Dr. Charles F. Mactutus
Professor and Department Chair

Dr. Mactutus's major research interests are in the areas of drug abuse neurotoxicity (specifically through studies on development and plasticity), addictive processes (as revealed through studies of psychostimulant sensitization and sex differences therein), and NeuroAIDS. Developmental neurotoxic effects caused by maternal use of licit (nicotine, caffeine) or illicit drugs (cocaine, amphetamine) via exposure to environmental agents (e.g., passive smoking), or virotoxins (e.g., Tat and/or gp120) are one primary focus. A second focus is on the structural and neurodevelopmental basis(es) of gender differences in response to psychostimulant sensitization, such as produced by cocaine, nicotine and the amphetamines. A third focus is on NeuroAIDS; using the viral proteins tat and gp120, we are studying pediatric AIDS, HIV dementia, and potential neuroprotective agents (e.g., estrogen) that may underlie the apparent gender differences in HIV infection. At least one project in each of these focuses is funded by NIH/NIDA.

Methodologically, our studies utilize a pronounced multidisciplinary approach. The program currently employs behavioral (spatial memory, conditioning, auditory startle), anatomical (immunocytochemistry, cell counting, cellular and subcellular morphometric analyses), pharmacological (GC/MS, blood gas analyses, in vivo drug probes, receptor binding and autoradiography, neurochemical enzyme activity and Western blotting), and molecular biological techniques (in situ hybridization and Northern blotting). Imaging (e.g., MRI) and gene chip technologies also are most recently being employed for our research.

In Utero Cocaine Exposure:

Our recent data provide convergence across a variety of disciplines that indicate prenatal cocaine is a neurobehavioral teratogen when administered by a clinically relevant route (IV) and at physiologically relevant peak arterial plasma levels, and moreover, that the central noradrenergic system is a very important target for these effects. Our current program maintains the hypothesis: Maternal cocaine abuse during a restricted portion of pregnancy causes long-term and selective alterations in 1) "attentionally sensitive" neurobehavioral paradigms and 2) the structure and function of the central noradrenergic system; both of which are attributable to early noradrenergic cell dysfunction/loss in the locus coeruleus.

The specific aims of the program are: First, to establish the critical exposure period for the neurobehavioral alterations which occur in the offspring consequent to intravenous maternal cocaine exposure during pregnancy. Using ontogenetic and longitudinal analyses, the proposed studies will replicate and extend our prior studies by specifically identifying the critical exposure period(s). We will use noradrenergically mediated and/or attentionally sensitive tasks to provide an assessment of both ascending and descending noradrenergic projections of the locus coeruleus. Multiple dependent measures within each task will provide the dissociation of specific neural and cognitive deficits from sensory or motor impair­ments. Second, To establish the critical exposure period for the structural and functional alterations in the central noradrenergic system alterations which occur in the offspring consequent to IV maternal cocaine exposure during pregnancy. Quantitative neuroanatomical measurements (unbiased cell-counting/optical disector technique), immunocytochemistry, synthetic enzyme activity, and in situ hybridization will be utilized to fundamentally establish whether the observed alterations in the central noradrenergic system, presumably reflecting compensatory processes in the developing CNS, occur in response to noradrenergic cell loss or, alternatively, to a less permanent cellular dysfunction. The goal of the proposed program is to determine whether the early cell dysfunction/loss in the locus coeruleus may provide a potential underlying basis for the long-term and selective alterations in attentionally sensitive neurobehavioral paradigms consequent to prenatal cocaine exposure.

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Addiction Processes and Sensitization:

Gender differences in response to psychostimulants have been reported both in animals and humans; however, the biological mechanisms which underlie these gender differences to psychostimulants remain for the most part, unexplained. The common observation is that females are more sensitive to psychostimulants, such as cocaine. Our hypothesis is: Activational as well as organizational effects of gonadal hormones on dopaminergic systems provide the underlying basis for the gender differences in behavioral sensitization produced by repeated IV cocaine administration.

First, we will determine whether pharmacokinetic differences between the sexes result in higher levels of cocaine in the female brain. We have successfully developed a technically simple, economical and practical non-tethered technique for repeatedly administering cocaine IV to freely moving, group-housed, rats. Detailed pharmacokinetic analysis has demonstrated rapidly peaking cocaine levels following IV dosing in rats, which is similar to that observed in humans, as opposed to SC, PO, or IP dosing. Using this clinically relevant IV rodent dosing model, we will determine whether pharmacokinetic factors contribute to the increased sensitivity of female animals to the effects of cocaine. Second, we will determine whether gonadal hormones regulate the expression of gender differences in response to cocaine in adulthood. We will test the ability of gonadal hormones to modulate dopamine receptor responsiveness to chronic cocaine administration. Third, we will determine whether the brain organizational effect of the perinatal hormonal milieu mediates the gender differences in cocaine responsiveness. We have pharmacologically characterized a recently discovered unique dopamine receptor subtype (D3) which is localized to the striatum/nucleus accumbens region of the brain. We hypothesize that alterations in dopaminergic systems, in particular the D3 receptor system, underlie the gender differences produced by repeated IV cocaine administration. Our long-term goal is to determine the role of the dopamine neurochemical system (emphasizing the dopamine D3 receptors) in gender differences following repeated IV cocaine administration. The ultimate goal of this research is to develop pharmacological interventions to assist in correcting the behavioral problems associated with chronic cocaine abuse in humans, and specifically to provide potential insight into effective treatment strategies for women drug abusers.

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NeuroAIDS:

Intravenous drug use among women is often associated with more frequent high-risk sexual behavior, placing them at risk not only for unwanted pregnancy, but also for contracting HIV infection. Given the intractable methodologi­cal and interpretative problems inherent in human developmental research on drug abuse as well as HIV/AIDS, appropriate animal models offer an unique oppor­tunity. The recent establish­ment of a technically simple, economical and practical technique for chronic IV studies in which a vascular port is implanted, prior to mating, offers a model for pregnant rats which rea­sonably mimics the route, pharmacokinetics and expected physiological effects of cocaine abuse in humans via inhalation or IV administration. Our hypothesis is that: Neonatal exposure to the HIV proteins, gp120 and Tat, will produce specific neurodevelopmental disruptions and that these disruptions will be exacerbated by prior in utero cocaine.

First, the relative contributions of the interactive effects of IV cocaine and HIV proteins (gp120/Tat) on the developing central nervous system of perinatal animals will be addressed using both well-established in vivo and in vitro procedures. Second, the nature and extent of the structural and functional alterations in the central noradrenergic system will be examined as a potential basis of synergistic effects of IV cocaine and HIV proteins (gp120/Tat). Third, the potential disruption of key developmental processes – neurogenesis and cell death – will be ascertained in a well-characterized model system that undergoes extensive postnatal development - the cerebellum.

Thus, this project will 1) contribute to our understanding of the individual and interactive mechanisms of gp120/Tat and cocaine neurotoxicity in a clinically relevant rodent model and 2) further provide a comprehensive examination of potential neuronal/glial targets responsible for early developmental disorders independent of secondary opportunistic infections. These studies will also 3) provide the foundation for an examination of these very same potential mechanisms for cocaine/HIV protein neurotoxicity in humans with the use of fetal autopsy tissue from pregnant chronic IV drug abusers. Our rodent model of IV cocaine, in combination with HIV protein neurotoxicity, is innovative and will be translational to the mechanisms of neuropathology in pediatric AIDS.

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