Alessandro Capra

Comparison of the effect of the GABAΒ receptor agonist, baclofen, and the positive allosteric modulator of the GABAB receptor, GS39783, on alcohol self-administration in 3 different lines of alcohol-preferring rats.

BACKGROUNDnAdministration of the GABA(B) receptor agonist, baclofen, and positive allosteric modulator, GS39783, has been repeatedly reported to suppress multiple alcohol-related behaviors, including operant oral alcohol self-administration, in rats. This study was designed to compare the effect of baclofen and GS39783 on alcohol self-administration in 3 lines of selectively bred, alcohol-preferring rats: Indiana alcohol-preferring (P), Sardinian alcohol-preferring (sP), and Alko Alcohol (AA).nnnMETHODSnRats 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-minute sessions. Once responding reached stable levels, rats were exposed to a sequence of experiments testing baclofen (0, 1, 1.7, and 3xa0mg/kg; i.p.) and GS39783 (0, 25, 50, and 100xa0mg/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.nnnRESULTSnThe 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 3 rat lines. Conversely, no dose of GS39783 altered lever-responding for food in any rat line.nnnCONCLUSIONSnThese results suggest that: (i) the strength of the reinforcing and motivational properties of alcohol differ among P, sP, and AA rats; (ii) the reinforcing and motivational properties of alcohol in P, sP, and AA rats are differentially sensitive to treatment with baclofen and GS39783; (iii) the heterogeneity in sensitivity to baclofen and GS39783 of alcohol self-administration in P, sP, and AA rats may resemble the differential effectiveness of pharmacotherapies among the different typologies of human alcoholics; and (iv) the GABA(B) receptor is part of the neural substrate mediating the reinforcing and motivational properties of alcohol.

Enhancement of shortening velocity, power, and acto-myosin crossbridge (CB) kinetics following long-term treatment with propionyl-L-carnitine, coenzyme Q10, and omega-3 fatty acids in BIO TO-2 cardiomyopathic Syrian hamsters papillary muscle.

Impaired functions of myocardial muscle cells in human and animals, is a primary defect associated with idiopathic dilated cardiomyopathy (DCM). The pathophysiological mechanisms implicated in the DCM are yet to be clarified and an effective therapy is still not available. The BIO TO‐2 cardiomyopathic Syrian Hamsters (CMSHs) represent an animal model of idiopathic DCM. The aim of this study was to investigate the effect of long‐term treatment (2 months) with propionyl‐L‐carnitine (PLC), coenzyme Q10, omega‐3 fatty acids and a combination of these three agents (formulation HS12607) on mechanical properties and acto‐myosin crossbridges (CBs) kinetics of left ventricular (LV) papillary muscle from control and treated 10 month old BIO TO‐2 CMSHs. Isometric and isotonic contractile properties of isolated papillary muscle from control and treated CMSHs were investigated, and acto‐myosin CB number, force and kinetics were calculated using Huxleys equations. Mechanical parameter values were higher in treated than in control hamsters, particularly when substances were administered together in a coformulation (HS12607). Compared to control, HS12607‐treated papillary muscles showed a significant increase of maximum peak isometric tension (Po) (30.06 ± 4.91 vs. 19.74 ± 5.00 mN/mm2), maximum extent of muscle shortening (0.13 ± 0.03 vs. 0.07 ± 0.02 L/Lmax), maximum unloaded shortening velocity (1.18 ± 0.24 vs. 0.53 ± 0.13 L/Lmax s−1) and maximum peak of power output (5.52 ± 1.61 vs. 1.58 ± 0.83). The curvature of the hyperbolic force‐velocity relationships did not differ between control and treated hamsters. When compared to controls, acto‐myosin CB number increased in treated hamsters [(6.67 ± 1.91) 1010/mm2 vs. (3.55 ± 2.08) 1010/mm2], whereas the unitary force of single CB was similar in control and treated animals. The peak value of the rate constant for CB attachment (f1) and detachment (g2) was higher in treated animals when compared to control. (93.87 ± 25.82 vs.47.28 ± 10.88 s−1 and 214.40 ± 44.64 vs. 95.56 ± 23.49 s−1, respectively). In conclusion, the present study illustrates that supplementation with PLC, CoQ10 and omega‐3 fatty acids improved motor parameters, energetic, and CB kinetics of BIO TO‐2 CMSH papillary muscle indicating that these naturally occurring substances may be a valid adjuvant to conventional therapy in DCM.

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.

Elevated reinforcing and motivational properties of alcohol at the end of the nocturnal period in sP rats

RationaleSardinian alcohol-preferring (sP) rats displayed high sensitivity to time schedule and consumed intoxicating amounts of alcohol during the last portion of the dark phase of the light/dark cycle when exposed to daily drinking sessions of 1xa0h, with concurrent availability of multiple alcohol concentrations and unpredictability of time of alcohol access.ObjectivesThe present study investigated whether sensitivity of sP rats to time schedule extended to operant procedures of alcohol self-administration.MethodsIn experiment 1, three different alcohol solutions (10, 20, and 30xa0%, v/v) were concurrently available under a fixed ratio 4 schedule of reinforcement and with unpredictable time schedule; water was available uncontingently. Experiments 2 and 3 assessed the sensitivity of the motivational properties of alcohol to time schedule; rats were exposed to (a) self-administration sessions under the progressive ratio (PR) schedule of reinforcement and (b) sessions of alcohol seeking under the extinction responding (ER) schedule.ResultsIn experiment 1, number of lever responses and amount of self-administered alcohol were positively correlated with time of alcohol access during the dark phase. When the self-administration session occurred at the first and latest hours of the dark phase, the amount of self-administered alcohol averaged 0.95–1.0 and 1.55–1.65xa0g/kg, respectively. In experiments 2 and 3, values of breakpoint and ER for alcohol were approximately 50xa0% higher when the sessions occurred at the last than first hour of the dark phase.ConclusionsThe reinforcing and motivational properties of alcohol were sensitive to time schedule and stronger at the end of the dark phase.