ESBRA 2009 ABSTRACTS - Symposium 11
INTRA-VTA INFUSION OF THE POSITIVE ALLOSTERIC MODULATORS OF THE
GABAB RECEPTOR MODULATES ACCUMBAL DOPAMINE DURING ALCOHOL
SEEKING BEHAVIOR IN RATS
Kimberly A. Leite-Morris, Heddy B. Kerrestes Boston University School of Medicine & VA Boston Healthcare System, Boston, MA, USA
The motivational behaviors that precede ethanol drinking namely seeking or "craving" are perhaps mediated by dopamine release in the nucleus accumbens. Our current data suggests that intra-ventral tegmental microinjection of baclofen inhibits ethanol seeking in a dose-dependent manner at (0.25, 0.5, 1.0 nmol/side) yet, without specificity. More recent preclinical studies examining intra-gastric administration of the novel GABA-B receptor positive allosteric modulator GS39783 (GS) resulted in a dose-dependent and specific reinforcement of ethanol but not sucrose in Sardinian alcohol-preferring rats. The GABA B receptor agonist although more potent than GS also has some concerning side effects. The object of this preliminary study was to examine the effects of intra-VTA GS compared with baclofen on the motivation for appetitive responding (lever pressing) and examine the corresponding dopamine changes in the nucleus accumbens. Male Long Evans rats were trained to perform a fixed number of lever presses (RR20) that resulted in a daily 20 minute presentation of 2% sucrose or 10% ethanol via a sipper tube. Prior to treatment baseline ethanol intake was 0.7-1.2 g/kg. Rats were surgically implanted with microdialysis and microinjection guides in the NAc and VTA respectively. GS (0,10,20 g/hemisphere) was microinjected into the VTA and during a single extinction session (with no access to the reinforcer solution) brain dialysate was collected from the NAc Core. Samples were collected every 5 minutes and dopamine levels were quantified via high performance liquid chromatography. Intra-VTA administration of GS (10,20 g/hemisphere) versus aCSF resulted in a significant dose-dependent inhibition of lever pressing in ethanol rats which corresponded to a decrease in NAc dopamine. GS produced a significant reduction of dopamine levels that returned to baseline at the time point when the lever (seeking) was presented. These results suggest that activation of VTA GABA (B) receptors via GS may modulate mesoaccumbens circuits that underlie the motivational behaviors of alcohol seeking that eventually leading to ethanol consumption. GABA-B receptor positive allosteric modulators may be distinguished as an efficacious treatment over the full agonist and a greater understanding of their modulation on mesoaccumbens circuits will have an impact on treatment implications for alcohol craving.
REDUCING EFFECT OF THE POSITIVE ALLOSTERIC MODULATORS OF THE
GABAB RECEPTOR ON ALCOHOL INTAKE AND ALCOHOL'S REINFORCING AND
MOTIVATIONAL PROPERTIES IN ALCOHOL-PREFERRING RATS
Giancarlo Colombo1, Paola Maccioni1, Klemens Kaupmann2,Wolfgang Froestl3, Pari Malherbe4, Andrew W. Thomas4,Gian Luigi Gessa1, Mauro A.M. Carai1 1CNR Institute of Neuroscience, Cagliari, Italy, 2Novartis Pharma AG, Basel, Switzerland, 3AC Immune SA, Lausanne, Switzerland,4 Hoffmann-La Roche Ltd, Basel, Switzerland
The present paper summarizes data demonstrating the reducing effect of the presently available in vivo effective positive allosteric modulators of the GABAB receptor (GABAB PAMs) on different alcohol-motivated behaviors. These studies have been conducted testing different procedures of alcohol intake and operant alcohol self-administration in selectively bred Sardinian alcohol-preferring (sP) rats. Acute and repeated administration of the GABAB PAMs, CGP7930, GS39783, BHF177, and rac-BHFF, resulted in the dose-dependent reduction of: (a) acquisition and maintenance of alcohol drinking behavior in sP rats exposed to the standard homecage 2-bottle "alcohol vs water" choice regimen; (b) oral self-administration of alcohol in sP rats trained to lever-press for alcohol on a fixed ratio (FR) 4 (FR4) schedule of reinforcement; (c) the motivational properties of alcohol, measured by the progressive ratio schedule of reinforcement in sP rats previously trained to self-administer alcohol on an FR4 schedule. These effects were specific for alcohol, as the tested GABAB PAMs did not alter, even minimally, food intake or self-administration of an alternative non-drug reinforcer (a sucrose solution). Together, these data (a) replicate those previously collected with the GABAB receptor direct agonist, baclofen, (b) suggest the involvement of the allosteric modulatory binding site of the GABAB receptor in the neural substrate controlling alcohol intake and mediating alcohol's reinforcing and motivational properties in alcohol-preferring rats, and (c) strengthen the hypothesis that the GABAB receptor complex may be the target for novel and potentially effective pharmacotherapies for alcoholism.
ESBRA 2009 ABSTRACTS - Symposium 11
REDUCING EFFECT OF THE POSITIVE ALLOSTERIC MODULATOR OF THE
GABA(B) RECEPTORS ON COCAINE SELF-ADMINISTRATION AND
REINSTATEMENT OF SEEKING BEHAVIOR IN RATS
Malgorzata Filip, Malgorzata Frankowska Institute of Pharmacology Polish Academy of Sciences, Krakow, Poland
Growing evidence suggests that GABA(B) receptor agonists could be promising pharmacotherapies for drug addiction. In fact, baclofen, a GABA(B) receptor agonist licensed as an anti-spastic drug, has yielded positive findings in clinical trials where it reduced cocaine use in heavy cocaine addicts (Shoptaw et al., 2003) and decreased limbic activation during cue-induced cocaine craving (Brebner et al., 2002). The present study investigated the effects of the GABA(B) receptor allosteric positive modulator CGP 7930 in cocaine rewarding and seeking behaviors. Male Wistar rats were trained to self-administer either cocaine (0.5 mg/kg/infusion) or food (sweet milk) under a fixed ratio 5 schedule of reinforcement. Then responding on the reinforcer-paired lever was extinguished. Reinstatement of responding was induced by a noncontingent presentation of the self-administered reinforcer (10 mg/kg cocaine), or a contextual cues previously paired with cocaine self-administration, or contingeous presentation of food. The GABA(B) receptor agonists baclofen and SKF 97541 were used for comparison. CGP 7930 (30-100 mg/kg), baclofen (2.5-5 mg/kg) or SKF 97541 (0.1-0.3 mg/kg) dose-dependently decreased the cocaine-maintained responding, while only the GABA(B) receptor agonists attenuated the food-maintained responding. CGP 7930 (10-30 mg/kg) attenuated responding during both reinstatement conditions without affecting reinstatement of food-taking behavior. Baclofen (1.25-5 mg/kg) and SKF 97541 (0.03-0.3 mg/kg) attenuated cocaine- or food-seeking behavior; the effect of the drugs appeared more effective for cocaine-seeking than reinstatement of food-taking. We found that pharmacological stimulation of GABA(B) receptors by allosteric positive modulation or direct agonists reduces cocaine reinforcement. A dissociation between effects of direct GABA(B) receptor agonists and a GABA(B) allosteric positive modulator on cocaine vs. food-maintained responding was demonstrated. The potent inhibitory responses on cocaine seeking behavior were also seen following the GABA(B) receptor agonist or the allosteric positive modulator, however, doses of baclofen and SKF 97541 that inhibited cocaine-seeking were the same or only threefold lower than those inhibiting food-taking, respectively. In conclusion, the GABA(B) receptor allosteric positive modulator CGP 7930 may hold the promise for attenuating cue-evoked relapses to cocaine and the rewarding properties of cocaine, while the effects of the agonists may have resulted from general decrease in motivation.
BACLOFEN IN THE TREATMENT OF ALCOHOL DEPENDENT SUBJECTS
Giovanni Addolorato1, Lorenzo Leggio1,2, Anna Ferrulli1, Silvia Cardone1, Roberta Agabio3, Otto M. Lesch4, Paul S. Haber5, Giovanni Gasbarrini1 1Catholic University of Rome, Rome, Italy, 2Brown University, Providence, RI, USA, 3University of Cagliari, Cagliari, Italy, 4University of Wien, Wien, Austria, 5University of Sydney, Sydney, Australia
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. 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 compared to placebo 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. 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. However a recent U.S. trial failed to find significant differences between baclofen and placebo in reducing alcohol intake and alcohol craving in alcoholic patients. Possible factors as the different psychological approach and the severity of alcohol dependence of the samples evaluated could account for these contrasting data, related in particular to the different placebo response of the patients. Some case-reports have also suggested that alcohol-dependent with anxiety benefit of higher doses of baclofen in order to reduce and suppress alcohol craving. A recent collaborative study conducted by our labs was designed to possibly address this hypothesis, although the sample size was no reached. Finally, pilot data suggest that future studies may investigate the application of
ESBRA 2009 ABSTRACTS - Symposium 11
subtypes and typologies of alcohol dependence in order to identify possible categories of alcohol dependent subjects better responding to a baclofen treatment.
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