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The Journal of Neuroscience, July 21, 2004, 24(29):6521-6530; doi:10.1523/JNEUROSCI.0075-04.2004

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Cellular/Molecular
Brain Steroidogenesis Mediates Ethanol Modulation of GABA_A Receptor Activity in Rat Hippocampus

Enrico Sanna,^1,2 Giuseppe Talani,^1,2 Fabio Busonero,^1,2 Maria Giuseppina Pisu,^1,2,3,4 Robert H. Purdy,⁴ Mariangela Serra,^1,2,3 and Giovanni Biggio^1,2,3

¹Department of Experimental Biology, Section of Neuroscience, and ²Center of Excellence for the Neurobiology of Dependence, University of Cagliari, 09123 Cagliari, Italy, ³Consiglio Nazionale delle Ricerche Institute of Neuroscience, 09123 Cagliari, Italy, and ⁴Department of Psychiatry, University of California, San Diego, California 92037-0603

An interaction with the GABA type A (GABA_A) receptor has long been recognized as one of the main neurochemical mechanisms underlying many of the pharmacological actions of ethanol. However, more recent data have suggested that certain behavioral and electrophysiological actions of ethanol are mediated by an increase in brain concentration of neuroactive steroids that results from stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. Neuroactive steroids such as 3-hydroxy-5-pregnan-20-one (3,5-THP) are, in fact, potent and efficacious endogenous positive modulators of GABA_A receptor function. Because neurosteroids can be synthesized de novo in the brain, we have investigated whether ethanol might affect both neurosteroid synthesis and GABA_A receptor function in isolated rat hippocampal tissue. Here, we show that ethanol increases the concentration of 3,5-THP as well as the amplitude of GABA_A receptor-mediated IPSCs recorded from CA1 pyramidal neurons in isolated hippocampal slices. These effects are shared by the neurosteroid precursor progesterone, the peripheral benzodiazepine receptor-selective agonist CB34, and -hydroxybutyrate, all of which are known to increase the formation of neuroactive steroids in plasma and in the brain. The action of ethanol on GABA_A receptor-mediated IPSC amplitude is biphasic, consisting of a rapid, direct effect on GABA_A receptor activity and an indirect effect that appears to be mediated by neurosteroid synthesis. Furthermore, ethanol affects GABA_A receptor activity through a presynaptic action, an effect that is not dependent on neurosteroid formation. These observations suggest that ethanol may modulate GABA_A receptor function through an increase in de novo neurosteroid synthesis in the brain that is independent of the HPA axis. This novel mechanism may have a crucial role in mediating specific central effects of ethanol.

Key words: GABA_A receptors; ethanol; neurosteroids; 3,5-THP; hippocampus; CA1 pyramidal cells; patch clamp; mIPSC; peripheral benzodiazepine receptor; -hydroxybutyrate (GHB)

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Received Jan 8, 2004; revised May 28, 2004; accepted June 2, 2004.

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