Cocaine potentiates ethanol-induced excitation of dopaminergic reward neurons in the ventral tegmental area.
The coabuse of cocaine and ethanol is one of the most frequently used substance abuse combinations in the United States. The dopamine (DA) neurons in the ventral tegmental area (VTA) are important in the rewarding mechanism of these two substances. Cocaine is known to block the reuptake of DA and serotonin (5-HT). At concentrations below 1 microM, cocaine preferentially blocks the reuptake of 5-HT compared with DA. We have previously shown that ethanol increases the firing rate of DA neurons in the VTA, and that this excitation is enhanced by 5-HT. Extracellular single-unit recordings were made from VTA dopaminergic neurons in coronal brain slices from young adult Fischer 344 rats. Cocaine (1-10 microM) reduced the spontaneous firing rate in VTA dopaminergic neurons in a concentration-related manner. A lower concentration of cocaine (500 nM), which is a concentration that is pharmacologically relevant in addicts, produced only a very small decrease in the firing rate of VTA neurons but potentiated ethanol excitation of these neurons. Higher concentrations of cocaine (1 microM) did not enhance ethanol excitation. Ethanol-induced excitation was potentiated by the higher concentrations of cocaine (1 and 2 microM) in the presence of the D(2) receptor antagonist sulpiride (1 microM). Furthermore, cocaine potentiation of ethanol-induced excitation was reversed by ketanserin (2 microM), a 5-HT(2) antagonist. The enhanced ethanol excitation of VTA dopaminergic neurons caused by cocaine may partially explain the high incidence of the coabuse of these two substances.
Bunney
E B
EB
Department of Emergency Medicine, University of Illinois at Chicago, College of Medicine, Chicago, Illinois 60612-7342, USA. bbunney@uic.edu
Appel
S B
SB
Brodie
M S
MS
D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D004298:Dopamine / Q000502:physiology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D000431:Ethanol / Q000494:pharmacology*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D007650:Ketanserin / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D012201:Reward; D012702:Serotonin Antagonists / Q000494:pharmacology; D013469:Sulpiride / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D002492:Central Nervous System Depressants; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D018765:Dopamine Uptake Inhibitors; D012702:Serotonin Antagonists; D000431:Ethanol; D013469:Sulpiride; D007650:Ketanserin; D003042:Cocaine; D004298:Dopamine