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Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2016/04/18/jpet.116.232983.DC1 1521-0103/357/3/580–590$25.00 http://dx.doi.org/10.1124/jpet.116.232983 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 357:580–590, June 2016 Copyright ª 2016 The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. Analysis of b-Subunit-dependent GABAA Receptor Modulation and Behavioral Effects of Valerenic Acid Derivatives s S. Khom,1 J. Hintersteiner,2 D. Luger,2 M. Haider, G. Pototschnig, M. D. Mihovilovic, C. Schwarzer,1 and S. Hering Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria (S.K., J.H., D.L., S.H.); Institute of Applied Synthetic Chemistry, TU Wien, Vienna, Austria (M.H., G.P., M.D.M.); and Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria (C.S.) Received February 20, 2016; accepted April 6, 2016 Downloaded from ABSTRACT Valerenic acid (VA)—a b2/3-selective GABA type A (GABAA) 40.4 6 1.4 mg/kg PTZ versus VA 10 mg/kg: 49.0 6 1.8 mg/kg receptor modulator—displays anxiolytic and anticonvulsive ef- PTZ versus VA-A 3 mg/kg: 57.9 6 1.9 mg/kg PTZ, P , 0.05). fects in mice devoid of sedation, making VA an interesting drug Similarly, VA’s methylamide (VA-MA) enhancing IGABA through candidate. Here we analyzed b-subunit-dependent enhance- b3-containing receptors more efficaciously than VA (Emax 5 jpet.aspetjournals.org ment of GABA-induced chloride currents (IGABA) by a library of VA 1043 6 57%, P , 0.01, n 5 6) displayed stronger anticonvulsive derivatives and studied their effects on pentylenetetrazole (PTZ)- effects. Increased potency of IGABA enhancement and anticon- induced seizure threshold and locomotion. Compound-induced vulsive effects at lower doses compared with VA were observed IGABA enhancement was determined in oocytes expressing for VA-tetrazole (a1b3g2S: VA-TET: EC50 5 6.0 6 1.0 mM, P , a1b1g2S, a1b2g2S, or a1b3g2S receptors. Effects on seizure 0.05; VA-TET: 0.3 mg/kg: 47.3 6 0.5 mg/kg PTZ versus VA: threshold and locomotion were studied using C57BL/6N mice 10 mg/kg: 49.0 6 1.8 mg/kg PTZ, P , 0.05). At higher doses and compared with saline-treated controls. b2/3-selective VA ($10 mg/kg), VA-A, VA-MA, and VA-TET reduced locomotion. derivatives such as VA-amide (VA-A) modulating a1b3g2S In contrast, unselective VA derivatives induced anticonvulsive at ASPET Journals on September 27, 2021 (VA-A: Emax 5 972 6 69%, n 5 6, P , 0.05) and a1b2g2S recep- effects only at high doses (30 mg/kg) or did not display any tors (Emax 5 1119 6 72%, n 5 6, P , 0.05) more efficaciously than behavioral effects. Our data indicate that the b2/3-selective VA (a1b3g2S: VA: Emax 5 632 6 88%, n 5 9 versus a1b2g2S: compounds VA-A, VA-MA, and VA-TET induce anticonvulsive VA: Emax 5 721 6 68%, n 5 6) displayed significantly more effects at low doses (#10 mg/kg), whereas impairment of pronounced seizure threshold elevation than VA (saline control: locomotion was observed at doses $10 mg/kg. Introduction (Miller and Aricescu, 2014). The human genome comprises genes encoding for 19 different GABAA receptor subunits Interaction of GABA with GABA type A (GABAA) receptors [a1-6, b1-3, g1-3, d, «, r1-3, p, and u (Simon et al., 2004)], enables fast inhibitory neurotransmission in the mammalian theoretically allowing the formation of multiple GABAA re- brain (Barnard et al., 1998; Olsen and Sieghart, 2008; Sigel ceptor subtypes. The receptor’s subunit composition deter- and Steinmann, 2012). Like other members of the family of mines its pharmacological properties including agonist pentameric ligand-gated ion channels, GABA receptors are A sensitivity as well as its sensitivity for drugs (Barnard et al., constituted by pseudosymmetrical assembly of five identical 1998; Sigel and Steinmann, 2012). In addition, the highly or homologous subunits forming a chloride-conducting ion specific cellular and subcellular distribution of GABAA re- ceptor subunits/subtypes (Pirker et al., 2000; Schwarzer et al., The authors thank the Austrian Science Fund for financial support (P-22395, 2001; Olsen and Sieghart, 2008) and in particular the as- TRP-107; D.L., J.H., and G.P. are fellows of the FWF-funded doctoral program signment of therapeutic effects of commonly applied GABAA “Ion channels and transporters as drug targets” W-1232). M.H. is supported by receptor modulators such as benzodiazepines (e.g., Möhler the Initiativkolleg Functional Molecules IK 1041-N. Synthesis of VA-derivatives was supported by FFG Innovationsscheck 839639. et al., 2001; Rudolph et al., 2001; Rudolph and Knoflach, 2011; 1S.K. and C.S. contributed equally to this work as co-corresponding authors. Gallos et al., 2012, 2015; Rudolph and Möhler, 2014) or 2J.H. and D.L. contributed equally to this work. dx.doi.org/10.1124/jpet.116.232983. anesthetics (Jurd et al., 2003) to single GABAA receptor sub- s This article has supplemental material available at jpet.aspetjournals.org. units raises the possibility of developing drugs selectively ABBREVIATIONS: ANOVA, analysis of variance; DMSO, dimethylsulfoxide; GABAA,GABAtypeA;IGABA, GABA-induced chloride currents; PTZ, pentylenetetrazole; VA, valerenic acid; VA-A, VA-amide [(E)-3-((4S,7R,7aR)-3,7-dimethyl-2,4,5,6,7,7a-hexahydro-1H-inden-4-yl)-2-methylacrylamide]; VA-CN, VA-nitrile [(E)-3-((4S,7R,7aR)-3,7-dimethyl-2,4,5,6,7,7a-hexahydro-1H-inden-4-yl)-2-methylacrylonitrile]; VA-DEA, VA-diethylamide [(E)-3-((4S,7R, 7aR)-3,7-dimethyl-2,4,5,6,7,7a-hexahydro-1H-inden-4-yl)-N,N-diethyl-2-methylacrylamide)]; VA-DMA, VA-dimethylamide [{E)-3-((4S,7R,7aR)-3,7-dimethyl- 2,4,5,6,7,7a-hexahydro-1H-inden-4-yl)-N,N,2-trimethylacrylamide)]; VA-EA, VA-ethylamide [(E)-3-((4S,7R,7aR)-3,7-dimethyl-2,4,5,6,7,7a-hexahydro-1H- inden-4-yl)-N-ethyl-2-methylacrylamide)]; VA-MA, VA-methylamide [(E)-3-((4S,7R,7aR)-3,7-dimethyl-2,4,5,6,7,7a-hexahydro-1H-inden-4-yl)-N, 2-dimethylacrylamide]; VA-TET, VA-tetrazole; [5-((E)-1-((4S, 7R,7aR)-3,7-dimethyl-2,4,5,6,7,7a-hexahydro-1H-inden-4-yl)prop-1-en-2-yl)-1H-tetrazole)]. 580 VA Derivatives as Anticonvulsants 581 targeting specific brain circuits. Such subunit-selective of experiments, they were transferred to the testing facility, continu- GABAA receptor modulators are predicted to display the ing ad libitum access to food and water. desired therapeutic effects with reduced side effects. The temperature in the holding (for mice and frogs) and testing 6 Valerenic acid (VA), a sesquiterpenoid compound found in facilities was fixed to 22 2°C; the humidity ranged between 40 and common Valerian, selectively modulates g-aminobutyric acid 60%; a 12-hour light-dark cycle was in operation (lights on from 0700 to 1900). type A (GABA ) receptors containing b2- or b3-subunits, while A Chemicals. All chemicals used in this study were obtained from displaying only negligible effects on GABAA receptors incorpo- Sigma Aldrich (Vienna, Austria) except where stated otherwise. VA rating b1-subunits (Khom et al., 2007; Benke et al., 2009). In was purchased from HWI Pharma Solutions (Rülzheim, Germany). vivo, VA induces anxiolytic (Benke et al., 2009; Khom et al., 2010; VA derivatives (structural formulae are depicted in Fig. 1) were Hintersteiner et al., 2014) and anticonvulsive (Hintersteiner synthesized as previously described: description of the syntheses of et al., 2014) effects. Most notably, VA does not significantly VA-A [(E)-3-((4S,7R,7aR)-3,7-dimethyl-2,4,5,6,7,7a-hexahydro-1H-inden- reduce locomotor activity even at high doses (Khom et al., 2010). 4-yl)-2-methylacrylamide)], VA-MA [(E)-3-((4S,7R,7aR)-3,7-dimethyl- These findings combined with a promising pharmacokinetic 2,4,5,6,7,7a-hexahydro-1H-inden-4-yl)-N,2-dimethylacrylamide)], VA-DMA profile (Sampath et al., 2012) make VA an interesting drug [(E)-3-((4S,7R,7aR)-3,7-dimethyl-2,4,5,6,7,7a-hexahydro-1H-inden- candidate. Previously, we reported more pronounced anxio- 4-yl)-N,N,2-trimethylacrylamide)], VA-EA [(E)-3-((4S,7R,7aR)-3,7-di- methyl-2,4,5,6,7,7a-hexahydro-1H-inden-4-yl)-N-ethyl-2-methylacrylamide)], lytic and/or anticonvulsive effects by selected VA amide VA-DEA [(E)-3-((4S,7R,7aR)-3,7-dimethyl-2,4,5,6,7,7a-hexahydro-1H-inden- (Khom et al., 2010) and ester derivatives (Hintersteiner 4-yl)-N,N-diethyl-2-methylacrylamide)] can be found in (Khom et al., 2010) Downloaded from et al., 2014). In contrast to VA ester derivatives that are and for VA-TET [5-((E)-1-((4S,7R,7aR)-3,7-dimethyl-2,4,5,6,7,7a-hexahydro- significantly less active in vitro and thus might act as 1H-inden-4-yl)prop-1-en-2-yl)-1H-tetrazole)] and VA-CN [(E)-3-((4S,7R,7aR)- prodrugs (Hintersteiner et al., 2014), both VA amide deriva- 3,7-dimethyl-2,4,5,6,7,7a-hexahydro-1H-inden-4-yl)-2-methylacrylonitrile)], tives (Khom et al., 2010; Kopp et al., 2010) as well as VA’s see Kopp et al., 2010. Stock solutions (100 mM for in vitro experiments and nitrile and tetrazole analogs (Kopp et al., 2010) efficaciously 1mg/10ml for in vivo experiments, respectively) were prepared in 100% dimethylsulfoxide (DMSO).
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    Review Hooked on benzodiazepines: GABAA receptor subtypes and addiction Kelly R. Tan1, Uwe Rudolph2 and Christian Lu¨ scher1,3 1 Department of Basic Neurosciences, Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland 2 Laboratory of Genetic Neuropharmacology, McLean Hospital and Department of Psychiatry, Harvard Medical School, Belmont, MA 02478, USA 3 Clinic of Neurology, Department of Clinical Neurosciences, Geneva University Hospital, CH-1211 Geneva, Switzerland Benzodiazepines are widely used clinically to treat anxi- ment approaches even more difficult. The knowledge of how ety and insomnia. They also induce muscle relaxation, BDZs induce addiction might help in the development of control epileptic seizures, and can produce amnesia. anxiolytics and hypnotics with lower addictive liability. Moreover, benzodiazepines are often abused after chron- All addictive drugs, as well as natural rewards, increase ic clinical treatment and also for recreational purposes. dopamine (DA) levels in the mesolimbic dopamine (DA) Within weeks, tolerance to the pharmacological effects system, also termed the reward system (Box 2). Several can develop as a sign of dependence. In vulnerable indi- landmark studies with monkeys have shown that DA viduals with compulsive drug use, addiction will be diag- neurons play a role in signaling ‘reward error prediction’, nosed. Here we review recent observations from animal and thus are involved in learning processes related to models regarding the cellular and molecular basis that reward and intrinsic value. Specifically, DA neurons are might underlie the addictive properties of benzodiaze- excited following the presentation of an unexpected re- pines. These data reveal how benzodiazepines, acting ward. Once this reward becomes predictable (by an experi- through specific GABAA receptor subtypes, activate mid- mentally controlled cue), DA neurons shift their phasic brain dopamine neurons, and how this could hijack the activation from the reward to the cue.
  • The Effect of Chronic Alcohol Abuse on the Benzodiazepine Receptor

    The Effect of Chronic Alcohol Abuse on the Benzodiazepine Receptor

    f Ps al o ych rn ia u tr o y J Journal of Psychiatry Shushpanova et al., J Psychiatry 2016, 19:3 DOI: 10.4172/2378-5756.1000365 ISSN: 2378-5756 Research Article OpenOpen Access Access The Effect of Chronic Alcohol Abuse on the Benzodiazepine Receptor System in Various Areas of the Human Brain Shushpanova TV1*, Bokhan NA2, Lebedeva VF2, Solonskii AV1 and Udut VV3 1Department of Clinical Neuroimmunology and Neurobiology, Mental Health Research Institute, Russia 2Department of Addictive Disorders, Mental Health Research Institute, Russia 3Department of Molecular and Clinical Pharmacology, Research Institute of Pharmacology and Regenerative Medicine, Russia Abstract Objective: Alcohol abuse induces neuroadaptive changes in the functioning of neurotransmitter systems in the brain. Decrease of GABAergic neurotransmission found in alcoholics and persons with a high risk of alcohol dependence. Benzodiazepine receptor (BzDR) is allosterical modulatory site on GABA type A receptor complex (GABAAR), that modulate GABAergic function and may be important in mechanisms regulating the excitability of the brain processes involved in the alcohol addiction. The purpose of this study was to investigate the effects of chronic alcohol abuse on the BzDR in various areas of the human brain. Materials and Methods: Investigation of BzDR properties were studied in synaptosomal and mitochondrial membrane fractions from different brain areas of alcohol abused patients and non-alcoholic persons by radioreceptor assay with using selective ligands: [3H] flunitrazepam and [3H] PK-11195. Brain samples obtained at autopsy urgent. In total 126 samples of human brain areas were obtained to study radioreceptor binding, including a study group and control group. Results: Comparative study of kinetic parameters (Kd, Bmax) of [3H] flunitrazepam and [3H] PK-11195 binding with membrane fractions in studding brain samples was showed that affinity of BzDR was decreased and capacity increased in different areas of human brain under influence of alcohol abuse.