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Neurosteroid Binding Sites on the GABAA Receptor Complex As Novel Targets for Therapeutics to Reduce Alcohol Abuse and Dependence

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Neurosteroid Binding Sites on the GABAA Receptor Complex As Novel Targets for Therapeutics to Reduce Alcohol Abuse and Dependence Hindawi Publishing Corporation Advances in Pharmacological Sciences Volume 2011, Article ID 926361, 12 pages doi:10.1155/2011/926361 Review Article Neurosteroid Binding Sites on the GABAA Receptor Complex as Novel Targets for Therapeutics to Reduce Alcohol Abuse and Dependence Mary W. Hulin,1, 2 Russell J. Amato,1 Johnny R. Porter,3 Catalin M. Filipeanu,1 and Peter J. Winsauer1, 2 1 Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, 1901 Perdido Street, New Orleans, LA 70112-1393, USA 2 Alcohol and Drug Abuse Research Center, LSU Health Sciences Center, New Orleans, LA 70112-1393, USA 3 Department of Physiology, LSU Health Sciences Center, New Orleans, LA 70112-1393, USA Correspondence should be addressed to Mary W. Hulin, [email protected] Received 10 May 2011; Accepted 17 July 2011 Academic Editor: Naheed R. Mirza Copyright © 2011 Mary W. Hulin et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Despite the prevalence of alcohol abuse and dependence in the US and Europe, there are only five approved pharmacotherapies for alcohol dependence. Moreover, these pharmacotherapeutic options have limited clinical utility. The purpose of this paper is to present pertinent literature suggesting that both alcohol and the neurosteroids interact at the GABAA receptor complex and that the neurosteroid sites on this receptor complex could serve as new targets for the development of novel therapeutics for alcohol abuse. This paper will also present data collected by our laboratory showing that one neurosteroid in particular, dehydroepiandrosterone (DHEA), decreases ethanol intake in rats under a variety of conditions. In the process, we will also mention relevant studies from the literature suggesting that both particular subtypes and subunits of the GABAA receptor play an important role in mediating the interaction of neurosteroids and ethanol. 1. Introduction that one neurosteroid in particular, dehydroepiandrosterone (DHEA), may be a key to discovering promising new The suggestion that neuroactive steroids could have potential therapeutics for treating alcohol abuse and dependence. In as new pharmacotherapies for alcohol abuse and dependence this process, we also hope to provide compelling evidence followed shortly after the discovery that ethanol admin- for the involvement of the GABAA receptor complex and the istration released specific neurosteroids. These same data role specific subunits of this complex may play in the effects also directly implicated the endogenous neurosteroids as of DHEA on ethanol intake. ff potential contributors to the behavioral e ects of ethanol If there is any doubt that new treatments for alcohol [1, 2]. However, elucidating the interaction between the abuse and dependence are needed, one need only to review ffi neuroactive steroids and ethanol has been especially di cult some of the most recent epidemiological data on excessive because both produce a wide variety of molecular and alcohol use. In 2009, an estimated 18.6 million persons ff behavioral e ects and both act at multiple receptors [3, 4]. aged 12 or older met criteria for alcohol dependence or Complicating matters even further, neurosteroids also have abuse, representing 7.4 percent of the US population [5]. both genomic and nongenomic effects [4] that are often Despite the prevalence of this problem, there are only five only dissociable in terms of their time course. Thus, the approved pharmacotherapies for alcohol dependence in the goal of this paper is to present pertinent literature regarding US and Europe [6]. Furthermore, these pharmacotherapeu- the interaction of ethanol and the neurosteroids while tic options have limited clinical utility. For instance, the also highlighting research from our laboratory suggesting opioid antagonist naltrexone has been shown to have limited 2 Advances in Pharmacological Sciences success apart from individuals with a family history of an increased tonic current amplitude, tonic current noise, alcohol dependence, those with an enhanced opioid response and spontaneous inhibitory postsynaptic current. However, to ingestion of alcohol, those who self-report enhanced using similar methods, Botta et al. [25] found that this alcohol cravings, and individuals with a specific μ-opioid mutation did not increase the sensitivity of GABAA receptors receptor polymorphism [7–9]. Acamprosate, a synthetic to ethanol; rather, they reported that ethanol modulated homotaurine derivative, has been shown to decrease alco- the currents of these channels indirectly via a presynaptic hol intake, purportedly via modulation of glutamate [9] mechanism. The importance of the α4 subunit in mediating and glycine [10] receptors. However, acamprosate had no the effects of ethanol also remains to be determined, as α4 direct effect on recombinant glutamate or glycine receptors knockout mice had similar anxiolytic, hypothermic, ataxic, expressed in Xenopus oocytes at low, clinically relevant and hypnotic responses to ethanol compared to wild-type concentrations [11], and therefore, the mechanism by which littermates [26]. acamprosate modulates ethanol consumption is still unde- In addition to modulating GABAA receptors directly, fined. Experiments involving acamprosate suggest that it is ethanol can also modulate them indirectly by altering the only fully effective in highly motivated subjects with a “goal levels of GABA-modulating neurosteroids, such as 3α,5α- of abstinence” [12] and that the combined experience of THP (allopregnanolone) and 3α,5α-THDOC (allotetrahy- acamprosate with ethanol is necessary for decreasing ethanol drodeoxycorticosterone) [1, 2, 27–29]. These neurosteroids intake [13]. are currently thought to contribute to the various behavioral effects of ethanol, including its sedative-hypnotic [30, 31], ff 2. Importance of the GABA System in anxiolytic [32], and discriminative-stimulus e ects [33–35]. A For example, a reduction in the levels of 3α,5α-THP and the Behavioral Effects of Ethanol 3α,5α-THDOC by the 5α-reductase inhibitor finasteride Although a variety of neurotransmitters and signaling path- blocked the acquisition of ethanol drinking and the devel- ways have been shown to be involved in the behavioral effects opment of ethanol preference in male C57BL/6J mice [36]. of ethanol (e.g., [14–16]), central GABAergic activity is In healthy, adult social drinkers, finasteride also reportedly ff widely accepted to be one of the most important components decreased the subjective e ects of ethanol, leading some of ethanol’s effects as a CNS depressant [17, 18]. Behaviorally, investigators to speculate that these neuroactive steroids were ff this supposition is supported by research showing that integral for producing ethanol’s subjective e ects [37]. In benzodiazepines and barbiturates that positively modulate rats trained to discriminate ethanol from saline, 10 mg/kg the GABA receptor complex can substitute for ethanol of pregnanolone partially substituted (60%–70% drug-lever A ff in drug-discrimination procedures [19, 20]. Electrophys- responding) for the discriminative-stimulus e ects of 1 g/kg iological and genetic techniques have also furthered our of ethanol subsequent to chronic administration of either understanding of the interaction between ethanol and the saline or ethanol during adolescence [38]. Similarly, in rats trained to discriminate 5.6 mg/kg of pregnanolone from GABAA receptor complex by showing that it has both direct and indirect effects on the composition of this saline, 1 g/kg of ethanol only partially substituted for this heteropentameric chloride ion channel. For example, in neurosteroid [39]. Together, these symmetrical discrimi- nation data indicate that the neurosteroid pregnanolone vitro studies with native and recombinant GABAA receptors indicate ethanol is able to enhance GABA-mediated currents has overlapping, but not identical, discriminative-stimulus ff at receptors containing a δ subunit (which are found almost e ects with ethanol. exclusively extrasynaptically in vivo) and at doses of ethanol In contrast to the partial substitution found with preg- consistent with those achieved during typical episodes of nanolone, Gurkovskaya and Winsauer [38] demonstrated ff social drinking in humans [18, 21, 22]. Studies with mice that the discriminative-stimulus e ects of DHEA, which in which the δ subunit has been knocked out have shown comes from a common precursor pregnenolone, were unlike those of ethanol in rats trained to discriminate 1 g/kg of the importance of δ subunit-containing GABAA receptor complexes in mediating many of the effects of ethanol. ethanol from saline. Furthermore, DHEA only modestly These knockout mice are less sensitive to the anticonvulsant shifted the curve for ethanol-lever responding to the right when it was administered shortly before varying doses effects of ethanol, demonstrate a decreased hyperexcitability of ethanol (0.18–1.8 g/kg). Bienkowski and Kostowski [33] during ethanol withdrawal, and show a lower preference δ also reported a similar finding in that the sulfated deriva- for ethanol compared to wild-type controls. In contrast, ff ff tive of DHEA, DHEAS, was ine ective at blocking the subunit knockouts did not di er from controls in ethanol- discriminative-stimulus effects of ethanol. Thus, the effects induced anxiolysis, ataxia, hypnosis, or hypothermia [23]. of DHEA on the discriminative-stimulus
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