The overall objective of these studies is to understand how ethanol acts on brain areas involved in the mediation of reward, and to determine how specific neurotransmitter systems modify the action of ethanol on brain reward pathways. This knowledge might be exploited to develop drugs which reduce alcohol craving, leading to effective treatments for alcohol abuse. Recent studies have shown that serotonin (5-HT) reuptake inhibitors decrease alcohol abuse in problem drinkers. Although the reason for this is not clear, it is possible that 5-HT reuptake inhibitors act in brain areas involved in reward to reduce alcohol craving. One brain area shown to be important for mediating the rewarding effects of many drugs of abuse is the ventral tegmental area of Tsai (VTA). The VTA is the source of dopaminergic innervation to a number of brain areas (e.g., the nucleus accumbens and the prefrontal cortex) thought to be involved in the rewarding effects of drugs of abuse, and dopamine is an important neurotransmitter in reward. Intracellular and extracellular recording in rat brain slices will be used to assess the action of ethanol and 5-HT on dopaminergic neurons in the VTA. Slices (400 micromoles thick) will be mounted and totally submerged in the recording chamber. Ethanol will be applied in known concentrations in the bath. Ethanol, in concentrations within the behaviorally active range, causes excitation of dopaminergic VTA neurons. Our preliminary data indicates that 5-HT potentiates the excitatory effect of ethanol on some of these VTA neurons. The electrophysiological effects of 5-HT on dopamine-containing neurons of the VTA will be characterized in order to elucidate the mechanism by which 5-HT enhances ethanol-induced excitation in these neurons. Furthermore, the specific 5-HT receptor subtype(s) which mediate this potentiation will be identified. 5-HT reuptake blockers will be examined to determine if they also potentiate the effects of ethanol on VTA neurons, and whether potentiation by these agents is due to their action at serotonergic synapses. In addition, inbred strains of rats (Lewis and Fisher 344) which differ in voluntary EtOH intake will be used to determine whether the sensitivity of VTA neurons to 5-HT potentiation of EtOH excitation is correlated with a genetic predisposition to drink more or less EtOH. Ultimately, these studies may provide a rationale for the efficacy of 5-HT reuptake inhibitors in reducing alcohol abuse, and might also provide a basis for the development of more selective 5-HT-related drugs which would be useful in the treatment of uncontrolled ethanol intake.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA009125-02
Application #
3113250
Study Section
Special Emphasis Panel (SRCA (56))
Project Start
1992-08-01
Project End
1995-07-31
Budget Start
1993-08-01
Budget End
1994-07-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Type
Schools of Medicine
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
Dutton 3rd, John W; Chen, Hu; You, Chang et al. (2017) Anaplastic lymphoma kinase regulates binge-like drinking and dopamine receptor sensitivity in the ventral tegmental area. Addict Biol 22:665-678
Nimitvilai, Sudarat; Herman, Melissa; You, Chang et al. (2014) Dopamine D2 receptor desensitization by dopamine or corticotropin releasing factor in ventral tegmental area neurons is associated with increased glutamate release. Neuropharmacology 82:28-40
Nimitvilai, Sudarat; McElvain, Maureen A; Brodie, Mark S (2013) Reversal of dopamine D2 agonist-induced inhibition of ventral tegmental area neurons by Gq-linked neurotransmitters is dependent on protein kinase C, G protein-coupled receptor kinase, and dynamin. J Pharmacol Exp Ther 344:253-63
Arora, Devinder S; Nimitvilai, Sudarat; Teppen, Tara L et al. (2013) Hyposensitivity to gamma-aminobutyric acid in the ventral tegmental area during alcohol withdrawal: reversal by histone deacetylase inhibitors. Neuropsychopharmacology 38:1674-84
Nimitvilai, S; Arora, D S; McElvain, M A et al. (2012) Reversal of inhibition of putative dopaminergic neurons of the ventral tegmental area: interaction of GABA(B) and D2 receptors. Neuroscience 226:29-39
Nimitvilai, Sudarat; Arora, Devinder S; Brodie, Mark S (2012) Reversal of dopamine inhibition of dopaminergic neurons of the ventral tegmental area is mediated by protein kinase C. Neuropsychopharmacology 37:543-56
Nimitvilai, Sudarat; Brodie, Mark S (2010) Reversal of prolonged dopamine inhibition of dopaminergic neurons of the ventral tegmental area. J Pharmacol Exp Ther 333:555-63
Melis, Miriam; Diana, Marco; Enrico, Paolo et al. (2009) Ethanol and acetaldehyde action on central dopamine systems: mechanisms, modulation, and relationship to stress. Alcohol 43:531-9
McDaid, John; McElvain, Maureen A; Brodie, Mark S (2008) Ethanol effects on dopaminergic ventral tegmental area neurons during block of Ih: involvement of barium-sensitive potassium currents. J Neurophysiol 100:1202-10
Koyama, Susumu; Brodie, Mark S; Appel, Sarah B (2007) Ethanol inhibition of m-current and ethanol-induced direct excitation of ventral tegmental area dopamine neurons. J Neurophysiol 97:1977-85

Showing the most recent 10 out of 24 publications