title: KK-92A, a novel GABABreceptor positive allosteric modulator, attenuates nicotine self-administration and cue-induced nicotine seeking in rats.
abstract: GABABreceptors (GABABR) play a critical role in GABAergic neurotransmission in the brain and are thought to be one of the most promising targets for the treatment of drug addiction. GABABR positive allosteric modulators (PAMs) have shown promise as potential anti-addictive therapies, as they lack the sedative and muscle relaxant properties of full GABABreceptor agonists such as baclofen.
  
  
  
  The present study was aimed at developing novel, selective, and potent GABABR PAMs with efficacy on abuse-related effects of nicotine.
  
  
  
  We synthetized ~100 analogs of BHF177, a GABABR PAM that has been shown to inhibit nicotine taking and seeking, and tested their activity in multiple cell-based functional assays. Among these compounds, KK-92A displayed superior PAM properties at the GABABR. Interestingly, our results revealed the existence of pathway-selective differential modulation of GABABR signaling by the structurally related GABABR allosteric modulators BHF177 and KK-92A. In vivo, similarly to BHF177, KK-92A inhibited intravenous nicotine self-administration under both fixed- and progressive-ratio schedules of reinforcement in rats. In contrast to BHF177, KK-92A had no effect on food self-administration. Furthermore, KK-92A decreased cue-induced nicotine-seeking behavior without affecting food seeking.
  
  
  
  These results indicate that KK-92A is a selective GABABR PAM with efficacy in inhibition of the primary reinforcing and incentive motivational effects of nicotine, and attenuation of nicotine seeking, further confirming that GABABR PAMs may be useful antismoking medications.
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Sturchler
authors.affiliation: The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kaczanowska
authors.affiliation: The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Cameron
authors.affiliation: The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Finn
authors.affiliation: The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Griffin
authors.affiliation: The Scripps Research Institute, Jupiter, FL, USA. mcdonaph@scripps.edu.|Department of Molecular Therapeutics, The Scripps Research Institute, 130 Scripps way, Jupiter, FL, 33458, USA. mcdonaph@scripps.edu.
authors.forename: Patricia
authors.initials: P
authors.lastname: McDonald
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
authors.forename: Athina
authors.initials: A
authors.lastname: Markou
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D016739:Behavior, Addictive / Q000517:prevention & control* / Q000523:psychology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003463:Cues; D004305:Dose-Response Relationship, Drug; D018757:GABA Modulators / Q000494:pharmacology / Q000627:therapeutic use*; D058786:GABA-B Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D009042:Motivation / Q000187:drug effects / Q000502:physiology; D009538:Nicotine / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D018080:Receptors, GABA-B / Q000502:physiology*; D012054:Reinforcement, Psychology; D012646:Self Administration / Q000379:methods
chemical_list: D018757:GABA Modulators; D058786:GABA-B Receptor Agonists; D018080:Receptors, GABA-B; D009538:Nicotine
keywords: Allosteric modulator; GABA receptor; GPCR; Nicotine; Relapse; Self-administration