CNR - Institute of Neuroscience CNR
Institute of Neuroscience
 

Project

GABAB receptor agonists and positive allosteric modulators: novel pharmacotherapies for alcoholism?

Within the frame of the project “Neurobiology of alcoholism”, one of the major topics of this laboratory over the last years has been the investigation of the effect of several ligands of the GABAB receptor – specifically, direct agonists and positive allosteric modulators – on different alcohol-related behaviors. This series of studies has used multiple, validated experimental models of alcohol dependence, including the Sardinian alcohol-preferring (sP) rats, one of the few rat lines selectively bred worldwide for excessive alcohol preference and consumption.

 

Initially, these studies led to the discovery that direct agonists of the GABAB receptor – including the prototype baclofen – effectively suppressed (a) acquisition and maintenance of alcohol drinking behavior, (b) relapse-like drinking, (c) alcohol’s reinforcing, rewarding, stimulating, and motivational properties, and (d) severity of alcohol withdrawal syndrome in rats and mice. Subsequent preliminary clinical studies extended these findings to human alcoholics: treatment with baclofen resulted indeed in the suppression of alcohol drinking, craving for alcohol, and alcohol withdrawal syndrome in human alcoholics.

More recently, the discovery of a positive allosteric modulatory binding site in the GABAB receptor macroprotein, together with the synthesis of in vivo effective ligands, opened a new avenue of research in GABAB pharmacology. Positive allosteric modulators of the GABAB receptor are devoid of substantial intrinsic agonistic activity, while they increase potency and efficacy of endogenous GABA in activating the orthosteric binding site of the GABAB receptor. As a consequence, positive allosteric modulators are expected to activate the GABAB receptor in a more “physiological” way and to display a higher therapeutic index than direct agonists, as they should produce the “desired” behavioral effect at doses far lower than those inducing adverse effects (e.g., sedation). Notably, accumulating lines of evidence, collected in this laboratory, suggest that positive allosteric modulators retain baclofen’s capacity to selectively suppress alcohol consumption and alcohol’s reinforcing and motivational properties in sP rats exposed to different experimental procedures. As predicted, these effects occurred at doses far from those producing behavioral toxicity. In view of the considerably higher therapeutic index of the positive allosteric modulators, in comparison to that of baclofen, these results suggest that the positive allosteric modulators may represent an advancement in the search of GABAB receptor ligands with therapeutic potential for alcoholism.

Publications

  • Maccioni P, Thomas AW, Carai MA, Gessa GL, Malherbe P, Colombo G (2010) The positive allosteric modulator of the GABA(B) receptor, rac-BHFF, suppresses alcohol self-administration. Drug Alcohol Depend 109:96-103.
  • Maccioni P, Colombo G (2009) Role of the GABA(B) receptor in alcohol-seeking and drinking behavior. Alcohol 43:555-8.
  • Maccioni P, Carai MA, Kaupmann K, Guery S, Froestl W, Leite-Morris KA, Gessa GL, Colombo G (2009) Reduction of alcohol's reinforcing and motivational properties by the positive allosteric modulator of the GABA(B) receptor, BHF177, in alcohol-preferring rats. Alcohol. Clin. Exp. Res. 33:1749-56.
  • Maccioni P, Fantini N, Froestl W, Carai MA, Gessa GL, Colombo G (2008) Specific reduction of alcohol's motivational properties by the positive allosteric modulator of the GABAB receptor, GS39783--comparison with the effect of the GABAB receptor direct agonist, baclofen. Alcohol. Clin. Exp. Res. 32:1558-64.
  • Maccioni P, Bienkowski P, Carai MA, Gessa GL, Colombo G (2008) Baclofen attenuates cue-induced reinstatement of alcohol-seeking behavior in Sardinian alcohol-preferring (sP) rats. Drug Alcohol Depend 95:284-7.
  • Maccioni P, Pes D, Orrù A, Froestl W, Gessa GL, Carai MA, Colombo G (2007) Reducing effect of the positive allosteric modulator of the GABA(B) receptor, GS39,783, on alcohol self-administration in alcohol-preferring rats. Psychopharmacology (Berl.) 193:171-8.
  • Colombo G, Serra S, Vacca G, Carai MA, Gessa GL (2006) Baclofen-induced suppression of alcohol deprivation effect in Sardinian alcohol-preferring (sP) rats exposed to different alcohol concentrations. Eur. J. Pharmacol. 550:123-6.
  • Addolorato G, Leggio L, Agabio R, Colombo G, Gasbarrini G (2006) Baclofen: a new drug for the treatment of alcohol dependence. Int. J. Clin. Pract. 60:1003-8.
  • Addolorato G, Leggio L, Abenavoli L, Agabio R, Caputo F, Capristo E, Colombo G, Gessa GL, Gasbarrini G (2006) Baclofen in the treatment of alcohol withdrawal syndrome: a comparative study vs diazepam. Am. J. Med. 119:276.e13-8.
  • Maccioni P, Serra S, Vacca G, Orrù A, Pes D, Agabio R, Addolorato G, Carai MA, Gessa GL, Colombo G (2005) Baclofen-induced reduction of alcohol reinforcement in alcohol-preferring rats. Alcohol 36:161-8.
  • Orrù A, Lai P, Lobina C, Maccioni P, Piras P, Scanu L, Froestl W, Gessa GL, Carai MA, Colombo G (2005) Reducing effect of the positive allosteric modulators of the GABA(B) receptor, CGP7930 and GS39783, on alcohol intake in alcohol-preferring rats. Eur. J. Pharmacol. 525:105-11.
  • Colombo G, Serra S, Vacca G, Gessa GL, Carai MA (2004) Suppression by baclofen of the stimulation of alcohol intake induced by morphine and WIN 55,212-2 in alcohol-preferring rats. Eur. J. Pharmacol. 492:189-93.
  • Colombo G, Serra S, Brunetti G, Vacca G, Carai MA, Gessa GL (2003) Suppression by baclofen of alcohol deprivation effect in Sardinian alcohol-preferring (sP) rats. Drug Alcohol Depend 70:105-8.
  • Colombo G, Vacca G, Serra S, Brunetti G, Carai MA, Gessa GL (2003) Baclofen suppresses motivation to consume alcohol in rats. Psychopharmacology (Berl.) 167:221-4.
  • Addolorato G, Caputo F, Capristo E, Domenicali M, Bernardi M, Janiri L, Agabio R, Colombo G, Gessa GL, Gasbarrini G (0) Baclofen efficacy in reducing alcohol craving and intake: a preliminary double-blind randomized controlled study. Alcohol Alcohol. 37:504-8.
  • Colombo G, Serra S, Brunetti G, Atzori G, Pani M, Vacca G, Addolorato G, Froestl W, Carai MA, Gessa GL (0) The GABA(B) receptor agonists baclofen and CGP 44532 prevent acquisition of alcohol drinking behaviour in alcohol-preferring rats. Alcohol Alcohol. 37:499-503.
  • Colombo G, Agabio R, Carai MA, Lobina C, Pani M, Reali R, Addolorato G, Gessa GL (2000) Ability of baclofen in reducing alcohol intake and withdrawal severity: I--Preclinical evidence. Alcohol. Clin. Exp. Res. 24:58-66.

Collaborations

  • Giovanni Addolorato, Istituto di Medicina Interna, Università Cattolica di Roma.
  • Przemyslaw Bienkowski, Department of Pharmacology, Institute of Psychiatry and Neurology, Varsavia, Polonia.
  • Federico Corelli, Dipartimento Farmaco Chimico Tecnologico, Università di Siena.
  • Basalingappa L. Hungund, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
  • Lawrence Lumeng, Indiana University School of Medicine, Institute of Psychiatric Research, Indianapolis, IN, USA.
  • Erika Roman, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Svezia.
  • Boris Tabakoff, Department of Pharmacology, University of Colorado, Aurora, CO, USA.

 

PI photo

Giancarlo Colombo

Contact information

email  E-mail

email  +39 070 302227

Participating staff

Mauro A.M. Carai

Noemi Fantini

Gian Luigi Gessa (supervisor)

Barbara Loi

Carla Lobina

Paola Maccioni