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«A Dissertation Presented to the Faculty of the Graduate School of Cornell University In Partial Fulfillment of the Requirements for the Degree of ...»

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THE ROLE OF ALTERED CATECHOLAMINERGIC ACTIVITY IN THE

ATTENTIONAL DYSFUNCTION INDUCED BY LEAD EXPOSURE OR

PRENATAL COCAINE EXPOSURE

A Dissertation

Presented to the Faculty of the Graduate School

of Cornell University

In Partial Fulfillment of the Requirements for the Degree of

Doctor of Philosophy

by

Lorna Elissa Bayer

August 2008

© 2008 Lorna Elissa Bayer

THE ROLE OF ALTERED CATECHOLAMINERGIC ACTIVITY IN THE

ATTENTIONAL DYSFUNCTION INDUCED BY LEAD EXPOSURE OR

PRENATAL COCAINE EXPOSURE

Lorna Elissa Bayer, Ph. D.

Cornell University 2008 Attentional dysfunction is associated with numerous genetic and environmental factors that disrupt brain development. Evidence implicates catecholaminergic systems in attentional processing, suggesting that alterations in catecholamine neurochemistry may underlie these attentional dysfunctions. The goal of the present experiments was to use a pharmacological challenge approach to examine underlying neural changes that relate to attentional dysfunctions induced by two developmental insults, lead (Pb) exposure and prenatal cocaine exposure, and to test the hypothesis that exposure-induced alterations in catecholaminergic systems contribute to these attentional deficits. In each experiment, adult rats were administered a visual attention task which assessed subjects’ ability to monitor an unpredictable light cue and maintain performance when presented with olfactory distractors. In the first study, Pb-exposed subjects demonstrated significant impairments in accuracy relative to controls, providing evidence for Pb-induced attentional dysfunction. The alpha-2 adrenergic antagonist idazoxan improved accuracy, specifically in the most attentionally demanding conditions. However, this effect of idazoxan did not differ between Pb-exposed and control subjects, failing to support the hypothesis that the attentional dysfunction was due to alterations in noradrenergic systems. In the second study, prenatal cocaine-exposed subjects did not differ from controls in their response to idazoxan’s effect on errors of commission, but were more sensitive to idazoxan’s effects on errors of omission and nontrials. The pattern of effects suggested that the differential treatment response to idazoxan resulted from prenatal cocaine-induced alterations in norepinephrine-modulated dopamine release, reflecting lasting changes in dopaminergic and/or noradrenergic systems underlying attention. The final study was designed to assess whether cocaine exposed and control subjects differ in sensitivity to attentional effects of the D1 dopamine agonist SKF81297. Prenatal cocaine-exposed subjects were more sensitive to the impairing effects of SKF81297 on errors of omission, providing specific evidence that prenatal cocaine exposure produces lasting changes in dopaminergic systems mediating attention. In conclusion, environmental Pb exposure impairs attention; however, these impairments do not appear to reflect alterations in noradrenergic function, suggesting the involvement of other neurochemical systems.

In contrast, prenatal cocaine-induced attentional impairments appear to be related to lasting changes in dopaminergic systems underlying attention, suggesting possible targets for pharmacotherapeutic intervention in affected children.

BIOGRAPHICAL SKETCH

Lorna Elissa Bayer earned an A.B. Magna Cum Laude in Psychology from Cornell University in 1990. During her undergraduate years, she pursued undergraduate research projects on the development of cognition in infancy under the direction of Dr. Elizabeth Spelke of the Cornell University Department of Psychology, and on neurotransmitter interactions and plasticity in the rat septohippocampal pathway under the direction of Dr. Teresa Milner of Weill Cornell Medical College Department of Neurology and Neuroscience, Division of Neurobiology. Prior to her graduate studies, Lorna worked as a Research Specialist at the Cornell University New York State College of Veterinary Medicine on toxicology research projects under the supervision of Dr. Fred Quimby. Lorna’s primary academic interests are within the areas of neurobehavioral pharmacology and toxicology, functional neuroanatomy, and the neurobiology of memory, attention and executive function.

iii ACKNOWLEDGMENTS

I would like to express my sincerest gratitude to the chair of my committee, Dr. Barbara Strupp for her mentorship and guidance, and to my committee members, Drs. Greg Weiland, Timothy DeVoogd, and Michael Spivey for their advice and support. I am grateful to Mareike Kuypers for excellent technical assistance, to Drs.

Charles McCulloch and Ed Frongillo and to Myla Strawderman for expert statistical advice, to Dr. David Levitsky for apparatus development and support, and to postdoctoral associates Dr. Russ Morgan and Dr. Hugh Garavan for critical feedback and discussion throughout this project. I am also deeply grateful to the excellent undergraduate honors thesis students who assisted in data collection: Kelly Snow, Alison Brown, Sujani Kakamanu, and Beth Kellerman. My deepest thanks go to my husband Andrew Rappaport and my children Reuben Bayer Rappaport and Samuel Bayer Rappaport for their unwavering support for my completion of this project.





The research presented in these chapters was supported by grants from the National Institute of Drug Abuse (DA07559, DA09160, DA1137), the National Institute of Environmental Health Sciences (ES-05950-03, ES06259, ES07457), the March of Dimes Birth Defects Foundation (12-FY93-0730), the EPA STAR Fellowship Program (U-914718-01-0), and a President’s Council of Cornell Women 1993 Research Grant. The author was supported by NIMH Training Grant 5-T32MH19389-03, EPA STAR Fellowship U-914718-01-0, and Teaching Assistantships from the Cornell University Departments of Psychology and Cognitive Studies.

Portions of this research were presented previously at the Annual Meeting of the Society for Neuroscience, San Diego CA November 1995, Washington D.C.

November 1996, and Los Angeles CA November 1998, and at the Annual Meeting of the Neurobehavioral Teratology Society Palm Beach FL June 1997.

–  –  –

Attentional systems as a target of toxicity Deficits in attention are among the most common impairments seen in developmental disorders, and are associated with a wide variety of genetic and environmental factors that disrupt brain development. Attentional dysfunction is a commonly cited consequence of unrelated disorders such as attention deficit hyperactivity disorder (ADHD) (reviewed in Karatekin, 2001), fragile X syndrome (Baumgardner, et al, 1995; Hagerman, 1996; Lachiewicz, et al, 1994; Largo and Schinzel, 1985; Moon, et al, 2006; Turk, 1998), Down syndrome (Brown et al, 2003;

Driscoll, et al, 2004; Tomporowski, et al, 1990; Wilding et al, 2002), phenylketonuria (PKU) (Diamond, 2001; Pennington, et al, 1985), and conditions caused by exposure to a variety of substances such as environmental toxins and drugs of abuse. The prevalence of attentional impairments as a symptom of early insult relative to other types of cognitive impairment suggests that the attentional processing system appears to have increased vulnerability to disruption by genetic and environmental factors (Pennington, 1991). This differential vulnerability is likely due to the evolutionary history, developmental time-course, and neurochemical modulation of the prefrontal cortex (PFC), a critical brain region for attentional processing Prefrontal control of attentional function Considerable evidence suggests that the PFC mediates attentional processing, including both selective and sustained attention. Lesions to the PFC in human patients (Chao and Knight, 1995; Knight, et al, 1995; Mennemeir, et al, 1994; Ptito, et al, 1995; Rueckert and Grafman, 1996; Wilkins, et al, 1987), monkeys (Stuss and 1 Benson, 1986) and rats (Chudasama, et al, 2003; Muir, et al 1996; Passetti, et al, 2002;

2003) cause deficits in sustained attention, and increased distractibility to irrelevant stimuli in auditory, visual, and haptic modalities. Dorsolateral prefrontal patients (Eslinger and Grattan, 1993; Milner, 1995; Owen, et al, 1991), marmosets with dorsolateral prefrontal lesions (Dias, et al, 1996; 1997), and rats with lesions to the medial PFC (Birrell, et al, 2000) show deficits in the ability to shift attentional set to a previously irrelevant dimension. Human patients with lesions to the dorsolateral PFC are also impaired on tasks of divided attention (Godefroy, et al, 1996) and on performance of the Stroop task, a task of attentional selection and response inhibition (Stuss, et al., 2001; Vendrell, et al, 1995).

The prefrontal cortex shows selective activation during performance of attentional tasks. Human functional neuroimaging studies have demonstrated specific frontal activation during the performance of the continuous performance task (CPT), a standard test of visual sustained attention and response inhibition (Rezai, et al, 1993).

Differences in frontal evoked potentials produced in response to relevant target stimuli versus irrelevant distractor stimuli during visual and auditory attention tasks have also been reported (Baudena, et al, 1995; Zani, 1995). Dorsolateral prefrontal activation has been reported during shifting of attention between spatial locations (Corbetta, et al, 1993), between sorting categories on the Wisconsin Card Sorting Task (Konishi, et al, 1999; Rezai, 1993), and between competing tasks during dual-task performance (D’Esposito, et al, 1995; Loose, et al, 2003). Dorsolateral prefrontal activation has also been demonstrated during performance of the Stroop task, with greater activation exhibited on more attentionally demanding trials (Banich, 2000). Single-unit recordings from rhesus monkey dorsolateral PFC have identified a population of neurons that increased activity levels during the delay (or attention-demanding) period of a visual target detection task in which difficulty was manipulated by altering the 2 size and color contrast of the target (Lecas, 1995). Although these neurons were active during the delay under all conditions, average firing rate was proportional to attentional demand. Firing rate was highest in the difficult blocks, and lowest in the easy blocks, suggesting that these neurons control or code for the level of attention of the animal. Increases in unit activity of neurons in PFC under conditions of enhanced attentional demand have also been reported in rats during performance of sustained visual attention tasks in which visual distractors were presented (Gill, et al, 2000).

The critical role of the PFC in attentional processing may provide insight into the differential vulnerability of this functional brain system. The relatively large size of the human PFC occurred late in evolutionary history, and maturation of this brain region occurs relatively late in brain development; both factors which can increase susceptibility to developmental disruption (Pennington, 1991). Prefrontal control of attention relies on multiple neurotransmitter systems, making this system vulnerable to a variety of different neurochemical insults. Finally, evidence suggests that the dopamine (DA) neurons in this brain area have a greater dependence on precursor availability than those of other brain systems (Tam, et al, 1990), providing an additional mechanism for the greater vulnerability of this region.

Evolutionary History The large prefrontal cortices of primates, especially humans, are a recent development in evolutionary history. Both the absolute and relative size of this brain region have increased significantly over recent evolution. According to Lieberman (1984), recently evolved brain systems tend to demonstrate a higher level of genetic variation both within and across species when compared to evolutionarily older, more highly conserved brain systems. Thus, the prefrontal attentional system’s recent 3 evolutionary history should result in greater variation and, consequently greater vulnerability to developmental pathologies (Pennington, 1991).

Late development compared to other brain systems A second relevant feature of the PFC is its protracted developmental timecourse. The PFC is the last brain region to develop in humans and does not reach full maturity until early adulthood (Huttenlocher, et al, 1979, 1982, 1984, 1990; Rosenberg and Lewis, 1994; Sowell, et al, 1999; Thatcher, et al, 1987; Yakovlev, et al 1967).

Thus, childhood exposure to toxins may cause alterations in this prefrontal attentional system while sparing other brain systems that are more fully developed at the time of exposure. Recent studies also suggest that the first two years, especially the second half of the first year of life, is an important transition period in prefrontal cortical anatomical development. Studies show that specific changes in and maturation of prefrontal cortical neurons and their associated cognitive functions are occurring during this period (Diamond, 2002). During this period, both the levels of DA (Brown, et al, 1977) and density of DA receptors increase (Lidow and Rakic, 1991) in dorsolateral PFC and significant changes occur in the distribution of tyrosine hydroxylase containing axons in this brain region (Lewis and Harris, 1991; Rosenberg and Lewis, 1995) in rhesus macaques. These neurochemical and anatomical changes parallel the development of PFC dependent cognitive tasks in human infants (Diamond and Doar, 1989). During this same period, longitudinal EEG studies of human infants show an increase in frontal electrical activity correlating with increasing proficiency at the performance of PFC dependent cognitive tasks (Bell and Fox, 1992). Toxin-exposure that occurs during this period may therefore have more marked effects on dorsolateral PFC dependent functions such as attention because it is during this period that the system undergoes critical developmental changes. For 4 example, the late development of the PFC relative to other brain regions may make this system particularly sensitive to insult caused by exposure to environmental lead (Pb) during post-natal development, the time of maximal Pb-exposure due to increases in hand-to-mouth behavior (Bellinger, et al, 1994).



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