title: Evaluation of anxiolytic-like, anticonvulsant, antidepressant-like and antinociceptive properties of new 2-substituted 4-hydroxybutanamides with affinity for GABA transporters in mice.
abstract: OBJECTIVE
  The inhibition of plasma membrane GABA transporters (GATs) is responsible for anxiolytic-like, anticonvulsant, antinociceptive and antidepressant-like effects in mice. It also influences animals' motor coordination and their sensitivity to ethanol. The aim of this study was to assess the pharmacological activity of two novel 2-substituted 4-hydroxybutanamides (BM 130 and BM 131) in some screening models. An attempt has been made to establish the relationship between the inhibition of GAT subtype and the observed in vivo activity.
  
  
  METHODS
  The affinity for GAT subtypes was evaluated by means of [(3)H]GABA uptake assay. It indicated that BM 130 inhibited GAT1 and GAT2, whereas BM 131 inhibited GAT1 and GAT3. In mice anxiolytic-like, antidepressant-like, anticonvulsant and antinociceptive properties of the test compounds were assessed. Their influence on motor coordination, locomotor activity and the ability to potentiate effects of subnarcotic doses of ethanol was also tested.
  
  
  RESULTS
  Both compounds administered intraperitoneally exerted a significant anxiolytic-like effect in the four plate test with ED50 values 3.4 and 7.9 mg/kg, respectively. At 30 mg/kg they reduced duration of immobility in the forced swim test for 33% and 19%, respectively. They had no effect on electroconvulsive threshold or pain reactivity in the hot plate assay but they were antinociceptive in the acetic acid-induced writhing test (ED50 values were 12.7 and 18.6 mg/kg, respectively) and in both phases of the formalin test (ED50 values in the first phase were 10.2 and 2.1 mg/kg for BM 130 and BM 131, respectively). No motor adverse effects were observed in mice pretreated with the test compounds in the rotarod or chimney tests but BM 131 caused a transient but statistically significant decrease of animals' locomotor activity.
  
  
  CONCLUSIONS
  In mice BM 130 and BM 131 have anxiolytic-like, antidepressant-like and antinociceptive properties which can be attributed to their affinity for not only mGAT1 but also mGAT2-4.
authors.affiliation: Department of Pharmacodynamics, Jagiellonian University, Medical College, Medyczna 9, 30-688 Cracow, Poland. Electronic address: salat.kinga@gmail.com.
authors.forename: Kinga
authors.initials: K
authors.lastname: Sałat
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kulig
authors.forename: Justyna
authors.initials: J
authors.lastname: Gajda
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Więckowski
authors.forename: Barbara
authors.initials: B
authors.lastname: Filipek
authors.forename: Barbara
authors.initials: B
authors.lastname: Malawska
mesh_terms: D000577:Amides / Q000737:chemistry; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000927:Anticonvulsants / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D050485:GABA Plasma Membrane Transport Proteins / Q000187:drug effects*; D006885:Hydroxybutyrates / Q000737:chemistry / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice
chemical_list: D000577:Amides; D000700:Analgesics; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D050485:GABA Plasma Membrane Transport Proteins; D006885:Hydroxybutyrates
keywords: 2-Substituted 4-hydroxybutanamides; Anxiety; ECT; GABA; GATs; MC; MES; Mice; Motor impairments; Pain; Plasma membrane GABA transporters; electroconvulsive threshold; gamma aminobutyric acid; maximal electroshock seizures; methylcellulose; plasma membrane GABA transporters; rotations per minute; rpm