Ethanol potentiates both GABAergic and glutamatergic signaling in the lateral habenula.
Ethanol's aversive property may limit it's use, but the underlying mechanisms are no well-understood. Emerging evidence suggests a critical role for the lateral habenula (LHb) in the aversive response to various drugs, including ethanol. We previously showed that ethanol enhances glutamatergic transmission and stimulates LHb neurons. GABAergic transmission, a major target of ethanol in many brain regions, also tightly regulates LHb activity. This study assessed the action of ethanol on LHb GABAergic transmission in rat brain slices. Application of ethanol accelerated spontaneous action potential firing of LHb neurons, and LHb activity was increased by the GABAAreceptor antagonist gabazine, and ethanol-induced acceleration of LHb firing was further increased by gabazine. Additionally, ethanol potentiated GABAergic transmission (inhibitory postsynaptic currents, IPSCs) with an EC50of 1.5 mM. Ethanol-induced potentiation of IPSCs was increased by a GABABreceptor antagonist; it was mimicked by dopamine, dopamine receptor agonists, and dopamine reuptake blocker, and was completely prevented by reserpine, which depletes store of catecholamine. Moreover, ethanol-induced potentiation of IPSCs involved cAMP signaling. Finally, ethanol enhanced simultaneously glutamatergic and GABAergic transmissions to the majority of LHb neurons: the potentiation of the former being greater than that of the latter, the net effect was increased firing. Since LHb excitation may contribute to aversion, ethanol-induced potentiation of GABAergic inhibition tends to reduce aversion.
Department of Anesthesiology, Pharmacology and Physiology, Rutgers, The State University of New Jersey, New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, USA.
Wanhong
W
Zuo
Department of Physiology, Medical College, Jinan University, Guangzhou, China.
Liwei
L
Wang
Department of Pharmacology, Medical College, Jinan University, Guangzhou, China.
Lixin
L
Chen
Department of Physiology, McGill University, McIntyre Centre, 3655 Promenade Sir William Osler, Montréal, QC H3G 1Y6, Canada.
Krešimir
K
Krnjević
Department of Anesthesiology, Pharmacology and Physiology, Rutgers, The State University of New Jersey, New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, USA.
Rao
R
Fu
Department of Anesthesiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Xia
X
Feng
Department of Geriatrics, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Wen
W
He
Department of Anesthesiology, Pharmacology and Physiology, Rutgers, The State University of New Jersey, New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, USA.
Seungwoo
S
Kang
Department of Anesthesiology, Pharmacology and Physiology, Rutgers, The State University of New Jersey, New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, USA.
Avi
A
Shah
Department of Anesthesiology, Pharmacology and Physiology, Rutgers, The State University of New Jersey, New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, USA.
Alex
A
Bekker
Department of Anesthesiology, Pharmacology and Physiology, Rutgers, The State University of New Jersey, New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, USA. Electronic address: ye@njms.rutgers.edu.
Jiang-Hong
JH
Ye
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D000431:Ethanol / Q000008:administration & dosage*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects*; D005260:Female; D058787:GABA-A Receptor Antagonists / Q000008:administration & dosage; D058788:GABA-B Receptor Antagonists / Q000008:administration & dosage; D018698:Glutamic Acid / Q000502:physiology*; D019262:Habenula / Q000187:drug effects* / Q000502:physiology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects*; D008297:Male; D009025:Morpholines / Q000008:administration & dosage; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D011724:Pyridazines / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000819:agonists; D017448:Receptors, Dopamine D2 / Q000819:agonists; D011963:Receptors, GABA-A / Q000502:physiology; D018080:Receptors, GABA-B / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
C095804:(+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid; D058787:GABA-A Receptor Antagonists; D058788:GABA-B Receptor Antagonists; D009025:Morpholines; D011724:Pyridazines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D000431:Ethanol; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C049853:gabazine; D000242:Cyclic AMP
Aversion; Dopamine receptors; GABA receptors; Lateral habenula; cAMP pathway