Irene Lorrai

R(+)-Baclofen, but Not S(-)-Baclofen, Alters Alcohol Self-Administration in Alcohol-Preferring Rats.

Racemic baclofen [(±)-baclofen] has repeatedly been reported to suppress several alcohol-motivated behaviors, including alcohol drinking and alcohol self-administration, in rats and mice. Recent data suggested that baclofen may have bidirectional, stereospecific effects, with the more active enantiomer, R(+)-baclofen, suppressing alcohol intake and the less active enantiomer, S(−)-baclofen, stimulating alcohol intake in mice. The present study was designed to investigate whether this enantioselectivity of baclofen effects may also extend to the reinforcing properties of alcohol in rats. To this end, selectively bred Sardinian alcohol-preferring (sP) rats were initially trained to lever respond on a fixed ratio 4 (FR4) schedule of reinforcement for alcohol (15%, v/v) in daily 30-min sessions. Once responding had stabilized, rats were tested with vehicle, (±)-baclofen (3 mg/kg), R(+)-baclofen (0.75, 1.5, and 3 mg/kg), and S(−)-baclofen (6, 12, and 24 mg/kg) under the FR4 schedule of reinforcement. Treatment with 3 mg/kg (±)-baclofen reduced the number of lever responses for alcohol and estimated amount of self-administered alcohol by approximately 60% in comparison to vehicle treatment. R(+)-baclofen was approximately twice as active as (±)-baclofen: treatment with 1.5 mg/kg R(+)-baclofen decreased both variables to an extent similar to that of the decreasing effect of 3 mg/kg (±)-baclofen. Conversely, treatment with all doses of S(−)-baclofen failed to affect alcohol self administration. These results (a) confirm that non-sedative doses of (±)-baclofen effectively suppressed the reinforcing properties of alcohol in sP rats and (b) apparently do not extend to operant alcohol self-administration in sP rats the capability of S(−)-baclofen to stimulate alcohol drinking in mice.

Microinjection of baclofen and CGP7930 into the ventral tegmental area suppresses alcohol self-administration in alcohol-preferring rats

ABSTRACT Systemic administration of the orthosteric agonist, baclofen, and several positive allosteric modulators (PAMs) of the GABAB receptor has repeatedly been reported to decrease operant oral alcohol self‐administration in rats. The aim of the present study was to evaluate the contribution of the mesolimbic dopamine system to the reducing effect of baclofen and GABAB PAMs on the reinforcing properties of alcohol. To this end, baclofen or the GABAB PAM CGP7930 were microinjected into the ventral tegmental area (VTA) of selectively bred, Sardinian alcohol‐preferring (sP) rats trained to self‐administer alcohol. Baclofen (0, 0.03, 0.1, and 0.3&mgr;g) or CGP7930 (0, 5, 10, and 20&mgr;g) were microinjected via indwelling unilateral guide cannula aiming at the left hemisphere of the VTA. Treatment with baclofen resulted in a dose‐related suppression of the number of lever‐responses for alcohol and the amount of self‐administered alcohol. No dose of baclofen altered rat motor‐performance, evaluated by the inverted screen test immediately before the self‐administration session. Treatment with CGP7930 halved the number of lever‐responses for alcohol and amount of self‐administered alcohol, with no effect on rat motor‐performance. Site‐specificity was investigated testing the effect of microinjection of baclofen and CGP7930 into the left hemisphere of deep mesencephalic nucleus: compared to vehicle, neither 0.3&mgr;g baclofen nor 20&mgr;g CGP7930 altered lever‐responding for alcohol and amount of self‐administered alcohol. Collectively, the results of the present study suggest the involvement of GABAB receptors located in the VTA in the mediation of alcohol reinforcing properties in sP rats. This article is part of the “Special Issue Dedicated to Norman G. Bowery”. HIGHLIGHTSGABAB receptor is involved in the mediation of several alcohol‐related behaviors.Systemic baclofen and CGP7930 reduced alcohol self‐administration in rats.Intra‐VTA microinjection of baclofen suppressed alcohol self‐administration in rats.Intra‐VTA microinjection of CGP7930 reduced alcohol self‐administration in rats.VTA GABAB receptors contribute to the mediation of alcohol reinforcement in rats.

Reducing effect of saikosaponin A, an active ingredient of Bupleurum falcatum, on alcohol self-administration in rats: Possible involvement of the GABAB receptor.

Recent studies demonstrated that treatment with saikosaponin A (SSA) - an active ingredient of the medicinal herb, Bupleurum falcatum L. - selectively suppressed, likely via a GABAB receptor-mediated mechanism, intravenous self-administration of morphine and cocaine in rats [Yoon et al., 2012; 2013]. The present study was designed to investigate whether the capacity of SSA to suppress morphine and cocaine self-administration extends to oral alcohol self-administration. To this end, selectively bred Sardinian alcohol-preferring (sP) rats were trained to lever-respond on a Fixed Ratio (FR) 4 (FR4) schedule of reinforcement for alcohol (15%, v/v) in daily 30-min sessions. Once responding had stabilized, rats were tested under the FR4 (measure of alcohol reinforcing properties) and Progressive Ratio (PR; measure of alcohol motivational properties) schedules of reinforcement. The possible involvement of the GABAB receptor system was investigated testing the effect of (a) pretreatment with the GABAB receptor antagonist, SCH50911, and (b) combined treatment with the positive allosteric modulator of the GABAB receptor, GS39783. Treatment with SSA (0, 0.25, 0.5, and 1mg/kg, i.p.) markedly reduced lever-responding for alcohol, amount of self-administered alcohol, and breakpoint for alcohol (defined as the lowest response requirement not achieved in the PR experiment). Pretreatment with 2mg/kg SCH50911 (i.p.) resulted in a partial blockade of the reducing effect of 0.5mg/kg SSA on lever-responding for alcohol and amount of self-administered alcohol. Combination of per se ineffective doses of GS39783 (5mg/kg, i.g.) and SSA (0.1mg/kg, i.p.) reduced lever-responding for alcohol and amount of self-administered alcohol. These results (a) extend to alcohol self-administration the capacity of SSA to suppress morphine and cocaine self-administration in rats and (b) suggest that the GABAB receptor system is likely part of the neural substrate underlying the reducing effect of SSA on alcohol self-administration.

Suppressing effect of saikosaponin A, an active ingredient of Bupleurum falcatum, on chocolate self-administration and reinstatement of chocolate seeking in rats

Recent lines of experimental evidence have indicated that saikosaponin A (SSA) - a bioactive ingredient of the medicinal plant, Bupleurum falcatum L. - suppressed alcohol, morphine, and cocaine self-administration in rats. The present paper was designed to assess whether the protective properties of SSA on addiction-related behaviors generalize to a hyperpalatable food such as a chocolate-flavored beverage (CFB). To this end, rats were initially trained to lever-respond for CFB [5% (w/v) Nesquik® powder in water] under fixed ratio (FR) 10 (FR10) schedule of reinforcement. Once lever-responding reached stable levels, rats were treated acutely with two different dose ranges of SSA (0, 0.25, 0.5, and 1mg/kg; 0, 1, 2.5, and 5mg/kg; i.p.) and exposed to the FR10 and progressive ratio (PR) schedules of reinforcement in four independent experiments. The effect of acutely administered SSA (0, 0.25, 0.5, and 1mg/kg; i.p.) on cue-induced reinstatement of seeking behavior for CFB was also assessed. Under the FR and PR schedules of reinforcement, treatment with SSA diminished lever-responding for CFB, amount of self-administered CFB, and breakpoint for CFB. All variables were virtually completely suppressed after treatment with 5mg/kg SSA. Treatment with SSA also suppressed reinstatement of CFB-seeking behavior. No dose of SSA altered rat motor-performance, evaluated exposing all rats to an inverted screen test immediately after the self-administration session. These results demonstrate that acute treatment with SSA potently suppressed several addictive-like behaviors motivated by highly hedonic nourishment. These data extend to a highly rewarding natural stimulus the anti-addictive properties of SSA recently disclosed in rats self-administering alcohol, morphine, and cocaine.

A Phaseolus vulgaris Extract Reduces Cue-Induced Reinstatement of Chocolate Seeking in Rats

Previous evidence has suggested that treatment with a standardized dry extract of Phaseolus vulgaris reduced intake and operant self-administration of highly palatable foods and fluids in rats and mice. The present study was designed to assess whether such extract was also effective in reducing seeking behavior for a highly hedonic chocolate-flavored beverage, using a “reinstatement” procedure adopted from the drug addiction research field and modeling relapse behavior. Rats were initially trained to lever-respond for the chocolate-flavored beverage under the Fixed Ratio (FR) 10 schedule of reinforcement. Subsequently, rats were exposed to an extinction responding phase, during which lever-responding – being unreinforced – diminished progressively up to extinction. Lever-responding was then powerfully reinstated by the non-contingent presentation of a complex of gustatory, olfactory, auditory, and visual stimuli previously associated to the availability of the chocolate-flavored beverage. Acute, intragastric administration of P. vulgaris dry extract (100 and 500 mg/kg) reduced lever-responding by 40–45%, in comparison to vehicle condition. These results indicate the ability of P. vulgaris dry extract to reduce seeking behavior for a highly palatable nourishment in an experimental model of relapse into disordered eating of palatable foods. The unavailability of the chocolate-flavored beverage in the reinstatement session tends to exclude that the observed effect of the P. vulgaris dry extract was secondary to any inhibition of carbohydrate metabolism; conversely, it is the likely consequence on a central action on the rewarding and hedonic properties of food.