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Suppressing Effect of the Cannabinoid CB1 Receptor Antagonist, Rimonabant, on Alcohol Self-Administration in Alcohol-Preferring

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Suppressing Effect of the Cannabinoid CB1 Receptor Antagonist, Rimonabant, on Alcohol Self-Administration in Alcohol-Preferring 40 The Open Neuropsychopharmacology Journal, 2009, 2, 40-44 Open Access Suppressing Effect of the Cannabinoid CB1 Receptor Antagonist, Rimonabant, on Alcohol Self-Administration in Alcohol-Preferring Rats Paola Maccioni, Noemi Fantini, Mauro A.M. Carai, Gian Luigi Gessa and Giancarlo Colombo* C.N.R. Institute of Neuroscience, Viale Diaz 182, I-09126 Cagliari (CA), Italy Abstract: Administration of the cannabinoid CB1 receptor antagonist, rimonabant (also known as SR 141716), has been reported to reduce alcohol intake (measured under the homecage 2-bottle “alcohol vs water” choice regimen) in selectively bred, Sardinian alcohol-preferring (sP) rats. The present study investigated whether rimonabant also had the capacity to decrease, in this rat line, alcohol’s reinforcing properties. To this end, male sP rats were initially trained to lever-press (on a fixed ratio 4 schedule of reinforcement) to orally self-administer alcohol (15%, v/v) in daily 30-min sessions. Once lever-pressing and self-administration behaviors reached stable levels (150-200 responses/session and 0.8- 1 g/kg alcohol per session, respectively), the effect of rimonabant (0, 0.3, 1, and 3 mg/kg, i.p.) on responding for alcohol and amount of self-administered alcohol was determined. Pretreatment with rimonabant resulted in a significant, dose- dependent reduction in both variables; specifically, the total number of lever responses for alcohol and amount of self- administered alcohol in the rat groups treated with 0.3, 1, and 3 mg/kg rimonabant were approximately 20%, 35%, and 60% lower than those recorded in vehicle-treated rats. Pretreatment with 3 mg/kg rimonabant also resulted in a significant increase in the latency to the first response on the “alcohol” lever. These results demonstrate the capacity of rimonabant to suppress alcohol’s reinforcing properties in alcohol-preferring sP rats. These data constitute a further piece of experimental evidence in support of the hypothesized role for the CB1 receptor in the control of alcohol drinking and reinforcement. INTRODUCTION The present study has been designed to provide a further piece of evidence to the “anti-alcohol” profile of rimonabant: Acute and repeated administration of the prototypic its capacity of suppressing operant, oral alcohol self- cannabinoid CB receptor antagonist, rimonabant (also 1 administration in Sardinian alcohol-preferring (sP) rats, one known as SR 141716), has been repeatedly reported to of the few rat lines selectively bred worldwide for excessive suppress alcohol seeking and drinking behaviors in rats and alcohol preference and consumption [see 31]. When tested mice exposed to multiple experimental procedures. under standard operant procedures of alcohol self- Specifically, treatment with rimonabant produced dose- administration, sP rats display a robust lever-pressing dependent reductions in: (a) acquisition [1-5] and behavior (e.g., 150-200 responses under the fixed ratio (FR) maintenance [5-15; see however also 13] of alcohol drinking 4 schedule of reinforcement in daily 30-min sessions) and under the homecage 2-bottle “alcohol vs water” choice self-administer pharmacologically revelant amounts of regimen in rats and mice; (b) “alcohol deprivation effect”, alcohol (0.8 g/kg/session) [e.g.: 32], suggesting that, in defined as the temporary increase in alcohol intake or these rats, alcohol functions as a reinforcer and has strong alcohol self-administration occurring after a period of forced incentive motivational capacities in directing lever-pressing abstinence from alcohol and validated as experimental model behavior. of alcohol relapse episodes, in rats [5, 14, 15]; (c) alcohol’s reinforcing properties, measured in rats exposed to Extension of the above-mentioned operant studies with conventional procedures of operant, oral alcohol self- rimonabant to sP rats is of interest since alcohol-preferring administration [16-23; see however also 24]; (d) alcohol’s rat lines – although selectively bred for the same phenotype motivational properties, measured by the progressive ratio (i.e., high alcohol preference and consumption under the schedule of responding [19, 25] and the extinction homecage 2-bottle “alcohol vs water” choice regimen) – responding procedure [26] in rats; (e) reinstatement of differ in a number of alcohol-related traits, including alcohol seeking behavior, triggered by injection of nicotine sensitivity of their alcohol drinking and seeking behavior to or exposure to cues previously associated to alcohol pharmacological manipulations [see 31], making these rat availability (another validated experimental models of alcohol lines potential animal models of the proposed different types, relapse episodes) in rats [15, 17, 19, 20]. Notably, most of or typologies, of alcoholism (in which pharmacotherapies these results have been replicated with other in vivo effective have often been observed to be differentially effective [e.g.: cannabinoid CB1 receptor antagonists, including surinabant 33]). [27-29], AM251 [30], and LH-21 [21]. MATERIALS AND METHODOLOGY All experimental procedures employed in the present *Address correspondence to this author at the C.N.R. Institute of study were in accordance with the Italian Law on the Neuroscience, Viale Diaz 182, I-09126 Cagliari (CA), Italy; Tel: +39 070 “Protection of animals used for experimental and other 302227; Fax: +39 070 302076; E-mail: [email protected] 1876-5238/09 2009 Bentham Open Rimonabant and Alcohol Self-Administration The Open Neuropsychopharmacology Journal, 2009, Volume 2 41 scientific reasons”, which fully incorporates Directive solution was presented at the final concentration of 15% 86/609/EEC of the European Union Legislation. (v/v). Rats were then exposed to 4 consecutive sessions during which the “water” lever or the “alcohol” lever alone Animals was available every other day; water and alcohol were Male sP rats, from the 69th generation and 75-days-old at available on FR1 and FR4, respectively. From then onwards, the start of the study, were used. Rat body weight averaged both levers were concomitantly available (maintenance 290 ± 7 g and 530 ± 10 g at the start and at the end of the phase); these sessions were conducted with FR4 and FR1 on study, respectively. Rats were housed four per cage in the “alcohol” and “water” lever, respectively. standard plastic cages with wood chip bedding. The animal After approximately 20 self-administration sessions of facility was under an inverted 12:12 hour light-dark cycle the maintenance phase, rats were selected for inclusion in the (lights on at 7:00 p.m.), at a constant temperature of 22±2°C rimonabant experiment. Specifically, the 12 rats displaying and relative humidity of approximately 60%. Rats were the most stable responding behavior over the last 5 daily extensively habituated to handling and intraperitoneal sessions (less than 10% daily difference) were selected. Test injections. Food pellets (Harlan, San Pietro al Natisone, sessions were conducted on Fridays; four consecutive Italy) and water were always available in the homecage, (Monday-Thursday) baseline (no drug treatment) sessions except as noted. elapsed between test sessions. All doses of rimonabant were Apparatus tested in each rat under a latin-square design. Notably, after each test session alcohol self-administration immediately Self-administration sessions were conducted in modular recovered to baseline levels. Rimonabant (Sanofi-Aventis, chambers (Med Associates, St. Albans, VT, USA) located in Montpellier, France) was suspended in 2 ml/kg saline with a sound-attenuated cubicles, with fans for ventilation and few drops of Tween 80, and administered intraperitoneally – background white noise. The front panel of each chamber at the doses of 0, 0.3, 1, and 3 mg/kg – 30 min before the was equipped with (a) two retractable response levers, (b) start of the session. one dual-cup liquid receptacle positioned between the two levers, and (c) two stimulus lights (one green and one white) Measured Variables and Data Analysis mounted above each lever. The liquid receptacle was Measured variables were: total number of responses on connected by polyethylene tubes to two syringe pumps each lever; total amount of self-administered alcohol and located outside the chamber. A white house light was water (expressed in g/kg pure alcohol and ml/kg water, centered at the top of the back wall of each chamber. For half respectively, and determined from the total number of of the rats, the right lever was associated to alcohol, and reinforcers); latency (expressed in s) to the first response on achievement of response requirement (a) activated the the “alcohol” lever. “alcohol” pump, resulting in the delivery of 0.1 ml alcohol solution, and (b) switched on the green light for the 2-s Data on the effect of rimonabant on each variable were period of alcohol delivery; for these rats, the left lever was statistically analyzed by separate 1-way ANOVAs for associated to water, and achievement of the response repeated measures, followed by the Newman-Keuls test for requirement (a) activated the “water” pump, resulting in the post hoc comparisons. delivery of 0.1 ml water, and (b) switched on the white light RESULTS for the 2-s period of water delivery. For the other half of the rats, the opposite condition applied (left lever: alcohol During the 20-day maintenance phase, the 12 rats solution; right lever: water). subsequently selected for the rimonabant experiment displayed an average number of total responses for alcohol Experimental Procedure of 165 per session; the resulting average of the amount of Rats (n=16) were initially exposed to the homecage 2- self-administered alcohol was of 0.92 g/kg per session. bottle “alcohol (10%, v/v) vs water” choice regimen with Conversely, a negligible number of total responses for water unlimited access for 24 hours/day for 10 consecutive days. (averaging <2 per session) was recorded during the entire This initial phase was conducted to allow the rats to become maintenance phase as well as in vehicle-treated rats in the accustomed to the taste of alcohol and start to experience its subsequent test sessions.
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