Effects of Ethanol on Adenosine 5′‐Triphosphate–Gated Purinergic and 5‐Hydroxytryptamine₃ Receptors

Abstract

This report of the proceedings of a symposium presented at the 2005 annual meeting of the Research Society on Alcoholism highlights the actions of ethanol on purinergic (P2XRs) and 5-hydroxytryptamine 3 (5-HT 3 Rs) receptors. Both P2XRs and 5-HT 3 Rs, are modulated by pharmacologically relevant concentrations of ethanol, with inhibition or stimulation of P2XR subtypes and stimulation of 5-HT 3 Rs, respectively. With regard to ethanol-modulatory actions, these 2 distinctly different receptor classes have been studied to a much lesser extent than other LGICs. The organizers and chairs were Daryl L. Davies and Tina K. Machu. John J. Woodward discusses the molecular pharmacology and physiology of P2XRs and 5-HT 3 Rs and sets the stage for a detailed investigation into the ethanol sensitivity of these channels by the invited speakers. Daryl L. Davies discusses the results from recent electrophysiological studies conducted in his and Dr. Woodward's laboratories, highlighting the actions of ethanol on P2XR subtypes. Jiang-Hong Ye discusses results from recent studies using loose-patch and whole-cell recordings on purinergic receptors expressed on neurons from the ventral tegmental area (VTA) in rats. Tina K. Machu discusses electrophysiological studies conducted in her and Dr. David Lovinger's laboratories on nonpore lining residues of the second transmembrane domain (TM2) of the 5-HT 3A receptor. Li Zhang presents data demonstrating that F-actin cytoskeletons play a critical role in 5-HT 3 receptor clustering in hippocampal neurons. Collectively, the presentations provided strong evidence that P2X and 5-HT 3 receptors are important targets for ethanol action.

Acute Alcohol Action and Desensitization of Ligand-Gated Ion Channels

“…Compared with other ionotropic receptors gated by extracellular ligands, P2Xs constitute a relatively new family, yet their alcohol sensitivity (for review, see Weight et al, 1999; Dilger, 2002; Davies et al, 2006) has been explored since their initial pharmacological characterization. First reported in isolated bullfrog dorsal root ganglion neurons (Li et al, 1993), ethanol inhibition of native P2X receptors was also found in rat hippocampal CA1 neurons (Li et al, 2000) and in a slice preparation of rat ventral tegmental area that contains dopamine neurons and the GABAergic nerve endings impinging upon them, the P2X receptors being presumably located in the GABAergic presynaptic membrane (Xiao et al, 2008).…”

The Role of 5-HT3 Receptors in Drug Abuse and as a Target for Pharmacotherapy

“…This interaction has important implications for the effect of ethanol on neurotransmission and the role of 5-HT3 receptors in alcoholism [54, 75-78], and along with preclinical and clinical results, has increased interest in the 5-HT3 receptor as a potential site for pharmacological treatment of alcohol and drug abuse [79, 80]. Ethanol also binds to, and potentiates the function of, other structurally related ligand gated ion channels, such as nACh receptors [78, 81].…”

Ethanol Is a Fast Channel Inhibitor of P2X4 Receptors

“…P2XRs are becoming a focus of investigation in ethanol studies because of building evidence suggesting that P2XRs are important mediators of ethanol-induced effects Davies et al, 2006;Asatryan et al, 2008;Tabakoff et al, 2009). ATP-gated currents are inhibited by ethanol at intoxicating and anesthetic concentrations when measured in P2X2Rs and P2X4Rs expressed in Xenopus oocytes Davies et al, 2002Davies et al, , 2005, whereas ATP-gated currents are potentiated by ethanol in P2X3Rs (Davies et al, 2005).…”