingly, the behaviors that are altered have been used to validate animal models of schizophrenia and therefore, suggest that this preparation may be useful to learn more about some aspects of the pathophysiology of schizophrenia.

Age Factors↗

PubMed2004

Activity density in the open field: a measure for differentiating the effect of psychostimulants.

Traditional open-field activity measures do not provide a sharp behavioral differentiation across psychomotor stimulants such as d-amphetamine (AMPH) and cocaine (COC) in the mouse. We used Software for the Exploration of Exploration (SEE) to investigate and develop a novel behavioral endpoint to characterize the "structure" of AMPH- and COC-induced locomotor behavior in two inbred strains of mouse, C57BL/6 (B6) and DBA/2 (D2). We suggest a measure we term "activity density" as a means to differentiate the behavioral effects of COC and AMPH. Activity density is defined as the activity divided by the range over which it took place. It characterizes the restriction of behavioral repertoire that does not result merely from inactivity. In both the B6 and D2 mice, AMPH increased activity density in a dose-dependent fashion by restricting the range of activity compared with COC doses producing the same level of activity. While AMPH restricted the range in both genotypes, characterizing the geographical region in which the restriction took place further differentiated the genotypes. The newly developed activity density measure thus provides a more general measure than stereotypy of the path, and can differentiate the effects of AMPH and COC both within and across genotypes.

Animals↗

PubMed2004

New replicable anxiety-related measures of wall vs center behavior of mice in the open field.

Anxiety is a widely studied psychiatric disorder and is thought to be a complex and multidimensional phenomenon. Sensitive behavioral discrimination of animal models of anxiety is crucial for the elucidation of the behavioral components of anxiety and the physiological processes that mediate them. Commonly used behavior paradigms of anxiety usually include only a few automatically collected measures; these do not exhaust the behavioral richness exhibited by animals, thus perhaps missing important differences between preparations. The aim of the present study was to expand the repertoire of automatically collected measures in a classical test of anxiety: behavior in relation to the wall in the open field. We present an algorithm, based on the Software for the Exploration of Exploration strategy, which automatically partitions the mouse path into intrinsically defined patterns of movement near the wall and in the center. These patterns are used to design new end points, which provide an articulated description of various aspects of behavior near the wall and in the center. Sixteen new end points were designed with data from C57BL/6J and DBA/2J mice tested in three laboratories. The strain differences in all end points were evaluated on another data set to assess their validity and were found to remain stable. Ten of the sixteen end points were found to discriminate between the two strains in a replicable manner. The entire set of end points can be used on various genetic and pharmacological models of anxiety with good prospects of providing fine discrimination in a replicable manner.

Algorithms↗

PubMed2003

Darting behavior: a quantitative movement pattern designed for discrimination and replicability in mouse locomotor behavior.

In the open-field behavior of rodents, Software for Exploring Exploration (SEE) can be used for an explicit design of behavioral endpoints with high genotype discrimination and replicability across laboratories. This ability is demonstrated here in the development of a measure for darting behavior. The behavior of two common mouse inbred strains, C57BL/6J (B6) and DBA/2J (D2), was analyzed across three different laboratories, and under the effect of cocaine or amphetamine. "Darting" was defined as having higher acceleration during progression segments while moving less during stops. D2 mice darted significantly more than B6 mice in each laboratory, despite being significantly less active. These differences were maintained following cocaine administration (up to 20mg/kg) and only slightly altered by amphetamine (up to 5mg/kg) despite a several fold increase in activity. The replicability of darting behavior was confirmed in additional experiments distinct from those used for its design. The strategy leading to the darting measure may be used to develop additional discriminative and replicable endpoints of open-field behavior.

Amphetamine↗

PubMed2003

Cocaine-induced locomotor activity and cocaine discrimination in dopamine D4 receptor mutant mice.

RATIONALE: Previous studies have found a role for dopamine D(2)-like receptors in many of the behavioral effects of cocaine, including its stimulation of locomotor activity and interoceptive discriminative-stimulus effects. However, given the lack of selectivity of most of the available pharmacological tools among D(2), D(3) and D(4) dopamine receptors, the roles of these specific receptors remain unclear. OBJECTIVES: The roles of specific dopamine D(4) receptors in the behavioral effects of cocaine, including its locomotor stimulant and interoceptive discriminative-stimulus effects were investigated using dopamine D(4) receptor knockout (DA D(4)R KO) and wild-type (WT) mice. METHODS: The mice were trained in daily sessions to discriminate IP injections of saline from cocaine (10 mg/kg). Responses on one of two response keys intermittently produced a food pellet; one response was reinforced in sessions following cocaine injection (10 mg/kg), and the other response was reinforced in sessions following saline injection. Each 20th response produced a food pellet (fixed-ratio, or FR20 schedule of reinforcement). The dose-effects of cocaine and its interaction with the D(2)-like antagonist, raclopride, were assessed. Horizontal locomotor activity was also assessed in each genotype. RESULTS: As previously shown), cocaine was a more potent stimulant of locomotor activity in the DA D(4)R KO mice compared to WT littermate mice. In addition, cocaine was more potent in producing discriminative-stimulus effects in DA D(4)R KO mice (ED(50) value=0.50 mg/kg) compared to their WT littermates (ED(50) value=2.6 mg/kg). Raclopride shifted the cocaine dose-effect curve in both DA D(4)R KO and WT mice, though the shift was greater for the DA D(4)R KO mice. CONCLUSIONS: The present results on the stimulation of activity and interoceptive/subjective effects of cocaine are consistent with the previously reported disregulation of dopamine synthesis in DA D(4)R KO mice, and further suggest a role of the DA D(4)R in vulnerability to stimulant abuse.

Animals↗

PubMed2003

SEE locomotor behavior test discriminates C57BL/6J and DBA/2J mouse inbred strains across laboratories and protocol conditions.

Conventional tests of behavioral phenotyping frequently have difficulties differentiating certain genotypes and replicating these differences across laboratories and protocol conditions. This study explores the hypothesis that automated tests can be designed to quantify ethologically relevant behavior patterns that more readily characterize heritable and replicable phenotypes. It used SEE (Strategy for the Exploration of Exploration) to phenotype the locomotor behavior of the C57BL/6 and DBA/2 mouse inbred strains across 3 laboratories. The 2 genotypes differed in 15 different measures of behavior, none of which had a significant genotype-laboratory interaction. Within the same laboratory, most of these differences were replicated in additional experiments despite the test photoperiod phase being changed and saline being injected. Results suggest that well-designed tests may considerably enhance replicability across laboratories.

Animals↗

PubMed2002

Cocaine-induced locomotor activity and cocaine discrimination in dopamine D2 receptor mutant mice.

RATIONALE: Dopamine (DA) D2-like antagonists block several effects of cocaine, including its locomotor stimulant and interoceptive discriminative-stimulus effects. Because these compounds generally lack selectivity among the D2-like DA receptors, the specific roles of the subtypes remain unclear. OBJECTIVES: DA D2 receptor knockout (DA D2R KO), heterozygous (HET), and wild-type (WT) mice were used to study the role of D2 DA receptors in the effects of cocaine. Some effects of the relatively selective DA D2-like antagonist raclopride were also studied to further assess the role of D2 receptors. METHODS: DA D2R KO, HET, and WT mice were treated with cocaine (1-10 mg/kg) or vehicle, and their horizontal locomotor activity was assessed. The mice were also trained to discriminate i.p. injections of saline from cocaine (10 mg/kg) using a two-response key, fixed-ratio-20 response, food-reinforcement procedure. A range of doses of cocaine (1.0-17 mg/kg) was administered before 15-min test sessions. RESULTS: Both DA D2R KO and HET mice showed reduced levels of horizontal activity relative to WT mice. Cocaine dose dependently stimulated activity in each genotype, with the highest level of activity induced in the DA D2R WT mice. All three genotypes acquired the discrimination of 10 mg/kg cocaine; tested doses of 1.0-10.0 mg/kg produced dose-related increases in the number of cocaine-appropriate responses. Raclopride, at inactive to fully active doses (0.1-1.0 mg/kg), did not fully substitute for cocaine. Raclopride dose dependently shifted the cocaine dose-effect curve to the right in DA D2R WT and HET mice. However, in DA D2R KO mice, raclopride was inactive as an antagonist. CONCLUSIONS: The present data indicate an involvement of D2 DA receptors in the locomotor-stimulating effects and the interoceptive discriminative-stimulus effects of cocaine in WT subjects. However, the D2 receptor is not necessary for the effects, suggesting redundant dopaminergic mechanisms for the discriminative-stimulus interoceptive effects of cocaine.

Animals↗

PubMed1998

Genetic variance in nociception and its relationship to the potency of morphine-induced analgesia in thermal and chemical tests.

The perceived intensity of a painful stimulus is determined in part by the stimulus intensity and environmental conditions. The purpose of this study was to determine the influence of genetic factors in nociception and its contribution to the potency of morphine to produce antinociception. Eight inbred strains of mice were tested across a range of stimulus intensities in thermal (hot plate) and chemical irritant (acetic acid) nociceptive tests. Stimulus intensities in the thermal test included hot plate temperatures of 51, 53, 55, 57 and 59 degrees C. Stimulus intensities in the chemical irritant test included acetic acid concentrations of 0.1, 0.3 and 0.6%. Linear interpolation of stimulus-effect curves revealed large genotype-dependent differences in the effective temperature resulting in a 10 s latency on the hot-plate (ET10") and the acetic acid concentration resulting in the same number of writhes as determined by the area under the curve (AUC50). There was no genetic correlation between sensitivity to thermal versus chemical stimuli. Morphine dose response curves were then determined at a fixed stimulus intensity in each test (55 degrees C and 0.6% acetic acid) to determine analgesic ED50 doses for each inbred strain. A significant effect of genotype on relative sensitivity to morphine-induced analgesia in both the thermal and chemical irritant tests was found, however there was no genetic correlation between the potency of morphine in each test. There was an inverse genetic correlation between sensitivity to thermal and chemical stimuli and morphine ED50 values in each respective test. In both tests, strains less sensitive to the nociceptive stimuli were more sensitive to the antinociceptive effects of morphine. Confirmation studies in a separate genetic population confirmed the inverse relationship between hot-plate sensitivity and antinociceptive potency. In summary, this study demonstrated (i) a large degree of genetically-determined variability in sensitivity to painful stimuli, (ii) sensitivity to thermal stimuli (hot-plate) is genetically unrelated to sensitivity to chemical (acetic acid) stimuli, (iii) the mechanism by which morphine produces its antinociceptive effects against thermal stimuli is largely genetically independent of the mechanism by which morphine produces its antinociceptive effects against chemical stimuli, and (iv) inherent differences in sensitivity to painful stimuli may be responsible, in part, for individual differences in the potency of morphine's antinociceptive effects.

Acetic Acid↗