Article thumbnail

Anti-Alcohol and Anxiolytic Properties of a New Chemical Entity, GET73

By Antonella Loche, Francesco Simonetti, Carla Lobina, Mauro A. M. Carai, Giancarlo Colombo, M. Paola Castelli, Domenico Barone and Roberto Cacciaglia

Abstract

N-[(4-trifluoromethyl)benzyl]4-methoxybutyramide (GET73) is a newly synthesized compound structurally related to the clinically used, alcohol-substituting agent, gamma-hydroxybutyric acid (GHB). The present study was designed to assess whether GET73 may share with GHB the capacity to reduce alcohol intake in rats. Additionally, the effect of treatment with GET73 on anxiety-related behaviors and cognitive tasks in rats was investigated. A series of in vitro binding assays investigated the capacity of GET73 to bind to the GHB binding site and multiple other receptors. GET73 (10−9–10−3 M) failed to inhibit [3H]GHB binding at both high- and low-affinity GHB recognition sites in rat cortical membranes. GET73 displayed minimal, if any, binding at dopamine, serotonin, GABA, and glutamate receptors in membranes from different rat brain areas. Acute treatment with low-to-moderate, non-sedative doses of GET73 (5–50 mg/kg, i.g. or i.p.) (a) reduced alcohol intake and suppressed “alcohol deprivation effect” (a model of alcohol relapse) in selectively bred, Sardinian alcohol-preferring (sP) rats, (b) exerted anxiolytic effects in Sprague-Dawley (SD) and sP rats exposed to the Elevated Plus Maze test, and (c) tended to induce promnestic effects in SD rats exposed to a modified water version of the Hebb–Williams maze test. Although the mechanism of GET73 action is currently unknown, the results of the present study suggest that GET73 has a multifaceted pharmacological profile, including the capacity to reduce alcohol drinking and anxiety-related behaviors in rats

Topics: Psychiatry
Publisher: Frontiers Research Foundation
OAI identifier: oai:pubmedcentral.nih.gov:3278888
Provided by: PubMed Central

Suggested articles

Citations

  1. (1981). [3H]-ketanserin (R41,468), a selective [3H]-ligand for serotonin2 receptor binding sites.
  2. (1991). [3H]CGP 39653: a new Nmethyl-D-aspartate antagonist radioligand with low nanomolar affinity in brain.
  3. (1946). A method of rating animal intelligence.
  4. (2011). accepted: 30
  5. (2001). Alcohol stimulates motor activity in selectively bred Sardinian alcoholpreferring (sP),but not in Sardinian alcohol-nonpreferring (sNP), rats.
  6. Altered amygdalar CRF release and increased anxiety-like behavior in Sardinian alcohol-preferring rats: a microdialysis and behavioral study.
  7. (1996). An open multicentric study evaluating 4-hydroxybutyric acid sodium salt in the medium-term treatment of 179 alcohol dependent subjects.
  8. (2011). An overview of gamma-hydroxybutyric acid: pharmacodynamics, pharmacokinetics, toxic effects, addiction, analytical methods, and interpretation of results.
  9. and Spooren,W.(2005).Theeffectof the mGlu5receptorantagonistMPEPin rodent tests of anxiety and cognition: a comparison. Psychopharmacology (Berl.)
  10. (1997). Animal models of anxiety: an ethological perspective.
  11. (2012). Antialcoholandanxiolyticpropertiesof anew chemical entity, GET73. Front. Psychiatry 3:8. doi: 10.3389/fpsyt.2012.00008 This article was submitted to Frontiers in Addictive Disorders, a specialty of Frontiers
  12. (2006). Anxiolytic-like effects of theselectivemetabotropicglutamate receptor 5 antagonist MPEP after its intra-amygdaloid microinjection in three different non-conditioned rat models of anxiety.
  13. (2007). Assessing appetitive and consummatory phases of ethanol self-administration in C57BL/6J mice under operant conditions: regulation by mGlu5 receptor antagonism.
  14. (2009). Behavioral analyses of GHB: receptor mechanisms.
  15. (2012). Behavioral profiling of multiple pairs of rats selectively bred for highandlowalcoholintakeusingthe MCSF test.
  16. (2002). Central effects of 1,4-butanediol are mediated by GABA(B) receptors via its conversion into gammahydroxybutyricacid.Eur.J.Pharmacol.
  17. (1987). Characterization of quisqualate recognition sites in rat brain tissue using DL-[3H]alpha-amino-3-hydroxy5-methyl-isoxazole-4-propionic acid (AMPA) and a filtration assay.
  18. (1984). Characterization of the binding of [3H]-SCH 23390, a selective D1 receptor antagonist ligand.
  19. (1988). Characterizationof[3H]-paroxetine binding in rat brain.
  20. (1993). Comparison of [3H]WIN 35,428 binding, a marker for dopamine transporter, in embryonic mesencephalic neuronal cultures with striatal membranes of adult rats.
  21. (1983). Conformational changes in benzodiazepine receptors induced by the antagonist Ro 15-1788.
  22. (2002). Double-blind controlled trial of γ-hydroxybutyrate and clomethiazole in the treatment of alcohol withdrawal.
  23. (2002). Effects of enriched environments with different durations and starting times on learning capacity during aging in rats assessed by a refined procedure of the HebbWilliams maze task.
  24. (2010). Effects of the mGlu2/3 agonist LY379268 and the mGlu5antagonistMTEPonethanol seeking and reinforcement are differentially altered in rats with a history of ethanol dependence.
  25. (1979). Evidence for two types of binding of [3H]-GABA and [3H]-muscimol in rat cerebral cortex and cerebellum.
  26. (2004). Functional interaction between NMDA and mGlu5 receptors:effects on working memory, instrumental learning, motor behaviors, and dopamine release.
  27. (2010). Gamma hydroxybutyric acid (GHB): a valid pharmacological opportunity for the treatment of alcohol dependence,”
  28. (1999). Gamma-hydroxybutyric acid (GHB) in the treatment of alcohol withdrawal syndrome: a randomized comparative study versus benzodiazepine.
  29. (2000). Gamma-hydroxybutyric acid and alcohol-related syndromes.
  30. (1989). Gamma-hydroxybutyric acid for treatment of alcohol withdrawal syndrome.
  31. (1992). Gamma-hydroxybutyric acid in the treatment of alcohol dependence: a double-blind study.
  32. (2002). Genetic factors involved in the effects of developmental low-level alcohol induced behavioral alterations in rats.
  33. (2011). GET73 modulates rat hippocampal glutamate transmission: evidence for a functional interaction with mGluR5.
  34. (1979). Hippocampus, space and memory.
  35. (2005). How to measure relapse in animals,” in Drugs for Relapse Prevention of Alcoholism,eds
  36. (1998). Hydroxybutyric acid in the treatmentofalcoholism:dosagefractioning utility in non-responder alcoholic patients. Drug Alcohol Depend.
  37. (1998). Hydroxybutyric acid reducing effect onethanolintake:evidenceinfavour ofasubstitutionmechanism.Alcohol Alcohol.
  38. (1992). Identification, characterization, and localization of the dopamine D3 receptor in rat brain using 7-[3H]hydroxyN,N-di-n-propyl-2-aminotetralin.
  39. (1977). Influences of ions, enzymes, and detergents on γ-aminobutyric acidreceptor binding in synaptic membranes of rat brain.
  40. (1977). Loss of striatal dopaminergic receptors after intrastriatal kainic acid injection. Brain Res.
  41. (1995). Low doses of gamma-hydroxybutyric acid (GHB) attenuate ethanol intake in alcoholpreferring (P) rats.
  42. (2009). Lower risk taking and exploratory behavior in alcohol-preferring sP rats than in alcohol non-preferring sNP rats in the multivariate concentricsquarefieldä(MCSF)test.Behav. Brain Res.
  43. (1998). Maintainingabstinencefromalcoholwith gamma-hydroxybutyric acid.
  44. (2011). Medications for unhealthy alcohol use. Alcohol Res.
  45. (1993). Modulation of [35S]-TBPS binding by GABAergic drugs in the cerebral cortex of newborn and adult rats.
  46. (1987). o c h ee ta l . Anti-alcohol and anxiolytic properties of GET73
  47. (2006). Phenotypic characterization of genetically selected Sardinian alcoholpreferring (sP) and -non preferring (sNP)rats.Addict.Biol.11,324–338.
  48. (2007). Preference for palatable food is reduced by the gammahydroxybutyrate analogue GET73, in rats.
  49. (2004). Prevalence and co-occurrence of substance use disorders and independent mood and anxiety disorders. Results from the national epidemiologic survey on alcoholandrelatedconditions.Arch.
  50. (2008). Regulation of motivation to selfadminister ethanol by mGluR5 in alcohol-preferring (P) rats.
  51. (2003). Sardinian alcohol-preferring and nonpreferring rats show different reactivitytoaversivestimuliandasimilar response to a natural reward. Brain Res.
  52. (1995). Sardinian alcohol-preferring rats: a genetic animal model of anxiety.
  53. (2003). Selective γ-hydroxybutyricacidreceptorligands increase extracellular glutamate in the hippocampus, but fail to activate G protein and to produce the sedative/hypnotic effect of γ-hydroxybutyric acid.
  54. (2002). Self-medication with gammahydroxybutyrate to reduce alcohol intake.
  55. (1976). Serotonin and lysergic acid diethylamide binding in rat brain membranes: relationship to postsynaptic serotoninreceptors.Mol.Pharmacol.
  56. (2012). Substitutiontherapyforalcoholism:timefor a reappraisal?
  57. (2008). Sucrose intake: increase in non-stressed rats and reductioninchronicallystressedrats are both prevented by the gammahydroxybutyrate (GHB) analogue,
  58. (2005). The antinociceptive and anxiolyticlike effects of the metabotropic glutamate receptor 5 (mGluR5) antagonists, MPEP and MTEP, and the mGluR1 antagonist, LY456236, in rodents: a comparison of efficacy and side-effect profiles.
  59. (1982). The distribution of [3H]kainic acid binding sites in rat CNS as determined by autoradiography. Brain Res.
  60. (2001). The hippocampus and declarative memory: cognitive mechanisms and neural codes.
  61. (2004). The mGluR5 antagonist 2-methyl6-(phenylethynyl)-pyridine(MPEP) potentiates PCP-induced cognitive deficits in rats.
  62. (2009). The therapeutic potential of gamma-hydroxybutyric acid for alcohol dependence: balancing the risksandbenefits.Afocusonclinical data.ExpertOpin.Investig.Drugs 18,
  63. (2002). Therapeutic uses of (-hydroxybutyrate,” in GammaHydroxybutyrate: Molecular, Functional and Clinical Aspects,
  64. (2008). Treatment implications: using neuroscience to guide the development of new pharmacotherapies for alcoholism. Alcohol Res.
  65. (2008). γ-Hydroxybutyric acid (GHB) suppresses alcohol’s motivational properties in alcohol-preferring rats.
  66. (2010). γ-Hydroxybutyric acid (GHB),”
  67. (2005). γ-Hydroxybutyric acid.

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.