NIDA/NIAAA Level of focus

The strengths and research directions of the training faculty comprise laboratories representing four levels of focus, although most investigators are obviously not strictly bounded by a given level. The first of these is represented by laboratories working principally at the cellular/molecular/biochemical level to investigate processes mediating drug responses. The faculty members most closely identified with this focus include Drs. Buck, Grandy, Jahr, Janowsky, Low, Meshul, Neve, Ryabinin, and Wiren. Studies ongoing in this area concentrate on the effects of acute and chronic drug treatment in a number of systems, including: characterization of key receptor genes such as the dopamine and opioid receptors and the dopamine transporter protein; examining dopamine and glutamate function using chimeras and receptors or transporters modified by site-directed mutagenesis; analyzing transcriptional regulation of endogenous opioid genes; expression of GABA and steroid receptor proteins and RNA derived from genetic animal models of drug sensitivity in Xenopus oocytes; studies of the trafficking of fluorescent-labeled proteins in cultured cells, use of microarray analysis to identify genes regulated by chronic drug treatment; biophysical studies of excitatory amino acid receptors using patch-clamp methods; functional studies of expression and enzyme activity for candidate genes identified from gene mapping efforts; studies of null mutant and overexpression transgenic mice; and ultrastructural examination of synaptic alterations in brain using electron microscopy.

The second level of focus is represented by those laboratories studying systems mediating drug-related responses at the neurochemical/neurophysiological/neuropharmacological level. Faculty working primarily at this level are Drs. Finn, Johnson, Kelly, Mark, McCleskey, Olsen, Ronnekleiv, and Williams. These studies include: use of in vivo voltammetry and microdialysis to study transmitter overflow; excitatory amino acid receptor, dopamine, and GABA function assessed by quantitative receptor autoradiography, in vitro binding, GTP S binding, immunocytochemistry, and in situ hybridization; opioid regulation of ion conductances (potassium, calcium and other cationic currents) using voltage clamp techniques in a number of cell types; evaluation of non-opioid mechanisms regulating pain circuitry; analysis of dopamine and serotonin circuitry using single cell recordings in brain slices; use of neural ensemble recording to study the influence of drugs of abuse on information processing in the limbic system; the role of neuroactive steroid hormones and stress in drug self-administration and withdrawal studied in vivo and in vitro; the role of potassium channels in hippocampal-dependent learning.

The third area of focus is represented by those investigators studying drug effects at the behavioral pharmacological/pharmacogenetic level. This group includes Drs. Belknap, Crabbe, Cunningham, Hitzemann, Phillips, and Raber. These studies are largely at the behavioral and genetic level, including: development of congenic and recombinant congenic strains and mouse lines selected on the basis of genotype at selected markers; relative contributions of initial sensitivity and tolerance to drug dependence, self-administration and withdrawal; chronic intravenous drug self-administration; studies with several other tasks assessing drug reinforcement, including place- and taste-conditioning, oral self-administration, locomotor stimulation, and locomotor sensitization; homeostatic models of drug tolerance and withdrawal, using temperature regulation and ataxia; studies of the role of contextual cues in several learning and conditioning paradigms; epidemiological analyses of drug dependence; and statistical association and linkage analyses to map chromosomal location of genes modulating drug responses using quantitative trait locus analysis. Recently, the gene discovery effort of this group of investigators has been among the pioneering efforts marrying gene expression array analyses with the more traditional sequence-based QTL mapping methods.

The fourth area of focus includes studies of drug effects at the cognitive neuroscience/human/clinical level. This group includes Drs. Berger, Hauser, Hauser, Mitchell, Oken, and Stevens. Studies by this group involve the use of behavioral tests, EEG, functional magnetic resonance imaging, and PET imaging to evaluate steroid and drug effects in the human brain, to characterize impulsivity in humans and rodents, and to develop novel therapeutics for the treatment of drug abuse.

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