Sarah B. Appel, Ph.D.
(formerly known as Sarah A. Shefner)

Professor
Ionic Mechanisms of Neurotransmitters, Drugs and Alcohol on Brain Neurons

The research interests of my laboratory are to understand the electrophysiological properties and pharmacology of dopaminergic neurons in the ventral tegmental area and noradrenergic neurons of the locus coeruleus. Our electrophysiological techniques include intracellular and extracellular recording in brain slices, whole cell patch-in-the-slice recording and cell-attached, whole cell and nystatin perforated patch clamp recording in acutely dissociated neurons. Current clamp recording is used to study the properties of the action potentials, and voltage clamp recording is used to characterize the voltage-gated ion channels in these neurons. For some time, we have focused on identifying the voltage-gated currents which contribute to the afterhyperpolarization (AHP) which follows the action potential in these cells and which paces their spontaneous firing. We have also studied the neuromodulatory actions of adenosine and the effects of ethanol on these neurons. Our studies on ethanol effects on the locus coeruleus neurons are relevant to understanding the sedative properties of ethanol and the alcohol withdrawal syndrome.

Our most recent work has focused on the dopaminergic neurons in the ventral tegmental area (DA VTA). These neurons are the cells of origin of the mesolimbic and mesocortical dopamine pathways and are involved in the rewarding properties of most drugs of abuse, including ethanol. Understanding the effect of ethanol and its mechanism of action on these neurons is crucial to understanding voluntary intake of ethanol and alcohol addiction. We have shown that acutely dissociated DA VTA neurons, stripped of all input from surrounding neurons, are robustly excited by behaviorally relevant concentrations of ethanol, strong evidence that ethanol directly excites these neurons. Current work in our laboratory combines electrophysiological and pharmacological approaches with molecular biological methods, including single cell RT-PCR, immunohistochemistry and oocyte expression to study the mechanism by which ethanol excites DA VTA neurons. We have also studied potentiation of the ethanol excitation of these neurons by serotonin, cocaine and cocaethylene.

Publications:

  1. Appel, S.B., McBride, W.J., Diana, M., Diamond, I., Bonci, A. and Brodie, M.S. Ethanol effects on dopaminergic "reward" neurons in the ventral tegmental area and the mesolimbic pathway. Alcoholism: Clin. Exp. Res., 28: 1768-1778, 2004.
  2. Liu, Z., Bunney, E.B., Appel, S.B. and Brodie, M.S. Serotonin reduces the hyperpolarization-activated current ( Ih) in ventral tegmental area dopamine neurons: involvement of 5-HT2 receptors and protein kinase C. J. Neurophysiology, 90: 3201-3212, 2003.
  3. Appel, S.B., Liu, Z., McElvain, M.A. and Brodie, M.S. Ethanol excitation of dopaminergic ventral tegmental area neurons is blocked by quinidine. J. Pharmacol. Exp. Ther., 306: 437-446, 2003.
  4. Bunney, E.B., Appel, S.B. and Brodie, M.S. Electrophysiological effects of cocaethylene, cocaine and ethanol on dopaminergic neurons of the ventral tegmental area. Journal of Pharmacology and Experimental Therapeutics, 297:696-703, 2001.
  5. Brodie, M.S. and Appel, S.B.   Dopaminergic neurons in the ventral tegmental area of C57BL/6J and DBA/2J mice differ in sensitivity to ethanol excitation. Alcoholism: Clinical and Experimental Research, 24:1120-1124, 2000.
  6. Bunney, E.B., Appel, S.B. and Brodie, M.S. Cocaine potentiates ethanol-induced excitation of dopaminergic reward neurons in the ventral tegmental area.  Journal of Pharmacology and Experimental Therapeutics, 293:383-389, 2000.
  7. Brodie, M.S.,  Pesold, C. and Appel, S.B. Ethanol directly excites dopaminergic ventral tegmental area reward neurons. Alcoholism: Clinical and Experimental Research 23:1848-1852, 1999.
  8. Brodie, M.S., McElvain, M. A., Bunney, E .B. and Appel, S. B. Pharmacological reduction of small conductance calciumactivated potassium current (SK) potentiates the excitatory effect of ethanol on ventral tegmental area dopamine neurons. Journal of Pharmacology and Experimental Therapeutics 290:325-333,1999.
  9. Giorgetti, M., Javaid, J.I., Davis, J.M., Costa, E., Guidotti, A., Appel, S.B. and Brodie, M.S.  Imidazenil, a positive allosteric GABAA receptor modulator, inhibits the effects of cocaine on locomotor activity and extracellular dopamine in the nucleus accumbens shell without tolerance liability.  Journal of Pharmacology and Experimental Therapeutics 287: 58-66, 1998.
  10. Brodie, M.S. and Appel, S.B. The effects of ethanol on dopaminergic neurons of the ventral tegmental area studied with intracellular recording in brain slices. Alcoholism: Clinical and Experimental Research 22: 236-244, 1998.
  11. Brodie, M.S., Trifunovic, R.D. and Shefner, S.A. Serotonin potentiates ethanol-induced excitation of ventral tegmental area neurons in brain slices from three different rat strains. Journal of Pharmacology and Experimental Therapeutics 273: 1139-1146, 1995.
  12. Pan, W.J., Osmanovic, S.S. and Shefner, S.A. Characterization of the adenosine A1 receptor-activated potassium current in rat locus coeruleus neurons. Journal of Pharmacology and Experimental Therapeutics 273: 537-544, 1995.
  13. Osmanovic, S.S. and Shefner, S.A. Ethanol enhances inward rectification in rat locus coeruleus neurons by increasing the extracellular potassium concentration. Journal of Pharmacology and Experimental Therapeutics 271: 334-342, 1994. 
  14. Pan, W.J., Osmanovic, S.S. and Shefner, S.A. Adenosine decreases action potential duration by modulation of A-current in rat locus coeruleus neurons. Journal of Neuroscience 14: 1114-1122, 1994. 
  15. Osmanovic, S.S. and Shefner, S.A. Calcium-activated hyperpolarizations in rat locus coeruleus neurons in vitro. Journal of Physiology (London) 469: 89-109, 1993.

mailto:sappel@uic.edu