Publications by authors named "Alessandro Orrù"

34 Publications

Repeated exposure to cocaine during adolescence enhances the rewarding threshold for cocaine-conditioned place preference in adulthood.

Addict Biol 2021 Jan 28:e13012. Epub 2021 Jan 28.

Experimental Psychopharmacology, Department of Neuroscience, Mario Negri Institute for Pharmacological Research IRCCS, Italy.

Previous studies have shown that adolescent exposure to cocaine increases drug use in adulthood, albeit incubation of cocaine seeking was found to be attenuated in rats trained to self-administer cocaine during adolescence. We here hypothesize that adolescent exposure to cocaine could alter the rewarding properties of the psychostimulant in adulthood. By employing two of the most widely used animal-experimental-preclinical models to investigate drug addiction, we evaluated whether contingent versus non-contingent cocaine self-administration during adolescence modulates its rewarding threshold in adulthood evaluated by conditioned place preference (CPP). Cocaine self-administration during adolescence increases the rewarding threshold in adulthood; CPP for cocaine was observed at the higher (20 mg/kg), but not at the lower (10 mg/kg), dose employed. Rats exposed to either contingent or non-contingent cocaine during adolescence exhibited the same behavior in the CPP paradigm suggesting that, under our experimental conditions, cocaine rewarding properties are shaped by the psychostimulant itself and not by its motivational effects. From a mechanistic standpoint, the preference for the 20 mg/kg cocaine-paired side in a CPP paradigm appears to depend, at least partially, upon the formation of GluA2-lacking Ca -permeable AMPA receptors and the consequent increase of αCaMKII activity in the NAc, both of which are instead reduced when the 10 mg/kg dose was used. In conclusion, contingent or non-contingent cocaine exposure during adolescence desensitizes adult animals to a rewarding dose of cocaine (10 mg/kg) elevating the rewarding threshold necessary (20 mg/kg) to drive conditioned place preference, an effect that may predispose to higher consumption of cocaine during adulthood.
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http://dx.doi.org/10.1111/adb.13012DOI Listing
January 2021

mGluR2/3 mediates short-term control of nicotine-seeking by acute systemic N-acetylcysteine.

Addict Biol 2018 01 24;23(1):28-40. Epub 2016 Aug 24.

Experimental Psychopharmacology, Department of Neuroscience, IRCCS-Mario Negri Institute for Pharmacological Research, Italy.

Chronic self-administration of nicotine induces maladaptive changes in the cortico-accumbal glutamate (Glu) network. Consequently, re-exposure to nicotine-associated cues raises extracellular Glu in the nucleus accumbens reinstating drug-seeking. Restoring basal concentrations of extracellular Glu, thereby increasing tonic activation of the presynaptic group II metabotropic Glu receptors (mGluR2/3) with N-acetylcysteine (N-AC), might offer a valid therapeutic approach for maintaining smoking abstinence. Although N-AC modulates nicotine-seeking behavior by drug-associated stimuli in abstinent rats, it is still unclear whether it occurs through activation of mGluR2/3. Male Wistar rats were trained to associate discriminative stimuli (S s) with the availability of intravenous nicotine (0.03 mg/kg/65 µl/2-second/infusion) or oral saccharin (100 µl of 50 mg/l) self-administration versus non-reward. Reinforced response was followed by a cue signaling 20-second time-out (CSs). Once the training criterion was met, rats underwent lever press extinction, without reinforcers, S s and CSs. Re-exposure to nicotine or saccharin S /CS , but not non-reward S /CS , revived responding on the previously reinforced lever. Acute N-AC, 100 but not 60 or 30 mg/kg i.p., reduced cue-induced nicotine-seeking. N-AC 100 mg/kg did not modify cue-induced saccharin-seeking behavior or influenced locomotor activity. Blocking mGluR2/3 with the selective antagonist LY341495, 1 mg/kg i.p., completely prevented the antirelapse activity of N-AC. The finding that N-AC prevents cue-induced nicotine-seeking by stimulating mGluR2/3 might indicate a therapeutic opportunity for acute cue-controlled nicotine-seeking. Future studies could evaluate the persistent effects of chronic N-AC in promoting enduring suppression of nicotine-cue conditioned responding.
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http://dx.doi.org/10.1111/adb.12443DOI Listing
January 2018

Contingent and non-contingent recreational-like exposure to ethanol alters BDNF expression and signaling in the cortico-accumbal network differently.

Psychopharmacology (Berl) 2016 Sep 1;233(17):3149-60. Epub 2016 Jul 1.

Experimental Psychopharmacology, Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Via Giuseppe La Masa 19, 20156, Milan, Italy.

Rationale: Although brain-derived neurotrophic factor (BDNF) is part of a homeostatic pathway involved in the development of alcohol dependence, it is not clear whether this is also true after recreational ethanol consumption.

Objectives: We examined BDNF expression and signaling in the cortico-striatal network immediately and 24 h after either a single intravenous (i.v.) ethanol operant self-administration session or the last of 14 sessions.

Methods: To compare contingent and non-contingent ethanol exposure, we incorporated the "yoked control-operant paradigm" in which rats actively taking ethanol (S-Et) were paired with two yoked controls receiving passive infusions of ethanol (Y-Et) or saline.

Results: A single ethanol exposure transiently reduced BDNF mRNA levels in the medial prefrontal cortex (mPFC) of Y-Et. Immediately after the last of 14 sessions, mRNA and mature BDNF protein levels (mBDNF) were reduced in the mPFC in both S-Et and Y-Et while mBDNF expression was raised in the nucleus accumbens (NAc), suggesting enhanced anterograde transport from the mPFC. Conversely, 24 h later mBDNF expression and signaling were raised in the mPFC and NAc of S-Et rats but reduced in the NAc of Y-Et rats, with concomitant reduction of downstream signaling pathways.

Conclusions: Our findings indicate that recreational-like i.v. doses of ethanol promote early changes in neurotrophin expression, depending on the length and modality of administration, the brain region investigated, and the presence of the drug. A rapid intervention targeting the BDNF system might be useful to prevent escalation to alcohol abuse.
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http://dx.doi.org/10.1007/s00213-016-4358-yDOI Listing
September 2016

Withania somnifera (L.) Dunal root extract alleviates formalin-induced nociception in mice: involvement of the opioidergic system.

Behav Pharmacol 2016 Feb;27(1):57-68

aNational Research Council (C.N.R.), Institute of Translational Pharmacology, U.O.S. of Cagliari, Science and Technology Park of Sardinia Polaris, Pula, Italy bDepartment of NVS, Division for Neurogeriatrics Novum, Center for Alzheimer Research, Karolinska Institutet, Huddinge, Sweden.

Withania somnifera (L.) Dunal extracts (WSEs) may possess therapeutic perspectives in the treatment of inflammation and pain. We aimed to evaluate the antinociceptive property of a WSE in the formalin test and to investigate the involvement of several neurotransmitter systems in this effect. The time spent licking the formalin-injected paw was recorded in CD1 mice after pretreatment with increasing doses of WSE. Also, c-Fos spinal cord expression and the effects of different compounds were investigated under these experimental conditions. Finally, the efficacy of WSE was analyzed following an injection of glutamate. WSE reduced the antinociceptive response during the tonic but not the acute phase of the formalin test and decreased formalin-induced c-Fos expression in spinal neurons. These effects were antagonized by the opioid antagonist naltrexone, whereas GABA, cannabinoid, δ-opioid, and nitric oxide compounds were ineffective. The administration of WSE also reduced nociception and c-Fos expression induced by glutamate injection. These results showed that WSE is effective in assays of chemical-induced nociception, indicating that this plant has potential valuable properties for the treatment of specific painful conditions. The antinocicetive effects of WSE in the formalin test appeared to be specifically mediated by the opioidergic system, although the involvement of the glutamatergic system cannot be excluded.
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http://dx.doi.org/10.1097/FBP.0000000000000195DOI Listing
February 2016

Methoxyflavones from Stachys glutinosa with binding affinity to opioid receptors: in silico, in vitro, and in vivo studies.

J Nat Prod 2015 Jan 6;78(1):69-76. Epub 2015 Jan 6.

Institute of Translational Pharmacology, UOS of Cagliari, National Research Council, Parco Scientifico e Tecnologico , Pula, Cagliari, Italy.

Fractionation of the bioactive dichloromethane extract from the aerial parts of Stachys glutinosa led to the isolation of four flavones, xanthomicrol (1), sideritoflavone (2), 8-methoxycirsilineol (3), and eupatilin (4), along with two neo-clerodane diterpenes, roseostachenone (8) and a new compound, 3α,4α-epoxyroseostachenol (7). In order to study structure-activity relationships, two methoxyflavones [5-demethyltangeretin (5) and tangeretin (6)] were synthesized by the methoxylation of xanthomicrol. The isolated compounds (1-4, 7, and 8) as well as the xanthomicrol semisynthetic derivatives (5 and 6) were evaluated for their binding affinity to the μ and δ opioid receptors. Xanthomicrol was the most potent binder to both μ and δ receptors, with a Ki value of 0.83 and 3.6 μM, respectively. Xanthomicrol administered intraperitoneally in mice at a dose of 80 mg/kg significantly reduced morphine-induced antinociception in the tail flick test. Our results suggested that xanthomicrol is a μ opioid receptor antagonist. Docking experiments were carried out to acquire a deeper understanding about important structural aspects of binding of xanthomicrol. In summary, these data suggest that xanthomicrol is a valuable structure for further development into a potential μ opioid receptor antagonist.
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http://dx.doi.org/10.1021/np500671vDOI Listing
January 2015

Prediction and prevention of the first psychotic episode: new directions and opportunities.

Ther Clin Risk Manag 2014 28;10:241-53. Epub 2014 Mar 28.

National Research Council, institute of Translational Pharmacology, Strategic Operating Unit of Cagliari, Cagliari, Italy.

In the last few decades, substantial research has focused on the possibility of early detection and prevention of the first psychotic episode in young individuals at risk of developing this mental disturbance; however, unresolved clinical and ethical issues still call for further investigations. New perspectives and opportunities may come from the identification of selective psychopathological and instrumental markers linking the appearance of subtle psychotic symptoms with the clinical outcome of specific mental pathologies. Furthermore, empirically derived algorithms and risk staging models should facilitate the identification of targeted prevention therapies, possibly improving the efficacy of well-tolerated therapeutic approaches, such as psychological interventions and natural compound supplementations. To date, the collected evidence on the efficacy and tolerability of pharmacological prevention therapies raises more doubts than hopes. A very early detection of risk and appropriate symptomatic pattern classifications may provide a chance to better match prevention strategies with the development of psychosis.
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http://dx.doi.org/10.2147/TCRM.S55770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3974689PMC
June 2014

Differential modulation of GABA(A) receptor function by aryl pyrazoles.

Eur J Pharmacol 2014 Jun 1;733:1-6. Epub 2014 Apr 1.

CNR - Institute of Translational Pharmacology, U.O.S. of Cagliari, Science and Technology Park of Sardinia Polaris, Pula, Italy.

Several aryl pyrazoles characterized by a different molecular structure (flexible vs constrained), but chemically related to rimonabant and AM251, were tested for their ability to modulate the function of recombinant α1β2γ2L GABAA receptors expressed in Xenopus laevis oocytes. The effects of 6Bio-R, 14Bio-R, NESS 0327, GP1a and GP2a (0.3-30 μM) were evaluated using a two-electrode voltage-clamp technique. 6Bio-R and 14Bio-R potentiated GABA-evoked Cl(-) currents. NESS 0327, GP1a and GP2a did not affect the GABAA receptor function, but they acted as antagonists of 6Bio-R. Moreover, NESS 0327 inhibited the potentiation of the GABAA receptor function induced by rimonabant. The benzodiazepine site seems to participate in the action of these compounds. In fact, flumazenil antagonized the potentiation of the GABAA receptor induced by 6Bio-R, and NESS 0327 reduced the action of lorazepam and zolpidem. On the contrary, NESS 0327 did not antagonize the action of "classic" GABAergic modulators (propanol, anesthetics, barbiturates or steroids). In α1β2 receptors 6Bio-R potentiated the GABAergic function, but flumazenil was still able to antagonize the potentiation induced by 6Bio-R. Aryl pyrazole derivatives activity at the GABAA receptor depends on their molecular structure. These compounds bind to both an αβγ binding site, and to an α/β site which do not require the γ subunit and that may provide structural leads for drugs with potential anticonvulsant effects.
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http://dx.doi.org/10.1016/j.ejphar.2014.03.039DOI Listing
June 2014

Withania somnifera root extract prolongs analgesia and suppresses hyperalgesia in mice treated with morphine.

Phytomedicine 2014 Apr 20;21(5):745-52. Epub 2013 Nov 20.

CNR-Institute of Translational Pharmacology, U.O.S. of Cagliari, Science and Technology Park of Sardinia Polaris, Pula, Italy. Electronic address:

Previous studies demonstrated that Withania somnifera Dunal (WS), a safe medicinal plant, prevents the development of tolerance to the analgesic effect of morphine. In the present study, we investigated whether WS extract (WSE) (100 mg/kg, i.p.) may also modulate the analgesic effect induced by acute morphine administration (2.5, 5, 10 mg/kg, s.c.) in the tail-flick and in the hot plate tests, and if it may prevent the development of 2.5 mg/kg morphine-induced rebound hyperalgesia in the low intensity tail-flick test. Further, to characterize the receptor(s) involved in these effects, we studied, by receptor-binding assay, the affinity of WSE for opioid (μ, δ, k), cannabinoid (CB1, CB2), glutamatergic (NMDA), GABAergic (GABAA, GABAB), serotoninergic (5HT2A) and adrenergic (α2) receptors. The results demonstrated that (i) WSE alone failed to alter basal nociceptive threshold in both tests, (ii) WSE pre-treatment significantly protracted the antinociceptive effect induced by 5 and 10 mg/kg of morphine only in tail-flick test, (iii) WSE pre-treatment prevented morphine-induced hyperalgesia in the low intensity tail-flick test, and (iv) WSE exhibited a high affinity for the GABAA and moderate affinity for GABAB, NMDA and δ opioid receptors. WSE prolongs morphine-induced analgesia and suppresses the development of morphine-induced rebound hyperalgesia probably through involvement of GABAA, GABAB, NMDA and δ opioid receptors. This study suggests the therapeutic potential of WSE as a valuable adjuvant agent in opioid-sparing therapies.
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http://dx.doi.org/10.1016/j.phymed.2013.10.021DOI Listing
April 2014

N-Alkyl dien- and trienamides from the roots of Otanthus maritimus with binding affinity for opioid and cannabinoid receptors.

Bioorg Med Chem 2013 Nov 19;21(22):7074-82. Epub 2013 Sep 19.

Institute of Translational Pharmacology, UOS of Cagliari, National Research Council, Parco Scientifico e Tecnologico-Pula, Cagliari, Italy.

Two new thienylheptatrienamides (1, 5) and one new neo-lignan (12), together with thirteen known compounds (2, 3, 4, 6-11, 13-16) were isolated from the roots of Otanthus maritimus. The structures of the new compounds were elucidated on the basis of extensive 1D and 2D NMR experiments as well as high resolution mass spectrometry. All the isolated amides (1-10), the known pontica epoxide (11) and the new neo-lignan (12) were evaluated for their binding affinity to the CB1 and CB2 as well as to the μ and δ opioid receptors. Some alkylamides showed moderately high binding affinity for CB2 receptors and 1-[(2E,4E,8Z)-tetradecatrienoyl]piperidine (10) resulted the most active one with a Ki value of 160 nM. As far as we know, this is the first example of a tertiary alkylamide that binds CB2 receptors with significant potency. Compounds that showed the highest affinity for cannabinoid receptors (6-8, 10) were much less potent against opioid receptors. Primary structure-activity relationship is discussed. Docking experiments were carried out with the aim to understand the key interactions of the most active compounds with CB2 receptor.
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http://dx.doi.org/10.1016/j.bmc.2013.09.017DOI Listing
November 2013

Short-term abstinence from cocaine self-administration, but not passive cocaine infusion, elevates αCaMKII autophosphorylation in the rat nucleus accumbens and medial prefrontal cortex.

Int J Neuropsychopharmacol 2014 Feb 19;17(2):323-9. Epub 2013 Aug 19.

IRCCS - Istituto di Ricerche Farmacologiche 'Mario Negri', Experimental Psychopharmacology, Department of Neuroscience, Via Giuseppe La Masa 19, 20156 Milan, Italy.

Increases in alpha calcium/calmodulin-dependent protein kinase type II (αCaMKII) activity in the nucleus accumbens shell has been proposed as a core component in the motivation to self-administer cocaine and in priming-induced drug-seeking. Since cocaine withdrawal promotes drug-seeking, we hypothesized that abstinence from cocaine self-administration should enhance αCaMKII as well. We found that short-term abstinence from contingent, but not non-contingent, cocaine i.v. self-administration (2 h/d for 14 d; 0.25 mg/0.1 ml, 6 s infusion) elevates αCaMKII autophosphorylation, but not the kinase expression, in a dynamic, time- and brain region-dependent manner. Increased αCaMKII autophosphorylation in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), but not dorsolateral striatum (dlS), was found 24 h, but not immediately, after the last cocaine self-administration session. Notably, in the mPFC, but not NAc and dlS, αCaMKII autophosphorylation was still enhanced 7 d later. The persistent enhancement in the mPFC of abstinent rats may represent a previously unappreciated contribution to initial incubation of cocaine-seeking.
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http://dx.doi.org/10.1017/S1461145713000916DOI Listing
February 2014

Six-month ischemic mice show sensorimotor and cognitive deficits associated with brain atrophy and axonal disorganization.

CNS Neurosci Ther 2013 Sep 7;19(9):695-704. Epub 2013 Jun 7.

IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Department of Neuroscience, Milan, Italy.

Aims: To identify long-term sensorimotor and cognitive deficits and to evaluate structural alterations in brain ischemic mice.

Methods: C57Bl/6J male mice were subjected to 30 min transient middle cerebral artery occlusion (tMCAo) or sham surgery. Sensorimotor deficits, exploratory behavior, and cognitive functions were evaluated up to 6 months. Cortical and subcortical damage were analyzed by MRI multiparameter analysis and histopathology.

Results: tMCAo mice showed significant sensorimotor deficits in the rotarod, negative geotaxis, neuroscore, and beam walk tests. They also showed impairment in exploratory behavior in the open field test and in spatial learning in the Morris water maze. T2-weighted MRI revealed a volume reduction in injured brain areas at 12 and 24 weeks postinjury. Brain atrophy was shown by MRI and conventional postmortem analysis. Diffusion tensor imaging on the external capsule showed increased values of axial and radial diffusivity. Fiber tracking revealed a reduction in the number and length of ipsilateral fibers.

Conclusions: tMCAo in mice induces sensorimotor and cognitive impairments detectable at least up to 6 months postinjury, associated with brain atrophy, and axonal and myelin damage of the external capsule. These behavioral tests and anatomical investigations may represent important tools in translational studies in cerebral ischemia.
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http://dx.doi.org/10.1111/cns.12128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6493425PMC
September 2013

Inhibition of glycine transporter-1 reduces cue-induced nicotine-seeking, but does not promote extinction of conditioned nicotine cue responding in the rat.

Addict Biol 2013 Sep 14;18(5):800-11. Epub 2013 Mar 14.

IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.

Pharmacological stimulation of N-methyl-D-aspartate receptors (NMDAr) could enhance the outcome of cue-exposure therapy for smoking cessation. NMDAr stimulation can be achieved by increasing pharmacologically the synaptic levels of glycine, a necessary co-agonist. Here, we evaluate the effects of SSR504734, a selective inhibitor of glycine type I transporter (GlyT1) in an extinction-reinstatement procedure inducing robust and lasting nicotine-seeking behavior in rats. Male Wistar rats were trained to associate discriminative stimuli (S(D)s) with the availability of nicotine (0.03 mg/kg/65 μL/2 second/infusion) or sucrose (45-mg pellet) versus non-reward in two-lever operant cages. Reinforced response was followed by cue signaling 20-second time-out (CSs). Once the training criterion was met, rats underwent extinction of lever presses, in the absence of reinforcers, S(D) s and CSs. Re-exposure to nicotine or sucrose S(D+)/CS(+), but not non-reward S(D-)/CS(-), revived responding at the previously reinforced lever. Acute pre-treatment with SSR504734 (10 mg/kg i.p.) reduced nicotine-seeking but not sucrose-seeking behavior without influencing rats' locomotor activity. Sub-chronic treatment (10 mg/kg i.p. for 5 days) during daily exposure to S(D+)/CS(+) reduced nicotine-seeking; however, this effect was transient, with return to S(D+)/CS(+) responding at 72 hours. Full recovery to S(D+)/CS(+) responding was observed after 1 month suggesting that SSR504734 sub-acute treatment did not engage the long-term plasticity mechanisms probably involved in nicotine-seeking. In conclusion, GlyT1-inhibitors might offer a therapeutic opportunity for acute cue-controlled nicotine-seeking, but the lack of persistent effects of the sub-chronic treatment associated with nicotine cues exposure suggests that short-term administration of GlyT1-inhibitor SSR504734 is not sufficient to promote extinction of nicotine-cue conditioned responding.
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http://dx.doi.org/10.1111/adb.12049DOI Listing
September 2013

Withania somnifera prevents acquisition and expression of morphine-elicited conditioned place preference.

Behav Pharmacol 2013 Apr;24(2):133-43

Institute of Translational Pharmacology, UOS of Cagliari, National Research Council, Scientific and Technological Park of Sardinia - Polaris, Pula, Italy.

Previous studies have reported that some of the central effects of morphine are counteracted by the administration of the methanolic extract of the root of Indian ginseng, Withania somnifera Dunal (WSE). The present study sought to determine whether WSE affects acquisition and expression of morphine-elicited conditioned place preference (CPP) in CD-1 mice. In CPP acquisition experiments, WSE (0, 25, 50, and 100 mg/kg) was administered, during conditioning, 30 min before morphine (10 mg/kg), whereas in expression experiments, WSE (0, 25, 50, and 100 mg/kg) was administered 30 min before the postconditioning test. The results demonstrate (i) that WSE was devoid of motivational properties; (ii) that WSE (100 mg/kg) was devoid of effects on spontaneous and morphine-stimulated motor activity and on spatial memory; and (iii) that WSE (50 and 100 mg/kg) significantly prevented the acquisition and expression of CPP. Further, to characterize the receptor(s) involved in these effects, we studied, by receptor-binding assay, the affinity of WSE for µ-opioid and γ-aminobutyric acid B receptors. These experiments revealed a higher affinity of WSE for γ-aminobutyric acid B than for µ-opioid receptors. Overall, these results point to WSE as an interesting alternative tool, worthy of further investigation, to study opiate addiction.
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http://dx.doi.org/10.1097/FBP.0b013e32835f3d15DOI Listing
April 2013

Region-specific effects on BDNF expression after contingent or non-contingent cocaine i.v. self-administration in rats.

Int J Neuropsychopharmacol 2013 May 20;16(4):913-8. Epub 2012 Nov 20.

Centro di Neurofarmacologia, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.

Brain-derived neurotrophic factor (BDNF) dynamic changes were investigated in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) during use and the early phases of cocaine abstinence after 14 sessions (2 h self-administration/d; 0.25 mg/0.1 ml.6 s infusion) by employing a 'yoked control-operant paradigm'. The effect on BDNF was region-specific and dependent on the withdrawal time. In the NAc, BDNF protein levels increased immediately after the last self-administration session, with a larger increase in passively cocaine-exposed rats. In the mPFC, BDNF expression was elevated 24 h after the last self-administration session, independently of how the drug was encountered. No changes were found in NAc and mPFC 7 d after the last self-administration session. Analysis of transcript levels in the mPFC indicated that action on exon I might contribute to BDNF's cortical induction. These findings indicate a finely tuned modulation of BDNF expression during use and early phases of cocaine abstinence.
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http://dx.doi.org/10.1017/S146114571200096XDOI Listing
May 2013

Hydroxytyrosol attenuates peripheral neuropathy in streptozotocin-induced diabetes in rats.

J Agric Food Chem 2012 Jun 31;60(23):5859-65. Epub 2012 May 31.

Mario Negri Institute for Pharmacological Research, via La Masa 19, 20156 Milan, Italy.

Peripheral neuropathy is one of the most frequent and severe complications of diabetes. Hydroxytyrosol (HT), the major antioxidant polyphenolic compound of olive oil, has been investigated as a new potential treatment to counteract the progression of peripheral diabetic neuropathy in rats. An established model of streptozotocin-induced diabetes has been used. After confirmation of hyperglycemia, diabetic and nondiabetic animals were randomized to receive either a low dose or a high dose of HT, or the corresponding vehicle, for 6 weeks. At the end of the 6-week period of treatment, HT blunted plasma thiobarbituric acid-reactive substances increase (p < 0.05) and significantly reduced nerve conduction velocity (p < 0.05) and thermal nociception impairment in diabetic rats (p < 0.05). Sciatic nerve Na(+), K(+)-ATPase activity reduction was also abolished by HT (p < 0.05). The present study provides evidence of the therapeutic potential of the natural substance hydroxytyrosol in the early stage of diabetic neuropathy.
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http://dx.doi.org/10.1021/jf2049323DOI Listing
June 2012

Operant, oral alcoholic beer self-administration by C57BL/6J mice: effect of BHF177, a positive allosteric modulator of GABA(B) receptors.

Psychopharmacology (Berl) 2012 Aug 13;222(4):685-700. Epub 2012 Mar 13.

Experimental Psychopharmacology, Department of Neuroscience, "Mario Negri" Institute for Pharmacological Research, Via La Masa 19, 20156 Milan, Italy.

Rationale: With its high palatability, near-beer has been successfully used in rats as a vehicle to induce ethanol oral self-administration.

Objectives: The study aimed to develop an operant model of oral alcoholic beer self-administration promoting a stable intake of pharmacologically relevant amounts of ethanol in free-feeding C57BL/6J mice. It also aimed to assess the model's predictive validity by evaluating the influence of baclofen, a GABA(B) agonist, and BHF177, a GABA(B) positive allosteric modulator, on alcoholic beer self-administration.

Methods: Mice were trained to self-administer, under a fixed ratio three schedule of reinforcement, 10 μl of beer containing increasing ethanol concentrations (0-18% v/v) in daily 30-min sessions. The effects on motor coordination (rotarod), locomotor activity (open field, automated cages) and anxiety-like behavior (elevated plus maze, EPM) were examined. Baclofen (1.25-5 mg/kg, intraperitoneal, i.p.) and BHF177 (3.75-30 mg/kg, i.p.) were used to see the effects on 9% alcoholic beer and near-beer self-administration.

Results: Near-beer stably maintained operant oral self-administration in mice. Adding ethanol to near-beer reduced the number of active lever presses, while the corresponding amount of ethanol self-administration increased (0.8-1.0 g/kg/session). Motor impairment was observed when more than 1.3 g/kg/session of ethanol was self-administered with beer and slight but consistent hyperlocomotion with more than 0.9-1.0 g/kg/session. BHF177 (15 mg/kg) preferentially reduced 9% alcoholic beer self-administration, while the higher dose (30 mg/kg)-like baclofen 5 mg/kg-also reduced near-beer self-administration.

Conclusions: The operant model of oral alcoholic beer self-administration in C57BL/6J mice should prove useful for studying ethanol-reinforced behaviors and to identify candidate compounds for the pharmacological management of alcohol addiction.
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http://dx.doi.org/10.1007/s00213-012-2672-6DOI Listing
August 2012

Bifeprunox: a partial agonist at dopamine D2 and serotonin 1A receptors, influences nicotine-seeking behaviour in response to drug-associated stimuli in rats.

Addict Biol 2012 Mar 26;17(2):274-86. Epub 2011 Apr 26.

Experimental Psychopharmacology, Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Via Giuseppe La Masa 19, Milan, Italy.

Environmental stimuli repeatedly associated with the self-administered drugs may acquire motivational importance. Because dopamine (DA) D(2) /D(3) partial agonists and D(3) antagonists interfere with the ability of drug-associated cues to induce drug-seeking behaviour, the present study investigated whether bifeprunox, 7-[4-([1,1'biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone mesylate), a high-affinity partial agonist of the D(2) subfamily of DA receptors and of serotonin(1A) receptors, influences reinstatement of drug-associated cue-induced nicotine-seeking behaviour. The study also explored whether bifeprunox reduced motivated behaviour by evaluating its effects on reinstatement induced by stimuli conditioned to sucrose. To verify whether bifeprunox interferes with the primary reinforcing properties of either drug or sucrose, we compared its effects on nicotine self-administration and on sucrose-reinforced behaviour. Different groups of experimentally naïve, food-restricted Wistar rats were trained to associate a discriminative stimulus with response-contingent availability of nicotine or sucrose and tested for reinstatement after extinction of nicotine or sucrose-reinforced behaviour. Bifeprunox (4-16 µg/kg, s.c.) dose-dependently attenuated the response-reinstating effects of nicotine-associated cues. Higher doses (64-250 µg/kg, s.c.) reduced spontaneous locomotor activity and suppressed operant responding induced by sucrose-associated cues and by the primary reinforcing properties of nicotine or sucrose. Provided they can be extrapolated to abstinent human addicts, these results suggest the potential therapeutic use of partial DA D(2) receptor agonist to prevent cue-controlled nicotine-seeking and relapse. The profile of action of high doses of bifeprunox remains to be examined for potential sedation or anhedonia effects.
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http://dx.doi.org/10.1111/j.1369-1600.2011.00319.xDOI Listing
March 2012

The cannabinoid CB1 receptor antagonist, rimonabant, as a promising pharmacotherapy for alcohol dependence: preclinical evidence.

Mol Neurobiol 2007 Aug 3;36(1):102-12. Epub 2007 Jul 3.

C.N.R. Institute of Neuroscience, Viale Diaz 182, Cagliari (CA), 182 I-09126, Italy.

Several lines of preclinical evidence indicate the ability of the prototypic cannabinoid CB(1) receptor antagonist, rimonabant, to suppress various alcohol-related behaviors, including alcohol drinking and seeking behavior and alcohol self-administration in rats and mice. Together, these data-synthetically reviewed in the present paper-suggest (a) the involvement of the cannabinoid CB(1) receptor in the neural substrate controlling alcohol intake, alcohol reinforcement, and the motivational properties of alcohol and (b) that rimonabant may constitute a new and potentially effective medication for the treatment of alcohol dependence.
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http://dx.doi.org/10.1007/s12035-007-0017-yDOI Listing
August 2007

Repeated exposure to alcoholic beer does not induce long-lasting changes in alcohol self-administration and intake in Sardinian alcohol-preferring and Sardinian non-preferring rats.

Alcohol Alcohol 2007 Nov-Dec;42(6):513-24. Epub 2007 Sep 18.

Bernard B. Brodie, Department of Neuroscience, University of Cagliari, Viale Diaz 182, I-09126 Cagliari (CA), Italy.

Aims: Rats avidly consume non-alcoholic beer, and addition of alcohol to non-alcoholic beer may function as a medium to induce intake of large amounts of alcohol in rats. The present study investigated whether Sardinian alcohol-preferring (sP) and Sardinian non-preferring (sNP) rats, initially exposed to non-alcoholic beer, and subsequently to non-alcoholic beer containing increasing concentrations of alcohol, would develop unusually high alcohol self-administration and drinking behaviours: (i) when alcohol was added to non-alcoholic beer, and (2) once beer was withdrawn and a plain alcohol solution was made available.

Methods: In Experiment 1, rats were exposed to operant, 30-min/day self-administration sessions of non-alcoholic beer with increasing concentrations of alcohol [0, 2.5, 5, 7.5, and 10% (v/v)] for a total of 45 days. After a brief 'beer-fading' phase, the rats were exposed to self-administration sessions of a plain 10% (v/v) alcohol solution. In Experiment 2, the rats were exposed to non-alcoholic beer with increasing concentrations of alcohol [0, 2.5, 5, 7.5, and 10% (v/v)] and water under the 2-bottle choice regimen with unlimited access (24 h/day) for a total of 35 days. After a brief 'beer-fading' phase, the rats were exposed to the choice between a plain 10% (v/v) alcohol solution and water.

Results: sP and sNP rats did not differ in self-administration (Experiment 1) and intake (Experiment 2) of non-alcoholic beer. In Experiment 1, as alcohol content increased, the amount of self-administered alcohol increased progressively in sP rats (up to 1-1.2 g/kg) and remained stable in sNP rats (approximately 0.65 g/kg). When the plain 10% alcohol solution was available, the amount of self-administered alcohol in sP rats initially dropped, and tended to increase-up to approximately 0.6 g/kg-on continuing exposure. In sNP rats, their lever-pressing behaviour was rapidly extinguished after beer withdrawal. In Experiment 2, as alcohol content was increased, daily alcohol intake increased progressively in sP rats (up to 8-9 g/kg) and averaged approximately 2.4 g/kg in sNP rats. When the plain alcohol solution was available, daily alcohol intake in sP rats was initially low, reaching control values on continuing exposure; conversely, daily alcohol intake was completely suppressed in sNP rats.

Conclusions: These results suggest that exposure to alcoholic beer resulted in unusually high intakes of alcohol in both sP and sNP rats for as long as non-alcoholic beer was added to alcohol; however, these high levels of alcohol self-administration and intake were not maintained once non-alcoholic beer was withdrawn.
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http://dx.doi.org/10.1093/alcalc/agm067DOI Listing
January 2008

Cue-induced reinstatement of ethanol seeking in Sardinian alcohol-preferring rats.

Alcohol 2007 Feb;41(1):31-9

C.N.R. Institute of Neuroscience, Viale Diaz 182, I-09126, Cagliari, Italy.

The purpose of the present study was to characterize cue-induced reinstatement of ethanol seeking in selectively bred Sardinian alcohol-preferring (sP) rats trained to lever press for ethanol in 30-min self-administration sessions. Four responses on an "active" lever led to presentation of 0.1 ml of 15% (vol/vol) ethanol by a liquid dipper and concurrent activation of a set of discrete light and auditory cues. In a 70-min extinction/reinstatement session, responding was first extinguished for 60 min. Subsequently, different stimuli were delivered in a noncontingent manner and reinstatement of nonreinforced responding was assessed. Fifteen presentations of the ethanol-predictive stimulus complex, including the dipper cup containing 5 or 15% ethanol, potently reinstated responding on the previously active lever. The magnitude of reinstatement increased with the number of stimulus presentations and concentration of ethanol presented by the dipper cup. Fifteen presentations of the ethanol-predictive stimulus complex, including the dipper cup filled with water (0% ethanol), did not produce any reinstatement. These results indicate that (1) noncontingent presentations of the ethanol-predictive stimulus complex may reinstate ethanol seeking in sP rats and (2) the orosensory properties of ethanol may play an important role in reinstatement of ethanol seeking in sP rats. The latter finding concurs with clinical observations that odor and taste of alcoholic beverages elicit immediate craving responses in abstinent alcoholics.
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http://dx.doi.org/10.1016/j.alcohol.2007.02.006DOI Listing
February 2007

Reducing effect of the positive allosteric modulator of the GABA(B) receptor, GS39,783, on alcohol self-administration in alcohol-preferring rats.

Psychopharmacology (Berl) 2007 Aug 29;193(2):171-8. Epub 2007 Mar 29.

"Bernard B. Brodie" Department of Neuroscience, University of Cagliari, Viale Diaz 182, 09126, Cagliari, Italy.

Rationale And Objectives: The positive allosteric modulator of the GABA(B) receptor, GS39,783, has recently been found to suppress acquisition and maintenance of alcohol drinking behavior in selectively bred Sardinian alcohol-preferring (sP) rats exposed to the standard, homecage two-bottle "alcohol vs water" choice regimen. The present study was designed to extend the characterization of the "anti-alcohol" effects of GS39,783 to oral self-administration of alcohol under an operant procedure.

Materials And Methods: Two separate groups of male sP rats were trained to lever-press (on an FR4 schedule) to orally self-administer alcohol (15%, v/v) or sucrose (0.3%, w/v) in daily 30-min sessions. Once lever-pressing behavior reached stable levels, the effect of GS39,783 (0, 25, 50, and 100 mg/kg, i.g.) on responding for alcohol and sucrose was determined.

Results: Pretreatment with GS39,783 resulted in a significant, dose-dependent reduction in responding for alcohol; at the dose of 100 mg/kg GS39,783, the number of lever responses for alcohol was reduced by approximately 50% in comparison to vehicle-treated rats. The effect of GS39,783 on alcohol self-administration was specific, as responding for sucrose was completely unaffected by pretreatment with GS39,783.

Conclusions: These data demonstrate the capability of GS39,783 to attenuate the reinforcing properties of alcohol in alcohol-preferring rats. These data constitute a further piece of experimental evidence in support of the hypothesized role for the GABA(B) receptor in the control of alcohol drinking and reinforcement.
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http://dx.doi.org/10.1007/s00213-007-0776-1DOI Listing
August 2007

Evaluation for the withdrawal syndrome from gamma-hydroxybutyric acid (GHB), gamma-butyrolactone (GBL), and 1,4-butanediol (1,4-BD) in different rat lines.

Ann N Y Acad Sci 2006 Aug;1074:545-58

Division of Pediatric Pharmacology & Critical Care, Rainbow Babies & Children's Hospital, 11100 Euclid Avenue, Cleveland, OH 44106, USA.

A severe and life-threatening gamma-hydroxybutyric acid (GHB) withdrawal syndrome, clinically similar to the alcohol withdrawal syndrome, is increasingly being reported in GHB addicts. We investigated for the occurrence of withdrawal in Wistar and Sprague-Dawley rats, and in the selectively bred lines of GHB-sensitive (GHB-S) and Sardinian alcohol-preferring (sP) rats, following chronic administration of GHB, gamma-butyrolactone (GBL), and/or 1,4-butanediol (1,4-BD). Using validated rodent alcohol withdrawal scoring scales, little to no spontaneous or pharmacologically precipitated withdrawal effects were observed in Wistar, Sprague-Dawley, or GHB-S rats. Conversely, sP rats displayed both spontaneous and precipitated audiogenic seizures following abrupt cessation of chronic GHB or 1,4-BD administration and following pharmacological challenge with the GABA(B) receptor-selective antagonist, SCH 50911, respectively.
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http://dx.doi.org/10.1196/annals.1369.055DOI Listing
August 2006

Identification of miltirone as active ingredient of Salvia miltiorrhiza responsible for the reducing effect of root extracts on alcohol intake in rats.

Alcohol Clin Exp Res 2006 May;30(5):754-62

C.N.R. Institute of Neuroscience, Cagliari, Italy.

Background: Previous work found that extracts from the roots of Salvia miltiorrhiza, a Chinese medicinal herb, reduced alcohol intake in selectively bred Sardinian alcohol-preferring (sP) rats. The present study was designed to evaluate whether miltirone, one of the possible active constituents of S. miltiorrhiza, might be responsible for the reducing effect of the extracts on alcohol intake.

Methods: An initial experiment assessed the effect of 100 mg/kg (intragastric, i.g.) of 4 extracts of S. miltiorrhiza, differing in miltirone content (0, 2, 3, and 7%, respectively), on alcohol intake in alcohol-experienced sP rats exposed to the 2-bottle "alcohol (10%, volume in volume) versus water" choice regimen. Subsequently, the effect of pure miltirone (2.5-10 mg/kg, i.g., i.e., a dose range comparable to its content in the effective doses of the active extracts) on acquisition and maintenance of alcohol-drinking behavior was evaluated in alcohol-naive and alcohol-experienced sP rats exposed to the 2-bottle choice regimen. The effect of miltirone (10 mg/kg, i.g.) on blood alcohol levels was assessed after the i.g. and intraperitoneal (i.p.) administration of alcohol. Finally, the effect of miltirone (30-100 mg/kg, i.g.) on the severity of alcohol withdrawal syndrome was evaluated in Wistar rats made physically dependent on alcohol by the repeated administration of intoxicating doses of alcohol.

Results: The reducing effect of 4 different extracts of S. miltiorrhiza on alcohol intake was positively and significantly correlated with their miltirone content. Pure miltirone reduced alcohol intake in alcohol-experienced rats and delayed acquisition of alcohol-drinking behavior in alcohol-naive rats. Similar to S. miltiorrhiza extracts, miltirone markedly reduced blood alcohol levels when alcohol was administered i.g. but not i.p., suggesting that miltirone hampered alcohol absorption from the gastrointestinal system. Finally, miltirone failed to affect the severity of alcohol withdrawal syndrome in alcohol-dependent rats.

Conclusions: The results of the present study suggest that miltirone is the likely active constituent of S. miltiorrhiza responsible for the reducing effect of its extracts on alcohol intake in different experimental models of excessive alcohol consumption.
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http://dx.doi.org/10.1111/j.1530-0277.2006.00088.xDOI Listing
May 2006

Coronary artery aneurysm: management and association with abdominal aortic aneurysm.

Cardiovasc Pathol 2006 Mar-Apr;15(2):100-4

Department of Surgical Sciences, Cardiac Surgery Division, Varese University Hospital, 21100 Varese, Italy.

Background: Coronary artery aneurysm (CAA) is a dilatation that exceeds 1.5 times the diameter of a normal adjacent coronary artery. Several studies suggest that pathogenetic mechanisms involved in this disease and in abdominal aortic aneurysm (AAA) are similar. Surgery for CAA is mandatory when the aneurysm is three to four times larger than the original vessel diameter. We reviewed our experience in the surgical treatment of this unusual disease and analyzed its association with AAA.

Materials And Methods: Between October 1993 and March 2005, 11 patients (9 men; mean age=66 years) underwent surgery for CAA. In all cases, coronary aneurysms were diagnosed as incidental findings in coronary angiographies. The coronary aneurysms were isolated and longitudinally incised: the proximal and distal openings were identified and sutured. The sacs were obliterated with running sutures. Myocardial protection was achieved by retrograde cardioplegia only. Coronary artery bypass grafting was performed distally to the excluded aneurysms in all patients.

Results: One patient died of respiratory failure early after the operations; all other patients are alive, asymptomatic for angina, and free from repeated acute myocardial infarction after a median follow-up of 76 months (range=4-141 months). A total of six patients underwent surgical repair or endoprosthesis implantation because of AAAs.

Conclusions: Our operative techniques ensured durable results. We recommend screening for abdominal aneurysms in all affected patients because of the frequent association between CAA and AAA as a result of their similar pathogenetic mechanism.
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http://dx.doi.org/10.1016/j.carpath.2005.11.005DOI Listing
May 2006

Lack of tolerance to the suppressing effect of rimonabant on chocolate intake in rats.

Psychopharmacology (Berl) 2006 Apr 21;185(2):248-54. Epub 2006 Feb 21.

C.N.R. Institute of Neuroscience, Viale Diaz, 182, I-09126 Cagliari (CA), Italy.

Rationale And Objectives: Previous work indicated that tolerance to the anorectic effect of the cannabinoid CB1 receptor antagonist/inverse agonist, rimonabant, developed rather rapidly in rats and mice given access to a standard rodent chow. The present study was designed to investigate whether the reducing effect of rimonabant on intake of a highly palatable food such as a chocolate-flavoured beverage underwent a development of tolerance as rapid as that manifested on intake of a standard rodent chow.

Materials And Methods: To this aim, Wistar rats were concurrently exposed, with unlimited access for 24 h/day, to the chocolate-flavoured beverage, regular food pellets and water. Rimonabant (0, 1.25, 2.5 and 5 mg/kg; i.p.) was administered once a day for 21 consecutive days.

Results: Rimonabant administration resulted in a dose-dependent suppression of the high, daily intake of the chocolate-flavoured beverage; this effect lasted for the entire 21-day treatment period, without any apparent development of tolerance. Conversely, rimonabant-induced reduction in daily intake of regular food pellets was of a smaller magnitude and was limited to the first 3-4 days of treatment.

Conclusions: Together, these results indicate that chronically administered rimonabant was more effective and longer-lasting in reducing the intake of a highly palatable food than that of regular food pellets in rats. These results also suggest that rimonabant may be more active on the hedonic rather than nutritive properties of diets.
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http://dx.doi.org/10.1007/s00213-006-0327-1DOI Listing
April 2006

The role of zofenopril in myocardial protection during cardioplegia arrest: an isolated rat heart model.

J Card Surg 2006 Jan-Feb;21(1):44-9

Department of Surgical Sciences, Cardiothoracic Division, Varese University Hospital, Varese, Italy.

Background: Zofenopril has beneficial effects in acute myocardial infarction, and improves the functional recovery after ischemia and reperfusion.

Aim Of The Study: The aim of this study was to investigate the cardioprotective effects of zofenopril, when added to a standard cardioplegic solution or when orally administered as pretreatment.

Methods: A Langendorff model for isolated rat hearts was employed: three groups of eight hearts each were used, respectively, with plain St. Thomas cardioplegia as control (group A and C), and the same solution added with 12.5 mg of zofenopril (group B). The third group (C) was pretreated for 7days with oral administration of zofenopril (6.5 mg/day). The hearts had a baseline perfusion for 30 minutes with Krebs-Henseleit solution at 37 degrees C, cardioplegia administration for 3 minutes, then 30 minutes of ischemia without any perfusion, and finally 30 minutes of reperfusion with Krebs-Henseleit solution at 37 degrees C.

Results: Left ventricle developed pressure was significantly higher in the reperfusion period only in the pretreated group (group C) with respect to groups A and B (p = 0.016). Similar results were obtained regarding dP/dt curves (p = 0.020). No differences were demonstrated between groups for cellular viability expressed as creatine phospho-kinase (p = ns) and lactate dehydrogenase release (p = ns).

Conclusions: Zofenopril as oral pretreatment showed protective effects in an isolated model of cardioplegic arrest, although improvements in myocardial viability (enzymatic release) could not be demonstrated. Further experimental and clinical evaluations are necessary to assess the direct cardioprotective effect of zofenopril, modifying the length of treatment and the dosage of the drug.
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http://dx.doi.org/10.1111/j.1540-8191.2006.00167.xDOI Listing
May 2006

Baclofen-induced reduction of alcohol reinforcement in alcohol-preferring rats.

Alcohol 2005 Jul;36(3):161-8

Bernard B. Brodie Department of Neuroscience, University of Cagliari, Viale Diaz 182, I-09126 Cagliari, Italy.

Recent studies have demonstrated that treatment with the gamma-aminobutyric acid (GABA(B)) receptor agonist, baclofen, reduces alcohol intake in selectively bred Sardinian alcohol-preferring rats tested under the homecage two-bottle "alcohol versus water" choice regimen. This study was designed to investigate whether baclofen also reduces alcohol-reinforcing effects in Sardinian alcohol-preferring rats. To this aim, sP rats were trained to lever press for oral alcohol (15%, vol/vol) or sucrose (0.3%, wt/vol; included as alternative reinforcer to evaluate the specificity of baclofen effect on alcohol reinforcement) under a fixed ratio schedule of 4. Once steady levels of alcohol or sucrose self-administration behavior were established, the effects of acutely administered baclofen (0, 1.7, and 3 mg/kg, intraperitoneal [ip]) and naloxone (0, 1, and 3 mg/kg, ip; included as reference compound) on alcohol- or sucrose-reinforced responding were evaluated. Baclofen administration dose dependently, although not specifically, reduced alcohol-reinforced responding to an extent comparable to that of naloxone. Baclofen also produced a dose-dependent and specific delay in the onset of alcohol-reinforced responding, suggesting that it suppressed the rats' motivation to start drinking alcohol. These data are discussed in terms of adding further support to the hypothesized involvement of the GABA(B) receptor in the neural system mediating alcohol reinforcement. These data are also in agreement with the results of recent preliminary clinical studies suggesting that baclofen may have therapeutic efficacy in the treatment of alcohol dependence.
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http://dx.doi.org/10.1016/j.alcohol.2005.08.003DOI Listing
July 2005

Reducing effect of the positive allosteric modulators of the GABA(B) receptor, CGP7930 and GS39783, on alcohol intake in alcohol-preferring rats.

Eur J Pharmacol 2005 Nov 14;525(1-3):105-11. Epub 2005 Nov 14.

Bernard B. Brodie Department of Neuroscience, University of Cagliari, Viale Diaz 182, I-09126 Cagliari (CA), Italy.

The gamma-aminobutyric acidB (GABA(B)) receptor full agonists, baclofen and CGP44532, have been found to suppress different aspects of alcohol drinking behavior, including acquisition and maintenance, in selectively bred Sardinian alcohol-preferring (sP) rats. The present study was designed to assess whether this capability extends to the recently synthesized, positive allosteric modulators of the GABA(B) receptor, 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783). In the "acquisition" experiments, CGP7930 (0, 25, 50 and 100 mg/kg; i.g.) and GS39783 (0, 6.25, 12.5 and 25 mg/kg; i.g.) were administered for 5 consecutive days to alcohol-naive sP rats. In the "maintenance" experiments, (0, 50 and 100 mg/kg; i.g.) and GS39783 (0, 50 and 100 mg/kg; i.g.) were administered for 5 consecutive days to alcohol-experienced sP rats. Alcohol intake was evaluated under the standard, homecage 2-bottle "alcohol (10%, v/v) vs water" regimen with unlimited access for 24 h/day. Both CGP7930 and GS39783 dose-dependently suppressed the acquisition of alcohol drinking behavior. In the "maintenance" experiments, CGP7930 and GS39783 reduced daily alcohol intake by 30-40% only at the highest dose when compared to vehicle-treated rats; this effect tended to vanish on continuing treatment. The results of the present study suggest that positive allosteric modulation of the GABA(B) receptor produced an effect on alcohol drinking behavior similar to that produced by GABA(B) receptor full agonists. These data also suggest that positive allosteric modulation of the GABA(B) receptor may constitute a potential strategy for developing new drugs for treating alcohol dependence.
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http://dx.doi.org/10.1016/j.ejphar.2005.10.005DOI Listing
November 2005

Differential G-protein coupling to GABAB receptor in limbic areas of alcohol-preferring and -nonpreferring rats.

Eur J Pharmacol 2005 Oct 13;523(1-3):67-70. Epub 2005 Oct 13.

Bernard B. Brodie Department of Neuroscience, University of Cagliari, Cittadella Universitaria di Monserrato, 09042 Monserrato (CA), Italy.

The function of the gamma-aminobutyric acid(B) (GABAB) receptor, measured as baclofen-stimulated [35S]GTPgammaS binding, was evaluated in some brain regions of Sardinian alcohol-preferring (sP) and -nonpreferring (sNP) rats. EC50 value of baclofen-stimulated [35S]GTPgammaS in limbic areas was approximately 125% higher in alcohol-naive sP than sNP rats; voluntarily consumed alcohol reduced the EC50 value to a level similar to that of alcohol-naive sNP rats. These results suggest the presence of a genetically determined lower function of the GABAB receptor in limbic areas of sP than sNP rats; this differential functioning of the GABAB receptor may contribute to the opposite preference for alcohol in these rat lines.
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http://dx.doi.org/10.1016/j.ejphar.2005.09.011DOI Listing
October 2005

Suppression of maintenance of alcohol-drinking behavior by the concurrent availability of saccharin in Sardinian alcohol-preferring (sP) rats.

Alcohol 2005 Jan;35(1):35-41

C.N.R. Institute of Neuroscience, Section of Cagliari, Italy.

In the current study, we investigated the effect of the concurrent presentation of saccharin on the maintenance of alcohol-drinking behavior in selectively bred Sardinian alcohol-preferring (sP) rats. Rats were initially given access to alcohol [10% (volume/volume) in water] and water under the home cage, two-bottle, free-choice regimen, with unlimited access for 24 h/day for eight consecutive weeks. Next, a third bottle, containing saccharin [0%, 0.01%, 0.1%, 1%, or 3% (weight/volume) in water], was concomitantly offered for an additional 10 consecutive days. Intake of saccharin solution resulted as an inverted-U function of saccharin concentration, with the 0.1% saccharin solution being the highest accepted. Alcohol intake was a U function of saccharin concentration, being reduced by 65%-95% in the group of rats exposed to the 0.1% saccharin solution. These results indicate that (1) the concurrent presentation of highly palatable solutions of saccharin markedly reduced alcohol intake in alcohol-experienced sP rats and (2) the reducing effect of saccharin solutions on the alcohol intake in sP rats was positively related to their degree of acceptability. We hypothesized that saccharin solutions may have functioned as a reinforcer, partially substituting for alcohol reinforcement and rendering alcohol drinking less urgent.
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http://dx.doi.org/10.1016/j.alcohol.2004.10.006DOI Listing
January 2005