Reduction by the Positive Allosteric Modulator of the GABA(B) Receptor, GS39783, of Alcohol Self-Administration in Sardinian Alcohol-Preferring Rats Exposed to the "Sipper" Procedure (original) (raw)
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Alcoholism: Clinical and Experimental Research, 2012
Background-Administration of the GABA B receptor agonist, baclofen, and positive allosteric modulator (PAM), GS39783, has been repeatedly reported to suppress multiple alcohol-related behaviors, including operant oral alcohol self-administration, in rats. The present study was designed to compare the effect of baclofen and GS39783 on alcohol self-administration in three lines of selectively bred, alcohol-preferring rats: Indiana alcohol-preferring (P), Sardinian alcoholpreferring (sP), and Alko Alcohol (AA). Methods-Rats of each line were initially trained to respond on a lever, on a fixed ratio (FR) 4 (FR4) schedule of reinforcement, to orally self-administer alcohol (15%, v/v) in daily 30-min sessions. Once responding reached stable levels, rats were exposed to a sequence of experiments testing baclofen (0, 1, 1.7, and 3 mg/kg; i.p.) and GS39783 (0, 25, 50, and 100 mg/kg; i.g.) on FR4 and progressive ratio (PR) schedules of reinforcement. Finally, to assess the specificity of baclofen and GS39783 action, rats were slightly food-deprived and trained to lever-respond for food pellets. Results-The rank of order of the reinforcing and motivational properties of alcohol was: P>sP>AA rats. Under both FR and PR schedules of reinforcement, the rank of order of potency and efficacy of baclofen and GS39783 in suppressing alcohol self-administration was: P>sP>AA rats. Only the highest dose of baclofen reduced lever-responding for food pellets; this effect was common to all three rat lines. Conversely, no dose of GS39783 altered lever-responding for food in any rat line. Conclusions-These results suggest that: (a) the strength of the reinforcing and motivational properties of alcohol differ among P, sP, and AA rats; (b) the reinforcing and motivational properties of alcohol in P, sP, and AA rats are differentially sensitive to treatment with baclofen and GS39783; (c) the heterogeneity in sensitivity to baclofen and GS39783 of alcohol selfadministration in P, sP, and AA rats may resemble the differential effectiveness of
GABA(B) receptor agonist only reduces ethanol drinking in light-drinking mice
Pharmacology, biochemistry, and behavior, 2012
Baclofen, a GABA(B) agonist, reduces ethanol intake in animals and humans, but the contrary or no effect was also reported. Our previous study demonstrated that mice characterized as "loss of control over ethanol intake" had different Gabbr1 and Gabbr2 transcription levels, which express, respectively, the GABA(B1) and GABA(B2) subunits in brain areas related to addictive behavior. In the present study, we tested baclofen on ethanol intake in mice exposed to the free-choice paradigm. Sixty adult male Swiss mice, individually housed, had free access to three bottles: ethanol (5% and 10%) and water. The protocol had four phases: acquisition (AC, 10weeks), withdrawal (W, 4cycles during 2weeks of 2day-free-choice and 2day-only-water), reexposure (RE, 2weeks), and adulteration of ethanol solutions with quinine (AD, 2weeks). Then, mice characterized as "loss of control" (A, n=11, preference for ethanol in AC and maintenance of ethanol intake levels in AD), heavy (H, n=...
GABA A receptors modulate ethanol-induced conditioned place preference and taste aversion in mice
Psychopharmacology, 1999
Rationale: GABA A receptor antagonists have been shown to reduce ethanol self-administration and ethanol-induced conditioned taste aversion (CTA) in rats, suggesting a role for the GABA A receptor in modulating ethanol's motivational effects. Objectives: The present experiments examined the effects of the GABA A receptor antagonists, bicuculline and picrotoxin, on the acquisition of ethanol-induced conditioned place preference (CPP) and CTA in male DBA/2J mice. Methods: Mice in the CPP experiments received four pairings of ethanol (2 g/kg) with a distinctive floor stimulus for a 5-min conditioning session (CS+ sessions). During CS+ sessions, mice also received bicuculline (0, 1.0, 3.0, or 5.0 mg/kg) or picrotoxin (2.0 mg/kg) before an injection of ethanol. On intervening days (CS-sessions), the pretreatment injection was always vehicle followed by saline injections that were paired with a different floor type. For the preference test, all mice received saline injections and were placed on a half grid and half hole floor for a 60-min session. For the CTA experiments, mice were adapted to a 2-h per day water restriction regimen followed by five conditioning trials every 48 h. During conditioning trials, subjects received an injection of vehicle, bicuculline (0.5 and 2.0 mg/kg), or picrotoxin (0.75 and 2.5 mg/kg) before injection of 2 g/kg ethanol or saline following 1-h access to a saccharin solution. Results: Both picrotoxin and the lowest dose of bicuculline (1.0 mg/kg) significantly increased the magnitude of CPP relative to vehicle-treated controls. Picrotoxin alone did not produce place conditioning. Ethanol-stimulated locomotor activity was significantly reduced during con-ditioning trials with picrotoxin and the higher doses of bicuculline (3.0 and 5.0 mg/kg). Bicuculline did not alter ethanol-induced CTA; however, picrotoxin dose-dependently increased the magnitude of ethanol-induced CTA. Bicuculline and picrotoxin did not produce CTA when administered alone. Conclusions: Overall, these results suggest that blockade of GABA A receptors with bicuculline and picrotoxin enhances ethanol's motivational effects in the CPP paradigm; however, only picrotoxin enhances ethanol's motivational effects in the CTA paradigm.
Alcoholism: Clinical and Experimental Research, 2005
Background-Allopregnanolone (ALLO) and structurally related endogenous neurosteroids are potent modulators of GABA A receptor function at physiologically relevant concentrations. Accumulating evidence implicates a modulatory role for ALLO in behavioral processes underlying ethanol self-administration, discrimination and reinstatement. The purpose of this study was to evaluate the impact of exogenous neurosteroid challenges with the agonist ALLO and the partial agonist/antagonist epipregnanolone (EPI) on the microarchitecture of ethanol drinking patterns. Methods-Male C57BL/6J mice were initiated to consume an unsweetened 10% v/v ethanol solution (10E) by a saccharin fading procedure during daily 2-hour limited access sessions beginning 1 hour after dark phase onset. Cumulative lick responses were recorded for 10E and water using lickometer circuits. After establishing 10E intake baselines, mice were habituated to vehicle injection (VEH; 20% w/v β-cyclodextrin; i.p.), and then were treated with either VEH or neurosteroid immediately prior to the drinking session. Each mouse received a series of ALLO doses (3.2, 10, 17 and 24 mg/kg) alone and EPI doses (0.15, 1, 3 and 10 mg/kg) alone in a counterbalanced withingroup design. Results-The GABA A receptor positive modulator, ALLO, dose-dependently modulated overall ethanol intake throughout the 2-hr session with the 3.2 mg/kg dose eliciting a significant increase whereas the 24 mg/kg dose produced a significant suppression of ethanol intake versus vehicle pretreatment. ALLO-evoked alterations in intake corresponded with a significant, dose-dependent alterations in bout frequency and inter-bout interval. ALLO also elicited robust, dose-dependent elevations in 10E licks during the initial 5-minutes of access, but subsequently resulted in a dosedependent suppression of 10E licks during session minutes 20-80. In contrast, the partial agonist/ antagonist neurosteroid, EPI, exhibited no influence on any consumption parameter evaluated. Conclusions-The present findings suggest that GABA A receptor-active neurosteroids may modulate the regulatory processes that govern the onset, maintenance, and termination of drinking episodes. The differential influence of ALLO and EPI on ethanol intake patterns may reflect an alteration in GABAergic inhibitory tone that is likely due to each neurosteroid's pharmacological profile at GABA A receptors. Manipulation of endogenous ALLO may prove a useful strategy for diminishing excessive intake and protecting against the loss of regulatory control over drinking.
Oral alcohol self-administration and maintenance of operant behavior in rats
Oral alcohol self-administration and maintenance of operant behavior in rats , 2017
We evaluated the effects of two alcohol induction procedures on food-reinforced lever-pressing in rats. Nine outbreed Wistar rats were assigned to one of three groups. For all subjects a fixed-ratio (FR)11 food-reinforcement schedule was established. The induction group (IG) was exposed to alcohol at increasing concentrations over the course of 10 days up to a final concentration of 10%. The non-induction group (NG) received only the 10% alcohol dose during the same period. The control group (CG) received only water and never had alcohol. After induction, the responses in two groups (IG, NG) were food-reinforced for 10 days with free access to alcohol, followed by 15 days of food reinforcement when water was made available instead of alcohol. The alternating cycle of access to alcohol and water was repeated twice more to complete the experiment. Results were as follows: Rate of reinforcement per minute was lower, body weight increased, sessions duration increased, reduced food intake decreased, and alcohol consumption increased during induction and when ethanol was available. Results are discussed by comparing the behavioral effects of alcohol and water on operant behavior. Resumen En este estudio evaluamos los efectos de dos procedimientos de inducción al alcohol sobre presionar una palanca reforzada por comida en ratas. Nueve ratas Wistar fueron asignadas a uno de tres grupos. Para todos los sujetos se estableció un programa de reforzamiento de razón fija (RF)11 con comida. El grupo inducción (IG) fue expuesto al alcohol en concentraciones crecientes en el transcurso de 10 días hasta llegar a una concentración final de 10%. El grupo sin inducción (NG) recibió directamente la dosis de alcohol al 10% en el mismo periodo. El grupo control (CG) recibió solo agua y nunca alcohol. Posterior a la inducción, las respuestas en los grupos IG y NG fueron reforzadas con comida durante 10 días con libre acceso al alcohol, seguidas por 15 días de reforzamiento con comida cuando el agua estuvo disponible en vez del alcohol. El ciclo alternando el acceso al alcohol y al agua se repitió dos veces más para completar el experimento. Los resultados fueron: la tasa de reforzamiento por minuto fue menor, el peso corporal aumentó, la duración de las sesiones incrementó, la reducción de ingesta de comida fue 1 The reference to the article on the Web is:
Journal of Pharmacology and Experimental Therapeutics, 2011
GABA type A receptors (GABA A -Rs) are potential targets of ethanol. However, there are multiple subtypes of this receptor, and, thus far, individual subunits have not been definitively linked with specific ethanol behavioral actions. Interestingly, though, a chromosomal cluster of four GABA A -R subunit genes, including ␣2 (Gabra2), was associated with human alcoholism (Am J Hum Genet 74:705-714, 2004; Pharmacol Biochem Behav 90:95-104, 2008; J Psychiatr Res 42: 184 -191, 2008). The goal of our study was to determine the role of receptors containing this subunit in alcohol action. We designed an ␣2 subunit with serine 270 to histidine and leucine 277 to alanine mutations that was insensitive to potentiation by ethanol yet retained normal GABA sensitivity in a recombinant expression system. Knockin mice containing this mutant subunit were tested in a range of ethanol behavioral tests. These mutant mice did not develop the typical conditioned taste aversion in response to ethanol and showed complete loss of the motor stimulant effects of ethanol. Conversely, they also demonstrated changes in ethanol intake and preference in multiple tests. The knockin mice showed increased ethanolinduced hypnosis but no difference in anxiolytic effects or recovery from acute ethanol-induced motor incoordination. Overall, these studies demonstrate that the effects of ethanol at GABAergic synapses containing the ␣2 subunit are important for specific behavioral effects of ethanol that may be relevant to the genetic linkage of this subunit with human alcoholism.
Neuropharmacology, 2013
GABA type A receptors (GABA A-R) are important for ethanol actions and it is of interest to link individual subunits with specific ethanol behaviors. We studied null mutant mice for six different GABA A-R subunits (a1, a2, a3, a4, a5 and d). Only mice lacking the a2 subunit showed reduction of conditioned taste aversion (CTA) to ethanol. These results are in agreement with data from knock-in mice with mutation of the ethanol-sensitive site in the a2-subunit (Blednov et al., 2011). All together, they indicate that aversive property of ethanol is dependent on ethanol action on a2-containing GABA A-R. Deletion of the a2-subunit led to faster recovery whereas absence of the a3-subunit slowed recovery from ethanol-induced incoordination (rotarod). Deletion of the other four subunits did not affect this behavior. Similar changes in this behavior for the a2 and a3 null mutants were found for flurazepam motor incoordination. However, no differences in recovery were found in motor-incoordinating effects of an a1-selective modulator (zolpidem) or an a4-selective agonist (gaboxadol). Therefore, recovery of rotarod incoordination is under control of two GABA A-R subunits: a2 and a3. For motor activity, a3 null mice demonstrated higher activation by ethanol (1 g/kg) whereas both a2 (À/À) and a3 (À/Y) knockout mice were less sensitive to ethanol-induced reduction of motor activity (1.5 g/kg). These studies demonstrate that the effects of ethanol at GABAergic synapses containing a2 subunit are important for specific behavioral effects of ethanol which may be relevant to the genetic linkage of the a2 subunit with human alcoholism.
Behavioural Brain Research, 2006
Metabotropic glutamate (mGlu) receptors have been shown to mediate a number of behaviors including emotionality and responsivity to stress as demonstrated by efficacy in preclinical and clinical studies. The objective of this study was to assess the effects of the mGlu2/3 receptor agonist LY404039 (LY) on operant ethanol (EtOH) self-administration during alcohol seeking (pavlovian spontaneous recovery, PSR), alcohol relapse (alcohol deprivation effect, ADE), and maintenance responding for alcohol. Adult alcohol-preferring (P) rats were trained in 2-lever operant chambers to self-administer 15% EtOH (v/v) and water on a concurrent fixed-ratio 5-fixed-ratio 1 (FR5-FR1) schedule of reinforcement in daily 1h sessions. After at least 10 weeks of daily 1 h sessions, rats underwent seven extinction sessions, followed by 2 weeks of no manipulation, and then rats were tested for the expression of an EtOH PSR for four sessions. Rats were then given a week in their home cage before being returned to the operant chambers with access to EtOH and water (alcohol relapse). Finally, the effects of LY upon maintenance EtOH and water responding were assessed once stable responding was reestablished. The mGlu2/3 receptor agonist LY404039 reduced responding on the EtOH in the PSR test. LY also reduced the expression of an alcohol deprivation effect (ADE) during relapse, but did not reduce EtOH responding under maintenance conditions. The results of this study demonstrate that activating mGlu2/3 receptors inhibits the expression of alcohol seeking and relapse behavior without altering alcohol self-administration behavior.
European Journal of Pharmacology, 1999
. Male Wistar rats were trained to respond for ethanol 30 minrday in an oral self-administration procedure. A single lever press resulted in presentation of 0.1 ml of 8% ethanol from a liquid dipper. When responding for ethanol stabilised, reinstatement sessions started. In the 30-min reinstatement session, lever pressing was first extinguished for 20 min by switching the dipper off. Then, different Ž . kinds of stimuli were non-contingently delivered and reinstatement of lever pressing was assessed. Fifteen random random time s 15 s presentations of the dipper containing 8% ethanol potently reinstated ethanol-seeking. The reinstatement of lever pressing was immediate and most responses were emitted during the time needed for the first five presentations to occur. Presentations of the empty dipper or Ž . delivery of a non-specific stimulus high-amplitude tone did not produce any reinstatement. These results indicate that non-contingent presentations of the ethanol-associated stimulus complex may reinstate operant behaviour previously reinforced with ethanol. q 1999 Elsevier Science B.V. All rights reserved.
Reinstatement of ethanol-seeking behavior following intravenous self-administration in Wistar rats
Alcoholism, clinical and experimental research, 2007
Background: In animal models of alcoholism, subjects are traditionally trained to self-administer ethanol via the oral route. However, ethanol is also self-administered intravenously (IV), a paradigm which offers several advantages over oral self-administration methods, including immediate delivery to the bloodstream, more rapid onset of pharmacological effects, and elimination of the need to utilize tastants or sweeteners to mask the aversive orosensory properties of ethanol. However, no studies to date have examined reinstatement of ethanol-seeking behavior in animals with a history of IV ethanol self-administration.