Ethanol drives aversive conditioning through dopamine 1 receptor and glutamate receptor-mediated activation of lateral habenula neurons.
There has been increasing interest in the lateral habenula (LHb) given its potent regulatory role in many aversion-related behaviors. Interestingly, ethanol can be rewarding as well as aversive; we therefore investigated whether ethanol exposure alters pacemaker firing or glutamate receptor signaling in LHb neurons in vitro and also whether LHb activity in vivo might contribute to the acquisition of conditioned place aversion to ethanol. Surprisingly, in epithalamic slices, low doses of ethanol (1.4 mM) strongly accelerated LHb neuron firing (by ~60%), and ethanol's effects were much reduced by blocking glutamate receptors. Ethanol increased presynaptic glutamate release, and about half of this effect was mediated by dopamine subtype 1 receptors (D1Rs) and cyclic adenosine monophosphate (cAMP)-dependent signaling pathways. In agreement with these findings, c-Fos immunoreactivity in LHb regions was enhanced after a single administration of a low dose of ethanol (0.25 g/kg i.p.). Importantly, the same dose of ethanol in vivo also produced strong conditioned place aversion, and this was prevented by inhibiting D1Rs or neuronal activity within the LHb. By contrast, a higher dose (2 g/kg) led to ethanol conditioned place preference, which was enhanced by inhibiting neuronal activity or D1Rs within the LHb and suppressed by infusing aminomethylphosphonic acid or the D1R agonist SKF38393 within the LHb. Our in vitro and in vivo observations show, for the first time, that ethanol increases LHb excitation, mediated by D1R and glutamate receptors, and may underlie a LHb aversive signal that contributes to ethanol-related aversion.
Department of Anesthesiology, Pharmacology and Physiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.
Wanhong
W
Zuo
Department of Anesthesiology, Pharmacology and Physiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.
Rao
R
Fu
Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
Frederic Woodward
FW
Hopf
Department of Anesthesiology, Pharmacology and Physiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.
Guiqin
G
Xie
Department of Physiology, McGill University, Montreal, Canada.
Kresimir
K
Krnjević
Department of Anesthesiology, Pharmacology and Physiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.
Jing
J
Li
Department of Anesthesiology, Pharmacology and Physiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.
Jiang-Hong
JH
Ye
D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003214:Conditioning, Classical / Q000187:drug effects*; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D019262:Habenula / Q000502:physiology*; D008297:Male; D023421:Models, Animal; D009474:Neurons / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000502:physiology; D017470:Receptors, Glutamate / Q000187:drug effects* / Q000502:physiology
D002492:Central Nervous System Depressants; D011954:Receptors, Dopamine; D017470:Receptors, Glutamate; D000431:Ethanol
Alcohol abuse; conditioned place aversion and preference; cyclic AMP signaling; epithalamic slices from rats