Symposium 29 Wednesday Sept. 26th 9.00 am–10.30 am; Room: Lecture Hall 1
GABA-B receptor: a new target for treating alcohol dependence?: Chairpersons: Leite-Morris KA (USA), Colombo G (Italy)
 |
Abstract |
|---|
Presentation S29-1
Activation of the GABA(B) receptor in animal models of alcohol dependence
Colombo G, Maccioni P, Orrù A, Lobina C, Agabio R, Addolorato G, Gessa GL, Carai MAM (Italy)
Aims. The present paper summarizes the different lines of experimental evidence featuring the suppressing effect of the GABA(B) receptor full agonists, baclofen and CGP44532, and positive allosteric modulators, CGP7930 and GS39783, on different alcohol-motivated behaviors.
Methods. These studies have been conducted testing different procedures of alcohol intake and alcohol self-administration in Sardinian alcohol-preferring (sP) rats, one of the few rat lines selectively bred worldwide for high alcohol preference and consumption.
Results. Administration of non-sedative doses of baclofen, CGP44532, CGP7930, and GS39783 to sP rats have been found to suppress: (a) acquisition and maintenance of alcohol drinking behavior under the standard 2-bottle ‘alcohol vs water’ choice regimen; (b) relapse-like drinking after a period of alcohol abstinence (the so-called ‘alcohol deprivation effect’); (c) the increase in alcohol intake induced by the acute administration of opioids and cannabinoids; (d) oral self-administration of alcohol in rats trained to lever-press for alcohol on an FR4 schedule of reinforcement; (e) the motivational properties of alcohol, measured by the progressive ratio schedule of reinforcement and the extinction responding procedure in rats previously trained to self-administer alcohol on an FR4 schedule; (f) reinstatement (induced by the presentation of non-contigent, alcohol-associated stimuli) of alcohol-seeking behavior in rats trained to self-administer alcohol (another experimental model of alcohol relapse). Finally, acute administration of baclofen has been found to suppress the severity of different signs of alcohol withdrawal syndrome, including tremors and seizures, in Wistar rats made physically dependent on alcohol.
Conclusions. Taken together, these data suggest the involvement of the GABA(B) receptor in the neural substrate(s) controlling alcohol intake and relapse-like drinking, mediating alcohol's reinforcing and motivational properties, and underlying alcohol withdrawal syndrome. Of interest, subsequent preliminary clinical studies with baclofen have extended to human alcohol-dependent patients the majority of the above observations (Addolorato et al., this meeting).
Presentation S29-2
GABA(B) receptor activation modulates neurotransmitter levels during alcohol seeking
Leite-Morris KA (USA)
Aims. Dopamine neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and other forebrain regions are implicated in the motivational behaviors related to ethanol seeking and intake. This presentation will discuss the findings that direct activation of GABA (B) receptors in the VTA modulate mesoaccumbens circuits and alter dopamine responses in the NAc that underlie the motivation of appetitive behaviors.
Methods. An animal model combining in vivo microdialysis with alcohol self-administration was designed to collect brain dialysate concurrently while subjects were lever pressing (extinction sessions). Long Evans rats were trained to perform a fixed number of lever presses (RR20) for a 20 minute presentation of 2% sucrose or 10% ethanol. Subjects were surgically implanted with guide cannula into the VTA for microinjections and NAc for in vivo microdialysis.
Following administration of intra-VTA artificial cerebral spinal fluid (aCSF), or the GABA (B) receptor agonist baclofen (0.25, 0.5, 1.0 ug) and/or the antagonist CGP 35348 (10 ug), single extinction sessions were performed each week. Brain dialysate was collected at 5 minute intervals prior to and during extinction trials.
Results. Intra-VTA administration of baclofen (versus aCSF) resulted in a significant dose-dependent inhibition of ethanol seeking (lever pressing) during extinction sessions and altered NAc dopamine during the ethanol seeking behavior.
Conclusions. These results suggest that GABA (B) receptors in the VTA may modulate mesoaccumbens circuits that underlie the motivational behaviors of alcohol seeking eventually leading to ethanol consumption. A greater understanding of these circuits will have an impact on treatment implications for alcohol craving.
Presentation S29-3
Clinical evidence of the beneficial effects of baclofen in the treatment of alcohol dependence
Addolorato G, Leggio L, Ferrulli A, Abenavoli L, D'Angelo C, Vonghia L, Mirijello A, Cardone S, Leso V, Piano S, Nesci A, Agabio R, Colombo G, Gasbarrini G (Italy)
Aims. Recent preclinical and clinical studies have suggested that baclofen, the prototypic GABAB receptor agonist, is a promising pharmacological compound for the treatment of alcohol dependence.
Results. Specifically, baclofen has been found to suppress symptoms of alcohol withdrawal syndrome with an efficacy comparable to that of the ‘gold standard’ diazepam. Moreover baclofen has proven to be effective in the prevention of relapse, likely because of its ability to reduce alcohol intake and craving in alcoholic patients. Baclofen displayed good manageability, as it did not produce any significant side effect. Finally, a recent study extended to alcoholic patients affected by liver cirrhosis the efficacy and safety of baclofen in increasing abstinence rate.
Conclusions. Should the above preliminary results be confirmed in larger studies, the efficacy of the drug in the management of both alcohol withdrawal syndrome and relapse prevention should entail a vastly simplified pharmacotherapy of alcohol dependence.