Publications by authors named "Luigi Cervo"

40 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

Musclin, A Myokine Induced by Aerobic Exercise, Retards Muscle Atrophy During Cancer Cachexia in Mice.

Cancers (Basel) 2019 Oct 12;11(10). Epub 2019 Oct 12.

Department of Neurosciences, Mario Negri Institute for Pharmacological Research IRCCS, 20156 Milan, Italy.

Physical activity improves the prognosis of cancer patients, partly by contrasting the associated muscle wasting (cachexia), through still unknown mechanisms. We asked whether aerobic exercise causes secretion by skeletal muscles of proteins (myokines) that may contrast cachexia. Media conditioned by peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α)-expressing myotubes, reproducing some metabolic adaptations of aerobic exercise, as increased mitochondrial biogenesis and oxidative phosphorylation, restrained constitutively active Forkhead box-containing subfamily O3 (caFoxO3)-induced proteolysis. Microarray analysis identified amphiregulin (AREG), natriuretic peptide precursor B (NppB), musclin and fibroblast growth factor 18 (FGF18) as myokines highly induced by PGC1α. Notably, only musclin tended to be low in muscle of mice with a rare human renal carcinoma; it was reduced in plasma and in muscles of C26-bearing mice and in atrophying myotubes, where PGC1α expression is impaired. Therefore, we electroporated the Tibialis Anterior (TA) of C26-bearing mice with musclin or (its receptor) natriuretic peptide receptor 3 (Npr3)-encoding plasmids and found a preserved fiber area, as a result of restrained proteolysis. Musclin knockout (KO) mice lose more muscle tissue during growth of two distinct cachexia-causing tumors. Running protected C26-bearing mice from cachexia, not changing tumor growth, and rescued the C26-induced downregulation of musclin in muscles and plasma. Musclin expression did not change in overloaded plantaris of mice, recapitulating partially muscle adaptations to anaerobic exercise. Musclin might, therefore, be beneficial to cancer patients who cannot exercise and are at risk of cachexia and may help to explain how aerobic exercise alleviates cancer-induced muscle wasting.
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http://dx.doi.org/10.3390/cancers11101541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826436PMC
October 2019

Lasting reduction of nicotine-seeking behavior by chronic N-acetylcysteine during experimental cue-exposure therapy.

Addict Biol 2020 07 27;25(4):e12771. Epub 2019 May 27.

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

Nicotine-associated cues can trigger reinstatement in humans as well as in animal models of drug addiction. To date, no behavioral intervention or pharmacological treatment has been effective in preventing relapse in the long term. A large body of evidence indicates that N-acetylcysteine (N-AC) blunts the activation of glutamatergic (GLUergic) neurons in the nucleus accumbens (Nacc) associated with reinstatement. We evaluated the effect of an experimental cue exposure therapy (eCET) alone or in combination with N-AC to verify whether restoring GLU homeostasis enhances extinction of nicotine-associated cues. Rats were trained to associate discriminative stimuli with intravenous nicotine or saline self-administration. Reinforced response was followed by cue signals. After rats met the self-administration criteria, the lasting anti-relapse activity of i.p. N-AC or vehicle was assessed in three different experimental conditions after 14 days of treatment: treatment + eCET; treatment + lever-presses extinction (LP-EXT); and treatment + abstinence. N-AC 100 mg/kg, but not 60 mg/kg, induced anti-relapse activity that persisted 50 days after treatment only when paired with either LP-EXT or eCET with the greater activity found in the latter condition. To identify potential mechanisms for behavioral results, separate groups of rats that received either N-AC or vehicle + eCET were killed at different time points for Nacc Western-blot analysis. Seven days after treatment, chronic N-AC restored the expression of proteins crucial for GLU homeostasis, while at 50 days, it increased the expression of type II metabotropic GLU receptors. These results suggest that N-AC treatment in combination with eCET may offer a novel strategy to prevent relapse in nicotine addiction.
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http://dx.doi.org/10.1111/adb.12771DOI Listing
July 2020

The effect of exposure to low frequency electromagnetic fields (EMF) as an integral part of the housing system on anxiety-related behaviour, cognition and welfare in two strains of laboratory mouse.

PLoS One 2018 17;13(5):e0197054. Epub 2018 May 17.

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

Electromagnetic field (EMF) technology has the potential to improve scientific data capture and welfare assessment by allowing automated data collection from individual cages. However, it is important to determine any impact that a new technology itself may have on animal welfare, and previous studies have found contrasting results of EMF on laboratory rodent anxiety-like behaviour and cognition. We therefore investigated whether there was an effect of low frequency EMF experienced continuously over a six-week period, as an integral part of the animal housing system, on measures of mouse anxiety-related behaviour, cognition and welfare. We housed mice (N = 80) of two strains (BALB/cAnNCrl and C57BL/6NCrl) separately in Individually Ventilated Cages (IVCs) in groups of four, either with the EMF plate turned 'on' or 'off' (n = 5). Some measures, e.g. food and water utilisation, were collected at regular intervals, whereas measures of anxiety-like behaviour (e.g. open field test) and cognitive performance (novel-object recognition test) were collected only at the end of the study. We found expected strong strain differences in most measures, e.g. latency to leave the starting square in an open field test, with C57BL/6NCrl mice moving away sooner, and interactions between strain and time for those measures recorded at more than one time point, e.g. significant weight gain over time for both strains, but with BALB/cAnNCrl mice weighing more. However, we found no significant effects of treatment (EMF 'on'/'off') for any of the measures collected. These results indicate that, for the measures recorded here, there was no measurable impact on the behaviour and welfare of low frequency EMF exposure experienced continuously over a six-week period. Housing systems that include EMF monitoring technology may therefore be suitable for use without influencing either animal welfare or scientific outcomes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197054PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5957419PMC
August 2018

Brain disposition, metabolism and behavioral effects of the synthetic opioid AH-7921 in rats.

Neuropharmacology 2018 05 31;133:51-62. Epub 2018 Jan 31.

Department of Molecular Biochemistry and Pharmacology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.

3,4-Dichloro-N-benzamide (AH-7921) is a cyclohexyl-methylbenzamide derivative with analgesic activity, whose abuse was associated with several fatal intoxications, included in Schedule I of UN Single Convention on Narcotic Drugs. We validated an HPLC-MS/MS method to investigate its brain disposition and metabolism after single and repeated injections; in parallel, we evaluated its central behavioral effects. After an intraperitoneal injection of 10 mg/kg, the analgesic effect appeared after 5 min and persisted up to 4 h; brain absorption was rapid (t 30 min) and large (brain-to-plasma ratio 16), with active concentration >700 ng/g. By high-resolution MS we identified several metabolites in plasma and brain, the most important being N-demethylated and N,N-didemethylated metabolites; they showed high brain permeability, although they probably do not contribute to the analgesic effect of the parent compound (brain t>2 h). Starting 2 h after treatment, the two metabolites showed higher plasma and brain concentrations than the parent molecule, which persisted much longer, and could be used to evaluate drug intake in human consumers. Tolerance was observed after seven daily doses, when the compound's analgesic effect was 14% lower than after the first dose; since brain concentrations did not decrease in parallel, the development of pharmacodynamic tolerance can be suggested. However, pharmacokinetic tolerance is also likely, as brought to light by the data after a dose challenge, given after a 48 h washout period from the 7th dose, showing a lower brain-to-plasma ratio. We also describe the rewarding effect of AH-7921 (conditioned place preference), suggesting a high risk of addiction in humans.
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http://dx.doi.org/10.1016/j.neuropharm.2018.01.023DOI Listing
May 2018

Pharmacodynamic effects in the cerebrospinal fluid of rats after intravenous administration of different asparaginase formulations.

Cancer Chemother Pharmacol 2017 Jun 19;79(6):1267-1271. Epub 2017 Apr 19.

Clinical Cancer Pharmacology Unit, Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156, Milan, Italy.

Purpose: Asparaginase (ASNase) is used to treat various hematological malignancies for its capacity to deplete asparagine (ASN) in serum and cerebrospinal fluid (CSF). Since the biological mechanisms underlying CSF asparagine depletion in humans are not yet fully elucidated, this study compared, for the first time, the pharmacological properties of three clinically used ASNase formulations in a rodent model.

Methods: Male Wistar rats were treated with E.coli-ASNase, PEG-ASNase, or ERW-ASNase at different doses. Serum and CSF amino-acid levels and ASNase activities were evaluated at 1 and 24 h after the intravenous administration of different ASNase doses.

Results: All the ASNase formulations showed higher activities in serum after 1 h than 24 h and completely deplete ASN. Mean ASNase activity in the CSF at 1 h was higher with ERW-ASNase compared to PEG-ASNase (36 ± 29 vs 8 ± 7 U/L, p < 0.037) and similar to E.coli-ASNase (21 ± 9 U/L, ns). ERW-ASNase and E.coli-ASNase at the highest doses were able to deplete ASN in the CSF after 1 h. This effect was transient and not evident at 24 h after treatment.

Conclusions: Together with the ASN depletion in serum and CSF, a never before demonstrated transient penetration of ASNases into the CSF, more evident for non-pegylated formulations, was detected when the ASNases were administered at high dose.
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http://dx.doi.org/10.1007/s00280-017-3307-8DOI Listing
June 2017

Brain Disposition of --Methyl-4-Methylaminorex (-4,4'-DMAR) and Its Potential Metabolites after Acute and Chronic Treatment in Rats: Correlation with Central Behavioral Effects.

J Pharmacol Exp Ther 2017 06 12;361(3):492-500. Epub 2017 Apr 12.

Departments of Molecular Biochemistry and Pharmacology (J.L., M.G.), Neuroscience (C.M.M., A.D.C., F.M., L.C.), and Environmental Health Science (A.P., R.B.), IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.

-Methyl-4-methylaminorex (4,4'-DMAR) is a phenethylamine derivative with psychostimulant activity whose abuse has been associated with several deaths and a wide range of adverse effects. We recently validated a high-performance liquid chromatography-tandem mass spectrometry method to measure the compound's concentrations in plasma, and we applied it to describe the pharmacokinetic properties of 4,4'-DMAR after a single dose in rats. In this study, we investigated the brain disposition and metabolism of 4,4'-DMAR after intraperitoneal injection as well as its central behavioral effects. Locomotor activity increased after a single injection of 10 mg/kg, peaking at 2 hours and disappearing at 5 hours; in these conditions, brain absorption was very rapid, ( = 30-60 minutes) and large (brain-to-plasma ratio = 24); the half-life was approximately 50 minutes. After 14 daily doses, the compound's effect on locomotor activity was greater (approximately 20% compared with the effect after the first dose), but not for pharmacokinetic reasons. Using high-resolution mass spectrometry, we also identified four metabolites of 4,4'-DMAR in the plasma and brain of treated rats. Semiquantitative analysis indicated low brain permeability and very low brain concentrations, suggesting that these metabolites do not contribute to central behavioral effects; however, the metabolite originating from oxidation of the -methyl group (M2) persisted in the plasma longer and at higher concentrations than the parent molecule and could be used to evaluate drug intake in human consumers. Finally, we describe the rewarding effect of -4,4'-DMAR in the conditioning place preference test, suggesting a high risk of addiction in humans.
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http://dx.doi.org/10.1124/jpet.117.240788DOI Listing
June 2017

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

A validated, sensitive HPLC-MS/MS method for quantification of cis-para-methyl-4-methylaminorex (cis-4,4'-DMAR) in rat and human plasma: application to pharmacokinetic studies in rats.

Drug Test Anal 2017 Jun 21;9(6):870-879. Epub 2016 Sep 21.

Department of Biochemistry and Molecular Pharmacology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.

4,4'-DMAR is an analogue of the known psychostimulants 4-methylaminorex and aminorex. In the light of reports of deaths associated with its abuse, and the easy access from Internet vendors, the EU Council recently decided on control measures across member states. Here we describe a validated method for measuring plasma levels of cis-4,4'-DMAR, crucial for preclinical studies and analysis in human plasma. Chromatographic separation was done by gradient elution on a Kinetex C18 column with 0.1% formic acid in water and 0.1% formic acid in acetonitrile at 0.2 mL/min. Detection was by positive electrospray ionization (ESI+) in multiple reaction monitoring mode monitoring the quantifier transitions m/z 191.4 → m/z 148.3 for cis-4,4'-DMAR and m/z 259.3 → m/z 194.2 for carbamazepine (internal standard). Protein precipitation with 1% of formic acid in acetonitrile was used in cis-4,4'-DMAR extraction from plasma; recovery was high (>93%) with a negligible matrix effect. This method provides an accurate, precise, and sensitive method for cis-4,4'-DMAR quantification in human and rat plasma, following European Medicine Agency guidelines for bioanalytical method validation. Pharmacokinetic studies were conducted in rats. After an intravenous dose of 1 mg/kg, plasma levels declined rapidly (≥80% in 4 h), followed by a slow elimination phase (t of 5.14 ± 0.65 h). Absorption was rapid after intraperitoneal injection (t  = 15 min) with a rapid decline thereafter; C and AUC showed dose-proportionality over the dose range 1-10 mg/kg. This method was successfully applied to investigate pharmacokinetic properties in rats and could be used to quantify cis-4,4'-DMAR levels in human plasma. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/dta.2052DOI Listing
June 2017

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

Effects of dipeptidyl peptidase-4 (DPP-4) inhibition on angiogenesis and hypoxic injury in type 2 diabetes.

Life Sci 2016 Jun 31;154:87-95. Epub 2016 Mar 31.

Department of Cardiovascular Research, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", 20156 Milan, Italy.

Aims: We examined whether, in diabetic Ob/Ob mice, the dipeptidyl peptidase-4 (DPP-4) inhibitor (PKF275-055), an antihyperglycemic drug, that inhibits the biological inactivation of SDF-1 (stromal cell-derived factor-1), may increase endothelial progenitor cells (EPCs) mobilization and incorporation, which, in turn, may regenerate capillaries and reduce myocardial ischemia induced by strenuous exercise.

Main Methods: Half of sixteen control and Ob/Ob mice and eight Ob/Ob mice treated with PKF275-055 for four weeks underwent a forced swim protocol. Oral glucose tolerance, circulating EPCs, capillary ultrastructure and density, hypoxic areas and SDF-1 localization in myocardium were measured.

Key Findings: Ob/Ob mice were glucose intolerant, had a significant low number of circulating EPCs and myocardial capillaries compared to lean controls. The DPP-4 inhibitor significantly improved their glucose tolerance, doubled the number of circulating EPCs, stimulated the formation of functional vessels and SDF-1 localization in the endothelium of myocardial capillaries and arterioles. Cardiac hypoxia after forced swim in Ob/Ob mice was significantly reduced when they were treated with the DPP-4 inhibitor.

Significance: DPP-4 inhibition may re-establish an adequate capillary network in the myocardium of diabetic Ob/Ob mice by the mobilization and SDF-1-mediated incorporation of EPCs and, consequently, reducing the susceptibility to myocardial ischemic injury provoked by strenuous exercise.
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http://dx.doi.org/10.1016/j.lfs.2016.03.052DOI Listing
June 2016

Abstinence from cocaine-self-administration activates the nELAV/GAP -43 pathway in the hippocampus: A stress-related effect?

Hippocampus 2016 06 25;26(6):700-4. Epub 2016 Feb 25.

Experimental Psychopharmacology, Department of Neuroscience, IRCCS-Istituto Di Ricerche Farmacologiche "Mario Negri,", Milan, Italy.

We previously demonstrated that nELAV/GAP-43 pathway is pivotal for learning and its hippocampal expression is up-regulated by acute stress following repeated cocaine administration. We therefore hypothesized that abstinence-induced stress may sustain nELAV/GAP-43 pathway during early abstinence following 2 weeks of cocaine self-administration. We found that contingent, but not non-contingent, cocaine exposure selectively increases hippocampal nELAV, but not GAP-43, expression immediately after the last self-administration session, an effect that wanes after 24 h and that comes back 7 days later when nELAV activation becomes associated with increased expression of GAP-43, an effect again observed only in animals self-administering the psychostimulant. Such effect is specific for nELAV since the ubiquitous ELAV/HuR is unchanged. This nELAV profile suggests that its initial transient alteration is perhaps related to the daily administration of cocaine, while the increase in the nELAV/GAP-43 pathway following a week of abstinence may reflect the activation of this cascade as a target of stressful conditions associated with drug-related memories. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/hipo.22572DOI Listing
June 2016

Increased context-dependent conditioning to amphetamine in mice lacking TAAR1.

Pharmacol Res 2016 Jan 2;103:206-14. Epub 2015 Dec 2.

Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genova, Italy; Skolkovo Institute of Science and Technology, Skolkovo, 143025 Moscow Region, Russia; Institute of Translational Biomedicine, St. Petersburg State University, 199034 St. Petersburg, Russia. Electronic address:

Given the recent evidence indicating that amphetamine derivatives may also act as direct agonists of the G protein-coupled trace amine-associated receptor 1 (TAAR1), we hypothesized that TAAR1 could contribute to the reinforcing and addictive properties of amphetamines. Accordingly, the present study aimed to investigate the role of TAAR1 in the effects of psychostimulants by analyzing context-dependent sensitization and conditioned place preference (CPP) to d-amphetamine (AMPH) in TAAR1-KO mice. In context-dependent sensitization experiment, TAAR1-KO mice showed higher conditioned locomotor responses compared to wild-type mice. In the CPP test, TAAR1-KO animals were also more sensitive to priming-induced reinstatement of AMPH-induced conditioned place preference (CPP) than wild type mice. Importantly, saline-treated and AMPH-treated mice lacking TAAR1 demonstrated significant alterations in the total levels and phosphorylation of the critical subunit of NMDA glutamate receptors, GluN1, in the striatum, suggesting a role of TAAR1 in the modulation of frontostriatal glutamate transmission; this effect could underlie the observed alterations in conditioning processes. In conclusion, our data suggest that TAAR1 receptors play an inhibitory role with respect to conditioned responses to AMPH by modulating, at least in part, corticostriatal glutamate transmission.
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http://dx.doi.org/10.1016/j.phrs.2015.11.002DOI Listing
January 2016

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

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

Multiple drug delivery hydrogel system for spinal cord injury repair strategies.

J Control Release 2012 Apr 29;159(2):271-80. Epub 2011 Dec 29.

Department of Chemistry, Materials and Chemical Engineering Giulio Natta, Politecnico di Milano, via Mancinelli 7, 20131 Milan, Italy.

The multifactorial pathological progress of spinal cord injury (SCI) is probably the main reason behind the absence of efficient therapeutic approaches. Hence, very recent highlights suggest the use of new multidrug delivery systems capable of local controlled release of therapeutic agents. In this work, a biocompatible hydrogel-based system was developed as multiple drug delivery tool, specifically designed for SCI repair strategies. Multiple release profiles were achieved by loading gel with a combination of low and high steric hindrance molecules. In vitro, in vivo and ex vivo release studies showed an independent combination of fast diffusion-controlled kinetics for smaller molecules together with slow diffusion-controlled kinetics for bigger ones. A preserved functionality of loaded substances was always achieved, confirming the absence of any chemical stable interactions between gel matrix and loaded molecules. Moreover, the relevant effect of the cerebrospinal fluid flux dynamics on the drug diffusion in the spinal cord tissue was here revealed for the first time: an oriented delivery of the released molecules in the spinal cord tract caudally to the gel site is demonstrated, thus suggesting a more efficient gel positioning rostrally to the lesion.
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http://dx.doi.org/10.1016/j.jconrel.2011.12.025DOI Listing
April 2012

c-Jun N-terminal kinase regulates soluble Aβ oligomers and cognitive impairment in AD mouse model.

J Biol Chem 2011 Dec 27;286(51):43871-43880. Epub 2011 Oct 27.

Neuronal Death and Neuroprotection Laboratory, Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milano 20156, Italy. Electronic address:

Alzheimer disease (AD) is characterized by cognitive impairment that starts with memory loss to end in dementia. Loss of synapses and synaptic dysfunction are closely associated with cognitive impairment in AD patients. Biochemical and pathological evidence suggests that soluble Aβ oligomers correlate with cognitive impairment. Here, we used the TgCRND8 AD mouse model to investigate the role of JNK in long term memory deficits. TgCRND8 mice were chronically treated with the cell-penetrating c-Jun N-terminal kinase inhibitor peptide (D-JNKI1). D-JNKI1, preventing JNK action, completely rescued memory impairments (behavioral studies) as well as the long term potentiation deficits of TgCRND8 mice. Moreover, D-JNKI1 inhibited APP phosphorylation in Thr-668 and reduced the amyloidogenic cleavage of APP and Aβ oligomers in brain parenchyma of treated mice. In conclusion, by regulating key pathogenic mechanisms of AD, JNK might hold promise as innovative therapeutic target.
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http://dx.doi.org/10.1074/jbc.M111.297515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243502PMC
December 2011

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

Gamma-hydroxybutyrate does not maintain self-administration but induces conditioned place preference when injected in the ventral tegmental area.

Int J Neuropsychopharmacol 2010 Mar 2;13(2):143-53. Epub 2009 Jul 2.

School of Biosciences, Cardiff University, Museum Avenue, Cardiff, UK.

Gamma-hydroxybutyric acid (GHB) is an endogenous brain substance that has diverse neuropharmacological actions, including rewarding properties in different animal species and in humans. As other drugs of abuse, GHB affects the firing of ventral tegmental neurons (VTA) in anaesthetized animals and hyperpolarizes dopaminergic neurons in VTA slices. However, no direct behavioural data on the effects of GHB applied in the VTA or in the target regions of its dopaminergic neurons, e.g. the nucleus accumbens (NAc), are available. Here, we investigated the effects of various doses of intravenous GHB in maintaining self-administration (from 0.001 to 10 mg/kg per infusion), and its ability to induce conditioned place preference (CPP) in rats when given orally (175-350 mg/kg) or injected directly either in the VTA or NAc (from 10 to 300 microg/0.5 microl per side). Our results indicate that while only 0.01 mg/kg per infusion GHB maintained self-administration, although not on every test day, 350 mg/kg GHB given orally induced CPP. CPP was also observed when GHB was injected in the VTA (30-100 microg/0.5 microl per side) but not in the NAc. Together with recent in-vitro findings, these results suggest that the rewarding properties of GHB mainly occur via disinhibition of VTA dopaminergic neurons.
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http://dx.doi.org/10.1017/S1461145709990186DOI Listing
March 2010

Enhancement of cortical extracellular 5-HT by 5-HT1A and 5-HT2C receptor blockade restores the antidepressant-like effect of citalopram in non-responder mice.

Int J Neuropsychopharmacol 2009 Jul 5;12(6):793-803. Epub 2009 Jan 5.

Laboratory of Neurochemistry and Behaviour, Istituto di Ricerche Farmacologiche 'Mario Negri', Via La Masa 19, 20156 Milan, Italy.

We recently found that the response of DBA/2 mice to SSRIs in the forced swim test (FST) was impaired and they also had a smaller basal and citalopram-stimulated increase in brain extracellular serotonin (5-HT) than 'responder' strains. We employed intracerebral microdialysis, FST and selective antagonists of 5-HT1A and 5-HT2C receptors to investigate whether enhancing the increase in extracellular 5-HT reinstated the anti-immobility effect of citalopram in the FST. WAY 100635 (0.3 mg/kg s.c.) or SB 242084 (1 mg/kg s.c.), respectively a selective 5-HT1A and 5-HT2C receptor antagonist, raised the effect of citalopram (5 mg/kg) on extracellular 5-HT in the medial prefrontal cortex of DBA/2N mice (citalopram alone 5.2+/-0.3 fmol/20 microl, WAY 100635+citalopram 9.9+/-2.1 fmol/20 microl, SB 242084+ citalopram 7.6+/-1.0 fmol/20 microl) to the level reached in 'responder' mice given citalopram alone. The 5-HT receptor antagonists had no effect on the citalopram-induced increase in extracellular 5-HT in the dorsal hippocampus. The combination of citalopram with WAY 100635 or SB 242084 significantly reduced immobility time in DBA/2N mice that otherwise did not respond to either drug singly. Brain levels of citalopram in mice given citalopram alone or with 5-HT antagonists did not significantly differ. The results confirm that impaired 5-HT transmission accounts for the lack of effect of citalopram in the FST and suggest that enhancing the effect of SSRIs on extracellular 5-HT, through selective blockade of 5-HT1A and 5-HT2C receptors, could be a useful strategy to restore the response in treatment-resistant depression.
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http://dx.doi.org/10.1017/S1461145708009760DOI Listing
July 2009

Single session of cocaine intravenous self-administration shapes goal-oriented behaviours and up-regulates Arc mRNA levels in rat medial prefrontal cortex.

Int J Neuropsychopharmacol 2009 Apr 25;12(3):423-9. Epub 2008 Nov 25.

Center of Neuropharmacology, Department of Pharmacological Sciences, University of Milan, Milan, Italy.

To separate the direct pharmacological effects of cocaine from those associated with active drug self-administration we employed a yoked control-operant paradigm and investigated the expression of well established markers of the rapid action of cocaine, i.e. the inducible early genes Arc and Zif268 and trophic factors, i.e. brain-derived neurotrophic factor (BDNF) and basic fibroblast growth factor (FGF-2), in rats after a single intravenous (i.v.) cocaine self-administration session. Animals self-administering cocaine (SA, 0.25 mg/0.1 ml saline per infusion, 2-h session) did more active lever-presses than yoked-cocaine (YC) and yoked-vehicle (YV) animals. This goal-oriented behaviour was accompanied by a selective increase in Arc mRNA levels in the medial prefrontal cortex (mPFC). There were no changes in the expression of the other genes in this brain region. mRNA levels of Arc and Zif268 in striatum and Zif268 in the nucleus accumbens markedly increased both in SA and YC animals; but there was no change in the expression of FGF-2 and BDNF. No changes were observed in hippocampus, hypothalamus, frontal cortex, and midbrain in SA and YC animals compared to YV animals in any of the genes. These findings demonstrate that a single session of cocaine i.v. self-administration is sufficient to shape rat behaviour towards goal-directed behaviours and selectively up-regulate Arc expression in mPFC (of SA animals), providing the first evidence that the mPFC's function is already profoundly influenced by the first voluntary cocaine exposure.
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http://dx.doi.org/10.1017/S1461145708009681DOI Listing
April 2009

The chemokine receptor CX3CR1 is involved in the neural tropism and malignant behavior of pancreatic ductal adenocarcinoma.

Cancer Res 2008 Nov;68(21):9060-9

Department of Immunology and Inflammation, IRCCS Clinical Institute Humanitas, Rozzano, Milano, Italy.

Tumor perineural dissemination is a hallmark of human pancreatic ductal adenocarcinoma (PDAC) and represents a major source of local tumor recurrence after surgery. In this study, we provide in vitro and in vivo evidence that the chemokine receptor CX3CR1 may be involved in the neurotropism of PDAC cells to local peripheral nerves. Neoplastic cells from PDAC cell lines and surgical specimens express the chemokine receptor CX3CR1, absent in normal pancreatic ducts. Its unique ligand, the transmembrane chemokine CX3CL1, is expressed by neurons and nerve fibers. CX3CR1 + PDAC cell lines migrated in response to human recombinant CX3CL1 and specifically adhered to CX3CL1-expressing cells of neural origin via mechanisms involving activation of G proteins, beta1 integrins, and focal adhesion kinase. In vivo experiments with transplanted PDAC showed that only CX3CR1-transfected tumor cells infiltrated the local peripheral nerves. Immunohistochemistry of CX3CR1 in PDAC specimens revealed that 90% of the samples were positive with a heterogeneous pattern of expression. High receptor score was significantly associated with more prominent tumor perineural infiltration evaluated histologically (P = 0.026). Regression analyses (univariate and multivariate) showed that high CX3CR1 expression and perineural invasion were strongly associated with local and earlier tumor recurrence (P = 0.007). Collectively, this study shows that the CX3CR1 receptor may be involved in PDAC tumor neurotropism and is a relevant and independent risk factor to predict an early local tumor relapse in resected patients. Thus, the CX3CR1-CX3CL1 axis could represent a valuable therapeutic target to prevent tumor perineural dissemination in pancreatic cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-08-1810DOI Listing
November 2008

Strain differences in paroxetine-induced reduction of immobility time in the forced swimming test in mice: role of serotonin.

Eur J Pharmacol 2008 Oct 24;594(1-3):117-24. Epub 2008 Jul 24.

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

We studied the antidepressant-like effect of paroxetine in strains of mice carrying different isoforms of tryptophan hydroxylase-2 (TPH-2), the enzyme responsible for the synthesis of brain serotonin (5-HT). The effect of paroxetine alone and in combination with pharmacological treatments enhancing or lowering 5-HT synthesis or melatonin was assessed in the forced swimming test in mice carrying allelic variants of TPH-2 (1473C in C57BL/6 and 1473G in DBA/2 and BALB/c). Changes in brain 5-hydroxytryptophan (5-HTP) accumulation and melatonin levels were measured by high-performance liquid chromatography. Paroxetine (2.5 and 5 mg/kg) reduced immobility time in C57BL/6J and C57BL/6N mice but had no such effect in DBA/2J, DBA/2N and BALB/c mice, even at 10 mg/kg. Enhancing 5-HT synthesis with tryptophan reinstated the antidepressant-like effect of paroxetine in DBA/2J, DBA/2N and BALB/c mice whereas inhibition of 5-HT synthesis prevented the effect of paroxetine in C57BL/6N mice. The response to paroxetine was not associated with changes in locomotor activity, brain melatonin or brain levels of the drug measured at the end of the behavioral test. These results support the importance of 5-HT synthesis in the response to SSRIs and suggest that melatonin does not contribute to the ability of tryptophan to rescue the antidepressant-like effect of paroxetine.
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http://dx.doi.org/10.1016/j.ejphar.2008.07.031DOI Listing
October 2008

Stimulation of serotonin2C receptors influences cocaine-seeking behavior in response to drug-associated stimuli in rats.

Psychopharmacology (Berl) 2008 Jan 27;196(1):15-27. Epub 2007 Sep 27.

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

Rationale: It has been suggested that the increase in serotonin transmission induced by indirect agonists such as fenfluramine and fluoxetine attenuates cue-elicited reinstatement of cocaine-seeking in rats through a 5-HT2C receptor-dependent mechanism.

Objective: We investigated whether Ro 60-0175, a nonselective 5-HT2B-2C agonist, influences cue-elicited reinstatement of cocaine-seeking behavior. We evaluated the 5-HT2C receptor's role in Ro 60-0175 by studying its interaction with SB-242,084, a selective 5-HT2C antagonist. The study also explored whether Ro 60-0175 influences cue-elicited seeking behavior associated with sucrose, a highly palatable nutritive reinforcer.

Materials And Methods: Different groups of free-feeding rats were trained to associate discriminative stimuli (SDs) with the availability of cocaine or a sucrose pellet or no-reward in two-lever operant cages. Cocaine and sucrose pellets were available under an FR1 schedule of reinforcement, and each reinforcer was followed by a 20-s timeout signaled by a cue light coming above the active lever. After extinction of reinforced responding in the absence of cue, the reinforcer-associated stimuli were reintroduced in reinstatement sessions in which reinforcers were withheld.

Results: Ro 60-0175, at IP doses from 0.1 to 1 mg/kg, dose-dependently reduced cocaine-seeking behavior, while 1 mg/kg had no such effect for the sucrose pellet. Pretreatment with 1 mg/kg SC SB-242,084 completely prevented the effect on cocaine-seeking behavior.

Conclusions: These findings, provided they can be extrapolated to abstinent human addicts, suggest therapeutic potential for the selective 5-HT2C agonist in preventing cue-controlled cocaine-seeking and relapse.
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http://dx.doi.org/10.1007/s00213-007-0916-7DOI Listing
January 2008

Effects of naltrexone on cocaine- and sucrose-seeking behaviour in response to associated stimuli in rats.

Int J Neuropsychopharmacol 2008 Feb 5;11(1):103-9. Epub 2007 Mar 5.

Experimental Psychopharmacology, Department of Neuroscience, Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy.

The non-selective opioid receptor antagonist naltrexone reduces cocaine-induced reinstatement of drug-seeking behaviour in abstinent rats. The current study sought to determine whether the opioid system is also involved in cocaine-seeking behaviour induced by cocaine-associated stimuli in abstinent rats. Adult male rats were trained to press a lever either to self-administer cocaine or to obtain sucrose pellets in the presence of distinctive discriminative and conditioned stimuli. After a period of extinction, re-exposure to cocaine-associated cues selectively elicited robust and enduring responding at the active lever; sucrose pellet-associated cues revived seeking behaviour less pronouncedly. Pretreatment with naltrexone (0.25, 1, 2.5 mg/kg s.c., 20 min before reinstatement tests) dose dependently prevented cue-induced cocaine-seeking behaviour, whereas (2.5 mg/kg s.c.) did not affect the degree of cue-induced sucrose-seeking behaviour. These results provide the first evidence that naltrexone influences cocaine seeking induced by conditioned stimuli in abstinent rats; this effect appears selective for cocaine reinstatement as opposed to a non-drug reinforcer.
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http://dx.doi.org/10.1017/S1461145707007705DOI Listing
February 2008