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1997 March

Effect of Insulin on Performance of Two Behavioral Tasks that Assess Reward

Dianne Figlewicz Latteman, PhD
Research Associate Professor


Description: Chronic food restriction results in an enhancement of the reinforcing efficacy of a variety of addictive drugs. CNS midbrain dopaminergic (DA) neurons have been implicated as a major anatomic candidate for the mediation of the reinforcing properties of these drugs. One consequence of both acute and chronic food restriction is a decreases in circulating levels of the hormone insulin. We have previously proposed that this hormone is a physiological regulator of the midbrain DA neurons. Specifically, the re-uptake transporters (DATs) appear to be a molecular target for insulin action. The functional implication of these effects is that elevated CNS insulin should result in decreased performance in behavioral paradigms that have a dopaminergic component. I propose to test this by measuring the performance of rats in two well-established behavioral tasks--the sucrose preference test and CPP--in the presence or absence of centrally infused insulin. These studies may elucidate one molecular mechanism underlying a well-established phenomenon in drug addiction.

Molecular Events during the Development of Cannabinoid Tolerance

Ken Mackie, MD
Assistant Professor


Description: Cannabinoids, the principal psychoactive constituents of marijuana, have profound effects on mood, memory, movement, and nocioception. Acting via the neuronal cannabinoid receptor (CB1), these compounds are potent modulators of ion channel function and also inhibit adenylyl cyclase. These actions suggest that cannabinoids may elicit their behavioral effects by decreasing neuronal excitability.

Like many other signaling molecules that act through cell surface receptors, the effects of a fixed dose of cannabinoid diminish with successive administrations, a process termed desensitization. Almost nothing is known about what happens to the CB1 receptor during desensitization. Recent results from our lab demonstrate that the CB1 receptor is rapidly internalized during agonist exposure. The goal of the proposed study is to determine the cellular events associated with internalization during the development of desensitization. Our hypothesis is that the cannabinoid receptor is phosphorylated, and then internalized in an arrestin and dynamin-mediated process. This study will significantly advance our understanding of the cellular actions of cannabinoids, the effects of chronic cannabinoid use, and the regulation of cannabinoid receptor expression.

Signaling Pathways that Control Ethanol-Induced Neuronal Apoptosis

Zhengui Xia, PhD
Sheldon Murphy Assistant Professor

Environmental Health

Description: Alcohol abuse and alcoholism is a major health problem in the US affecting approximately 5% of the population. Alcoholism is associated with a number of well characterized physiological defects including confusion, visual hallucinations and memory impairment. Although the mechanisms for alcohol effects on memory are unclear, ethanol-induced neurotoxicity may contribute. The major objective of this proposal is to define molecular mechanisms for ethanol-induced neurotoxicity.

I hypothesize that ethanol causes apoptotic death in neurons of the hippocampus and cortex and that is does so by affecting the balance between signal transduction systems that dictate whether a neuron survives or is selected for programmed cell death. Elucidation of mechanisms of ethanol-induced neurotoxicity may provide insights for preventing or reducing the adverse physiological effects of alcohol abuse.

1997 October

Effect of Chronic Cocaine Exposure on Cerebral Blood Flow Autoregulation in Dogs

Christopher M. Bernards, PhD
Associate Professor


Description: Cocaine is one of the most widely abused drugs in the U.S. and its use is again on the increase. Too, cocaine is second only to alcohol as the most common drug of abuse associated with traumatic injuries. Consequently, an increasing number of patients with a history of cocaine abuse are presenting for both emergency and elective surgery and anesthesia. Unfortunately, little is known about how chronic cocaine use alters the normal physiology and pharmacology of anesthesia. The current proposal focuses on the impact of chronic cocaine exposure on cerebral blood flow autoregulation and will specifically address the hypothesis that chronic cocaine exposure impairs normal cerebral blood flow (CBF) autoregulation during anesthesia.

To address this hypothesis, transcranial Doppler will be used to non-invasively determine CBF autoregulation curves in 2 groups of beagle dogs at baseline prior to cocaine exposure and then weekly for 4 weeks. At the end of 4 weeks, one group of animals will be sacrificed and cerebral blood vessels removed for in vitro study of vasoconstriction/vasodilation mechanisms. In the second group of animals, cocaine administration will cease and CBF autoregulation determined 1, 3, and 10 days later to determine if cessation of cocaine use results in a rebound phenomenon. This group of animals will then be sacrificed and their cerebral vessels removed for study of vasoconstriction/vasodilation mechanisms. The findings from this proposed study will begin to supply the information we need to provide appropriate care to cocaine using patients during surgery and anesthesia.

Craniofacial Skeletal Anatomy in Children with Fetal Alcohol Syndrome (FAS)

M. Lena Omnell, DDS, MSD

Orthodontics, Dental Medicine

Description: Fetal Alcohol Syndrome (FAS) is characterized by growth deficiency, central nervous system dysfunction and organ malformations, at varying levels of severity. The facial FAS phenotype is unique and is a major feature in diagnosis, distinguishing FAS from other conditions with growth deficiency and brain dysfunction. The FAS facial phenotype is characterized by small palpebral fissures, a thin upper lip and a smooth philtrum that are often minimally expressed at birth, maximally expressed in childhood and may diminish again in adulthood. There is little understanding of the morphological basis for this variation.

A skeletal origin is implied by the lip and philtrum soft tissue changes. However, a detailed quantified examination of the FAS craniofacial complex is yet lacking. The purpose of this study is to seek craniofacial features such as premaxilla protrusion, increased midface height, decreased facial depth or reduced cranial base angle that correlate with the FAS facial phenotype. Subjects with documented prenatal alcohol exposure that were previously identified as having a smooth philtrum and a thin upper lip will be matched for age, gender, and race with subjects previously identified for having furrowed philtrum and a thick upper lip. Lateral head film, facial photos and direct measurements will be obtained and variation in cephalometric angular and linear measurements with change in FAS facial phenotype will be assessed.

Individual Differences to Nitrous Oxide in the Rat: Acute Tolerance and Self-Administration

Douglas S. Ramsay, PhD
Associate Professor

Orthodontics, Pediatric Dentistry

Description: The overall objective of this work is to identify individual difference characteristics that are apparent during an initial Nitrous Oxide (N20) administration and that will predict the way an individual will be affected over repeated N20 administrations. Based on preliminary data, we have been able to identify individual rats that are 1) initially insensitive to N20-induced hypothermia but develop acute tolerance during the 4-hour administration, 2) initially sensitive to N20-induced hypothermia but develop acute tolerance during the 4-hour administration, and 3) initially sensitive to N20-induced hypothermia but show no evidence of acute tolerance development during the 4-hour administration.

The first proposed experiment examines these individual differences in male Long-Evans rats with regards to the hypothermic effects of a 4-hour steady-state administration of 60% nitrous oxide (N20). Experiment #1 will determine whether the individual differences observed during the initial N20 exposure are sufficiently stable so that they still describe those same animals during a second exposure 10 days later. The second proposed experiment is derived from an important implication of our recently proposed theoretical model that suggests that these individual differences may be related to individual differences in subsequent drug seeking or self-administration behavior. Unfortunately, although a N20 self-administration method is available for humans and primates, no rat self-administration apparatus for different N20 concentrations has been developed to test our hypothesis. Therefore, experiment #2 will design, build, and test a N20 concentration gradient where rats learn to move within the gradient to choose the concentration of N20 that is being administered. This line of research is of theoretical importance for understanding the mechanisms of drug tolerance as well as what accounts for individual differences in vulnerability to addiction and drug abuse.

Neurocognitive Function: Its Relation to Readiness to Change Alcohol Abuse

Karen Schmaling, PhD
Associate Professor

Psychiatry & Behavioral Sciences

Description: Alcohol abuse increases the risk of neurocognitive insult. Neuropsychological testing has determined that alcohol abuse harms the frontal region of the brain, an important area for a number of abilities, including memory, planning and organizational skills, impulse control, and decision-making functions. Neurocognitive dysfunction linked to alcohol abuse has been associated with poor treatment outcome, but whether the mechanism underlying this relationship is related to motivation, skill or self-efficacy is unknown.

Cognitive processes are important for behavior change. Progressive movement through various stages of change is marked by interactions between motivation, skill, and self-efficacy or confidence to change. Memory abilities and executive functions are important skills for monitoring and managing behavior. Reduced ability to remember new information, plan, organize, control impulses, or solve problems would impede efforts to reduce alcohol consumption even in people motivated for change.

Subjects who meet criteria for alcohol abuse or dependence, without other neurocognitive risk factors, be administered neuropsychological tests that measure memory and executive function. It is hypothesized that cognitive abilities will predict level of motivation, quality of coping skills, and level of self-efficacy to change alcohol behavior. Support of these hypotheses would highlight the need to attend to neurocognitive function early in the processes of behavior change as an important determinant for successful outcome in alcohol treatment.

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