Mark S. Brodie, Ph.D.

Associate Professor
Interactions of neurotransmitters in the central nervous system

The action of ethanol on the reward pathways of the brain is strongly related to the underlying causes of alcoholism. The ventral tegmental area is a dopaminergic brain area which is important for the rewarding effects of drugs of abuse, including alcohol. I use electrophysiological methods to study the neurons of the ventral tegmental area, either in brain slices or as acutely dissociated neurons. The brain slice preparation allows us to study mature neurons with intra- and extracellular recording methods, and to test the effects of known concentrations of neurochemicals and drugs on those neurons. Our ongoing studies have focused on the effects of ethanol on ventral tegmental area neurons, and the enhancement of those effects by serotonin. We have shown that ethanol directly excites the dopaminergic neurons of the ventral tegmental area (Brodie, et al, 1999), which may make it a key brain area for pharmacotherapies which seek to treat alcoholism by altering the rewarding action of alcohol. In addition, we have discovered that excitation of dopaminergic ventral tegmental area neurons by ethanol is potentiated by serotonin (Brodie, et al, 1995), and by serotonergic drugs (Brodie, et al., 1996) acting at serotonin 5-HT2 type receptors. Cocaine also increases the effect of alcohol on brain reward neurons in the ventral tegmental area by blocking reuptake of serotonin (Bunney et al, 2000, 2001). In addition to our work with ethanol, we have discovered that serotonin enhances the action of dopamine on ventral tegmental area neurons (Brodie and Bunney, 1996), a finding which may have some implications for the development of antipsychotic drugs.

Recent work from my laboratory has centered on the investigation of the acute and chronic effects of ethanol on mouse dopaminergic ventral tegmental area neurons. Acute ethanol excites dopaminergic neurons of the ventral tegmental area from C57 and DBA mice, and dopaminergic ventral tegmental area neurons from DBA mice were significant ly more sensitive to ethanol excitation than dopaminergic ventral tegmental area neurons from C57 mice (Brodie and Appel, 2000). I recently investigated the sensitivity of dopaminergic ventral tegmental area neurons to acute administration of ethanol, GABA or NMDA after chronic ethanol treatment (Brodie, 2002). C57BL/6J mice were injected twice daily with either normal saline (17.5 ml/kg) or ethanol in saline (20 % v/v, 3.5 g/kg) for at least 21 days. Following this treatment, ethanol (20 to 120 mM) caused a concentration-dependent increase in firing rate of all neurons tested, but the dopaminergic ventral tegmental area neurons from ethanol-treated mice were excited by ethanol more potently than those from saline-treated mice. Dopaminergic ventral tegmental area neurons from ethanol-treated mice were inhibited less potently by GABA (50 to 500 :M) than those from saline-treated mice. There was no difference in the potency of NMDA (2 to 20 :M) to excite dopaminergic ventral tegmental area neurons from saline-treated and ethanol-treated mice. The sensitization to ethanol activation of ventral tegmental area neurons following chronic intermittent ethanol treatment may be an important change in reward area neurons, and may contribute to the development of alcoholism. The mechanism of this sensitization, and the involvement of pre- and postsynaptic factors, such as serotonin, in this sensitization are currently unknown.

 


Publications:

1. Brodie, M.S., Shefner, S.A. and Dunwiddie, T.V.  Ethanol increases the firing rate of dopamine neurons of the rat ventral tegmental area in vitro. Brain Research, 508:65-69, 1990.

2. Brodie, M.S. and Dunwiddie, T.V.  Cocaine effects in the ventral tegmental area: Evidence for an indirect dopaminergic mechanism of action.  Naunyn-Schmiedeberg's Archives of Pharmacology, 342:660-665, 1990.

3. Dunwiddie, T.V., Williams, J.T., Bobker, D.H., Pan, Z.Z., Gerhardt, G. and Brodie, M.S.  In vitro approaches to characterizing the electrophysiological effects of cocaine upon the central nervous system. Cocaine: Pharmacology, Physiology and Clinical Strategies, J.M. Lakoski, M.P. Galloway and F.J. White (eds.), CRC Press, Boca Raton, 1992, pp. 313-340.

4. Harris, R.A., Brodie, M.S. and Dunwiddie, T.V.  Possible substrates of ethanol reinforcement: GABA and dopamine.   ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, Volume 654, The Neurobiology of Drug and Alcohol Addiction, P.W. Kalivas and H.H. Samson, eds., 1992, pp. 61-69.

5. Brioni, J.D., Kim, D.J.B., Brodie, M.S., Decker, M.W. and Arneric, S.P. ABT 418: Discriminative stimulus properties and effect on ventral tegmental cell activity.   Psychopharmacology, 119: 368-375, 1995.

6. 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 (3): 1139-1146, 1995.

7. Trifunovic, R.D. and Brodie, M.S.  Effects of clomipramine on the excitatory action of ethanol on dopaminergic neurons of the ventral tegmental area in vitro.  Journal of Pharmacology and Experimental Therapeutics, 276(1): 34-40, 1996.

8. Brodie, M.S. and Bunney, E.B. Serotonin potentiates dopamine inhibition of ventral tegmental area neurons in vitro. J. Neurophysiol., 76(3): 2077-2082,1996.

9. Brioni, J.D., Kim, D.J.B., O'Neill, A., Brodie, M.S., Decker, M.W. and Arneric, S.P.  ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy) pyridine dihydrochloride]:  Discriminative stimulus properties and electrophysiological actions.  Drug Development Research, 40:259-266, 1997.

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(1): 236-244, 1998.

11.  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(1): 58-66, 1998.

12. Brodie, M.S., McElvain, M.A., Bunney, E.B. and Appel, S.B.   Pharmacological reduction of small conductance calcium-activated potassium current (SK) potentiates the excitatory effect of ethanol on ventral tegmental area dopamine neurons. Journal of Pharmacology and Experimental Therapeutics 290(1): 325-333, 1999.

13. 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.

14. 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.

15. 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: Clin. Exp. Res., 24(7): 1120-1124, 2000.

16. 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(2): 696-703, 2001.

17. Brodie, M.S.  Increased ethanol excitation of dopaminergic neurons of the ventral tegmental area following chronic ethanol treatment, Alcoholism: Clinical and Experimental Research, 26(7): 1024-1030, 2002.

18. Liu, Z.P., Appel, S.B. and Brodie, M.S. Serotonin reduces the hyperpolarization-activated cationic current (Ih) in dopaminergic neurons of the bentral tegmental area: involvement of protein kinase C. Journal of Neurophysiology, 90: 3201-3212, 2003.

19. Appel, S.B., Liu, Z.P., McElvain, M.A. and Brodie, M.S. Ethanol excitation of dopaminergic ventral tegmental area neurons is blocked by quinidine. Journal of Pharmacology and Experimental Therapeutics, 306 (2): 437–446, 2003.

20. Buck, K.J., Reilly, M.T., Rogers, L.M., Szeliga, K. Grant K., and Brodie, M.S., Serotonin 5-HT2 receptors and alcohol: Reward, withdrawal and discrimination. Alcoholism: Clinical and Experimental Research, 28(2): 211-216, 2004.

21. Budygin, E.A., Brodie, M.S., Sotnikova, T.D., Mateo, Y., John, C.E., Cyr, M., Gainetdinov, R.R., Caron, M.G., and Jones, S.R. Dissociation of dopamine transporter-mediated and rewarding properties of amphetamine. Proceedings of the National Academy of Sciences, 101 (20): 7781-7786, 2004.

22. Lupica C.R., Brodie M.S. Queer currents, steady rhythms, and drunken DA neurons. Focus on "hyperpolarization-activated cation current (Ih) is an ethanol target in midbrain dopamine neurons of mice". Journal of Neurophysiology 95(2) :585-586, 2006.

 

MBRODIE@uic.edu