title: Reducing effect of saikosaponin A, an active ingredient of Bupleurum falcatum, on alcohol self-administration in rats: Possible involvement of the GABAB receptor.
abstract: Recent studies demonstrated that treatment with saikosaponin A (SSA) - an active ingredient of the medicinal herb, Bupleurum falcatum L. - selectively suppressed, likely via a GABAB receptor-mediated mechanism, intravenous self-administration of morphine and cocaine in rats [Yoon et al., 2012; 2013]. The present study was designed to investigate whether the capacity of SSA to suppress morphine and cocaine self-administration extends to oral alcohol self-administration. To this end, selectively bred Sardinian alcohol-preferring (sP) rats were trained to lever-respond on a Fixed Ratio (FR) 4 (FR4) schedule of reinforcement for alcohol (15%, v/v) in daily 30-min sessions. Once responding had stabilized, rats were tested under the FR4 (measure of alcohol reinforcing properties) and Progressive Ratio (PR; measure of alcohol motivational properties) schedules of reinforcement. The possible involvement of the GABAB receptor system was investigated testing the effect of (a) pretreatment with the GABAB receptor antagonist, SCH50911, and (b) combined treatment with the positive allosteric modulator of the GABAB receptor, GS39783. Treatment with SSA (0, 0.25, 0.5, and 1mg/kg, i.p.) markedly reduced lever-responding for alcohol, amount of self-administered alcohol, and breakpoint for alcohol (defined as the lowest response requirement not achieved in the PR experiment). Pretreatment with 2mg/kg SCH50911 (i.p.) resulted in a partial blockade of the reducing effect of 0.5mg/kg SSA on lever-responding for alcohol and amount of self-administered alcohol. Combination of per se ineffective doses of GS39783 (5mg/kg, i.g.) and SSA (0.1mg/kg, i.p.) reduced lever-responding for alcohol and amount of self-administered alcohol. These results (a) extend to alcohol self-administration the capacity of SSA to suppress morphine and cocaine self-administration in rats and (b) suggest that the GABAB receptor system is likely part of the neural substrate underlying the reducing effect of SSA on alcohol self-administration.
authors.affiliation: Neuroscience Institute, National Research Council of Italy, Section of Cagliari, I-09042 Monserrato, CA, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Maccioni
authors.affiliation: Neuroscience Institute, National Research Council of Italy, Section of Cagliari, I-09042 Monserrato, CA, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Lorrai
authors.affiliation: Cagliari Pharmacological Research s.r.l., I-09127 Cagliari, CA, Italy.
authors.forename: Mauro A M
authors.initials: MAM
authors.lastname: Carai
authors.affiliation: Indena S.p.A., I-20139 Milan, MI, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Riva
authors.affiliation: Indena S.p.A., I-20139 Milan, MI, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Morazzoni
authors.affiliation: Department of Biotechnologies, Chemistry and Pharmacy, University of Siena, I-53100, Siena, SI, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Mugnaini
authors.affiliation: Department of Biotechnologies, Chemistry and Pharmacy, University of Siena, I-53100, Siena, SI, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Corelli
authors.affiliation: Neuroscience Institute, National Research Council of Italy, Section of Cagliari, I-09042 Monserrato, CA, Italy.
authors.forename: Gian Luigi
authors.initials: GL
authors.lastname: Gessa
authors.affiliation: Neuroscience Institute, National Research Council of Italy, Section of Cagliari, I-09042 Monserrato, CA, Italy. Electronic address: colomb@unica.it.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Colombo
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D029972:Bupleurum / Q000737:chemistry*; D003517:Cyclopentanes / Q000494:pharmacology; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D058788:GABA-B Receptor Antagonists / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009042:Motivation; D009043:Motor Activity / Q000187:drug effects; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D018080:Receptors, GABA-B / Q000378:metabolism*; D012054:Reinforcement, Psychology; D012503:Saponins / Q000494:pharmacology*; D012646:Self Administration
chemical_list: C095804:(+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid; D003517:Cyclopentanes; D058788:GABA-B Receptor Antagonists; D009025:Morpholines; C478058:N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine; D011743:Pyrimidines; D018080:Receptors, GABA-B; D012503:Saponins; D000431:Ethanol; D009828:Oleanolic Acid; C025759:saikosaponin D
keywords: Bupleurum falcatum; GABA(B) receptor antagonist, SCH50911; Operant, oral alcohol self-administration; Positive allosteric modulator of the GABA(B) receptor, GS39783; Saikosaponin A; Sardinian alcohol-preferring (sP) rats