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RSA 2004 Abstracts

Stanford University School of Medicine, Stanford, CA

SYMPOSIUM (Other abstracts presented at this symposium are included here though the research for them may have been conducted at other facilities)

NEUROIMAGING OF ANIMAL MODELS OF ALCOHOLISM: INITIAL REPORTS FROM THE INTEGRATIVE NEUROSCIENCES INITIATIVE ON ALCOHOLISM

ORGANIZERS/CHAIRS: Edith V. Sullivan and Kathleen A. Grant

Edith V Sullivan & Kathleen A Grant

Stanford University School of Medicine, Stanford, CA

The neuroadaptive effect of alcohol on the brain may itself contribute to the self-sustaining nature of alcoholism. Neuroimaging of animal models of alcoholism offers a unique path for translational research to the human condition. Animal models permit manipulation of variables uncontrollable in clinical, naturalist human investigation. This symposium presents neuroimaging studies from both centers of the Integrative Neuroscience Initiative on Alcoholism (INIA). Effects of alcohol exposure were assessed with in vivo glucose metabolic imaging of rat brain, in vitro neurotansmitter imaging of monkey brain, in vivo magnetic resonance (MR) imaging of monkey brain, and in vivo MR spectroscopic (MRS) quantification of alcohol metabolism kinetics in rat brain.

FUNCTIONAL NEURONAL ACTIVITY IN ALCOHOL-PREFERRING (P) RATS WITH CHRONIC ETHANOL DRINKING

H.J.K. Sable, W.N. Strother, D.G. Smith, L. Lumeng, T.-K. Li, W.J. McBride

Indiana University School of Medicine, Indianapolis, IN

Neurobiological changes associated with ethanol (E) drinking in alcohol-preferring (P) rats were examined using in vivo 2-deoxyglucose labeling coupled with in vitro quantitative autoradiography. In adults, widespread reductions in functional activity were observed after chronic scheduled-access drinking (4 hr/day) of 15% E (v/v) and water. Prolonged E deprivation produced functional recovery toward basal levels. Scheduled-access relapse drinking restored functional activity in some brain regions to the reduced state observed during earlier chronic drinking. Interestingly, 24-hr free-choice access to E and water in adults and adolescents does not produce the extensive changes seen under scheduled-access conditions. These studies suggest conditioning factors present during scheduled-access E drinking may play an important role in producing long-term changes in CNS neuronal activity in chronically drinking P rats. (Support: AA07611, AA10721, AA10256, AA13521)

IN VITRO IMAGING OF RECEPTOR CHANGES DUE TO CHRONIC ALCOHOL SELF-ADMINISTRATION IN CYNOMOLGUS MONKEYS

D. Friedman, A. Davenport

Wake Forest University School of Medicine, Winston-Salem, NC

Chronic alcohol abuse appears to alter the function of GABAA inhibitory, NMDA excitatory and serotonergic neurotransmission in many brain regions, including the orbital and medial prefrontal cortex, amygdala, hippocampus, ventral striatum and cerebellum. To examine the effects of chronic alcohol self-administration in a monkey model of alcoholism, we studied 20 adult cynomolgus macaques. Twelve monkeys self-administered ethanol for 18 months under ad libitum access to ethanol for 22 hr/day and 8 monkeys served as no alcohol controls. At necropsy one hemisphere was dissected and frozen for subsequent in vitro histological analyses and the other hemisphere was used for functional analyses with slice electrophysiological and neurochemical techniques. Receptor binding in homogenates of cerebral cortex and cerebellum indicate no differences in GABAA receptor density or in the relative proportions of alpha subunits. In addition, there were no differences in NMDA receptor numbers in these gross structures. These preliminary results suggest that functional differences resulting from chronic ethanol consumption are not due to changes in the densities of GABAA or NMDA receptors. In vitro autoradiography is being performed to confirm these findings in specific cortical and subcortical structures. (Support: AA 011997, AA13641)

MRI STUDIES IN RHESUS MONKEYS AT RISK FOR EXCESSIVE ALCOHOL SELF-ADMINISTRATION

J. Daunais, R. Kraft

Wake Forest University School of Medicine, Winston-Salem, NC

Early childhood stress and neglect is implicated as a risk factor for developing alcoholism. A well-established monkey model of early childhood stress is infant-maternal separation that results in lifetime alterations in physiology and behavior, including heightened HPA response, lower cognitive abilities, increased impulsivity and an increase in short-term alcohol consumption. However, few neurobiological markers have been documented in this model, including in vivo imaging of brain areas believed to mediate potential risk factors. MRI techniques can address pathological changes that occur as a consequence of chronic alcohol exposure, and are largely consistent with neuropathological reports. We have recently established MRI studies in non-human primates and are applying this method to address potential stress- and alcohol-induced pathologies in the macaque brain. The presence of pathology, including white matter hyperintensities, and changes in ventricular size and volume will be assessed in this model. Additional measures will include MR spectroscopy for GABA, GLU and ethanol. It is hoped that these measures will help to illuminate the neurobiological consequences of early stress and chronic alcohol exposure. (Support: AA 011997, AA13641)

INDIVIDUAL VARIABILITY IN ALCOHOL KINETICS IN RAT BRAIN MEASURED WITH MR SPECTROSCOPY

A. Pfefferbaum, E. Adalsteinsson, E. V. Sullivan

SRI International, Menlo Park, CA

To examine individual differences in alcohol metabolism kinetics, brain ethanol was quantified in vivo in Wistar rats. After sedation with isoflurane, proper catheter placement was ensured by abdominal MR imaging of contrast agent. Single-voxel, 2D J-resolved spectra were acquired before and after bolus injection of 1 g/kg ethanol. Peak frequencies were identified for Cr2, Cho, Cr, Glu, NAA, ethanol and each fit individually to a Gaussian function. Multiparametric, least squares fit for the NAA and ethanol peaks were used as basis functions for a linear, least-squares fit amplitude estimates for each time point. All animals achieved maximum MRS visible ethanol concentration within 4-8 min of injection, followed by a gradual decline over 1 hr (~40% at 1 hour). Assuming a rat brain NAA concentration of 10 mM, four animals achieved approximately 70-90 mg/dl and four ~50 mg/dl. The expected maximum at this dose with full absorption, instantaneous uptake, no metabolism, and full MRS visibility would be 100 mg/dl. Some animalsŤ data were well described by a single compartment model, whereas others had an "overshoot-undershoot" pattern in the first 5 minutes suggesting a second kinetic factor, perhaps initial water distribution being greater in the brain than the body as a whole. Large differences among animals suggest individual variability in uptake, distribution or metabolism of alcohol. (Support: AA13521, AA05965)

 

 

 

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