Mark S. Brodie, Ph.D.
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. 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). Our investigations into the ion channels that are affected by ethanol have led to some novel observations. We have found that ethanol reduces a specific potassium current called M-current, and this action, at least in part, accounts for some of the excitatory action of ethanol on these brain reward neurons. We are currently investigating other potassium currents that are affected by ethanol, and how ethanol reduces M-current. A recent study from our lab demonstrated that a barium-sensitive potassium current, possibly G-protein-linked inwardly rectifying potassium current, is increased by higher concentrations of ethanol (McDaid, et al., 2008). Our work continues to catalog the actions of ethanol on dopaminergic neurons of the VTA.
My laboratory also has investigated acute and chronic effects of ethanol on mouse dopaminergic ventral tegmental area neurons, in an effort to understand adaptations to the actions of ethanol on VTA 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). The sensitivity of dopaminergic ventral tegmental area neurons to acute administration of ethanol increases after chronic ethanol treatment (Brodie, 2002). 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.
Recent studies in my laboratory are examining the actions of long-duration increases in dopamine concentration on the physiology of putative dopaminergic neurons of the VTA. We have reported that long-duration administration of exogenous dopamine causes a desensitization of the dopamine D2 receptor which is dependent on concurrent stimulation of D2-like and D1-like receptors (Nimitvilai and Brodie, 2010). We are currently examining the cellular mechanism for this change and its relationship to drug abuse.
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