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Gianluca LAVANCO

10 publication(s) depuis Janvier 2016:

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12/01/2019 | Pharmacol Res   IF 5.6
Dopaminergic-GABAergic interplay and alcohol binge drinking.
Leggio GM, Di Marco R, Gulisano W, D'Ascenzo M, Torrisi SA, Geraci F, Lavanco G, Dahl K, Giurdanella G, Castorina A, Aitta-Aho T, Aceto G, Bucolo C, Puzzo D, Grassi C, Korpi ER, Drago F, Salomone S

The dopamine D3 receptor (D3R), in the nucleus accumbens (NAc), plays an important role in alcohol reward mechanisms. The major neuronal type within the NAc is the GABAergic medium spiny neuron (MSN), whose activity is regulated by dopaminergic inputs. We previously reported that genetic deletion or pharmacological blockade of D3R increases GABAA alpha6 subunit in the ventral striatum. Here we tested the hypothesis that D3R-dependent changes in GABAA alpha6 subunit in the NAc affect voluntary alcohol intake, by influencing the inhibitory transmission of MSNs. We performed in vivo and ex vivo experiments in D3R knockout (D3R (-/-)) mice and wild type littermates (D3R (+/+)). Ro 15-4513, a high affinity alpha6-GABAA ligand was used to study alpha6 activity. At baseline, NAc alpha6 expression was negligible in D3R(+/+), whereas it was robust in D3R(-/-); other relevant GABAA subunits were not changed. In situ hybridization and qPCR confirmed alpha6 subunit mRNA expression especially in the NAc. In the drinking-in-the-dark paradigm, systemic administration of Ro 15-4513 inhibited alcohol intake in D3R(+/+), but increased it in D3R(-/-); this was confirmed by intra-NAc administration of Ro 15-4513 and furosemide, a selective alpha6-GABAA antagonist. Whole-cell patch-clamp showed peak amplitudes of miniature inhibitory postsynaptic currents in NAc medium spiny neurons higher in D3R(-/-) compared to D3R(+/+); Ro 15-4513 reduced the peak amplitude in the NAc of D3R(-/-), but not in D3R(+/+). We conclude that D3R-dependent enhanced expression of alpha6 GABAA subunit inhibits voluntary alcohol intake by increasing GABA inhibition in the NAc.

19/06/2018 | pharmacol rep   IF 2.8
The role of (E)-6-chloro-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-2-styrylquinazolin-4(3H)-one in the modulation of cannabinoidergic system. A pilot study.
Plescia F, Plescia F, Raffa D, Cavallaro A, Lavanco G, Maggio B, Raimondi MV, Daidone G, Brancato A, Cannizzaro C

BACKGROUND: Compounds acting on endocannabinoid system regulate different neuronal processes through the cannabinoid receptors activation. The main aim of this study was determining whether the 2-styrylquinazolin-4(3H)-one 5, a structural analogue of rimonabant, was able to counteract the behavioural signs of the activation of the endocannabinoidergic system induced by CP 55.940. METHODS: Behavioural assessment was carried out using the tetrad task and the novel object recognition test. The endocannabinoidergic system activation was possible by the administration of CP 55.940 and 30min after rats were tested in the tetrad task for the evaluation of the antinociceptive-, cataleptic-, hypothermic- and locomotor- effects. The evaluation of the declarative memory was carried out through the novel object recognition test. The administration of the new compound was made at three different doses, 30min before CP 55.940 administration on a separate group of animals. RESULTS: Our results demonstrated that compound 5, at the highest dose, was able to counteract the effects exerted by CP 55.940, shown by an increase in body temperature, total distance travelled, latency to fall and decrease in tail flick latency, interfering conjointly in memory impairment. CONCLUSION: This study shows that compound 5 is able to counteract the cannabinoid activation induced by the agonist CP 55.940. Further investigations on its pharmacological profile are mandatory before considering it as a potential candidate for clinical studies and its possible employment as pharmacological agent for the management of different pathological conditions such as motor incoordination, obesity and brain related disorders.

16/05/2018 | clin exp pharmacol physiol   IF 2.3
The endocannabinoid-alcohol crosstalk: Recent advances on a bi-faceted target.
Lavanco G, Castelli V, Brancato A, Tringali G, Plescia F, Cannizzaro C

Increasing evidence has focusesed on the endocannabinoid system as a relevant player in the induction of aberrant synaptic plasticity and related addictive phenotype following chronic excessive alcohol drinking. In addition, the endocannabinoid system is implicated in the pathogenesis of alcoholic liver disease. Interestingly, whereas the involvement of CB1 receptors in alcohol rewarding properties is established, the central and peripheral action of CB2 signalling is still to be elucidated. This review aims at giving the input to deepen knowledge on the role of the endocannabinoid system, highlighting the advancing evidence that suggests that CB1 and CB2 receptors may play opposite roles in the regulation of both the reinforcing properties of alcohol in the brain and the mechanisms responsible for cell injury and inflammation in the hepatic tissue. The manipulation of the endocannabinoid system could represent a bi-faceted strategy to counteract alcohol-related dysfunction in central transmission and liver structural and functional disarrangement.

02/2018 | J Psychopharmacol   IF 4.2
Reward-related limbic memory and stimulation of the cannabinoid system: An upgrade in value attribution?
Brancato A, Cavallaro A, Lavanco G, Plescia F, Cannizzaro C

While a lot is known about the mechanisms promoting aversive learning, the impact of rewarding factors on memory has received comparatively less attention. This research investigates reward-related explicit memory in male rats, by taking advantage of the emotional-object recognition test. This is based on the prior association, during conditioned learning, between a rewarding experience (the encounter with a receptive female rat) and an object; afterwards rat discrimination and recognition of the 'emotional object' is recorded in the presence of a novel object, as a measure of positive limbic memory formation. Since endocannabinoids are critical for processing reward and motivation, the consequences of the stimulation of cannabinoid signalling are also assessed by the administration of WIN 55,212-2 at pre- and post-conditioning time. Our results show that rats encode the association between object and rewarding experience, form positive limbic memory of the emotional object, and retrieve this information in the face of novelty. Stimulation of the cannabinoid system at pre-conditioning time is able to strengthen reward-related explicit memory in the presence of novelty, whereas post-conditioning activation increases approach behaviour to novel stimuli. The assessment of limbic memory by the emotional-object recognition test can help unveiling the addictive and confounding properties of psychotropic drugs.

Although binge drinking is on the rise in women of reproductive age and during pregnancy, the consequences in the offspring, in particular the inheritance of alcohol-related mood disturbances and alcohol abuse vulnerability, are still poorly investigated. In this study, we modeled both Habitual- and Binge Alcohol Drinking (HAD and BAD) in female rats by employing a two-bottle choice paradigm, with 20% alcohol and water. The exposure started 12 weeks before pregnancy and continued during gestation and lactation. The consequences induced by the two alcohol drinking patterns in female rats were assessed before conception in terms of behavioral reactivity, anxiety- and depressive-like behavior. Afterwards, from adolescence to young-adulthood, male offspring was assessed for behavioral phenotype and alcohol abuse vulnerability. At pre-conceptional time BAD female rats showed higher mean alcohol intake and preference than HAD group; differences in drinking trajectories were attenuated during pregnancy and lactation. Pre-conceptional BAD induced a prevalent depressive/anhedonic-like behavior in female rats, rather than an increase in anxiety-like behavior, as observed in HAD rats. In the adolescent offspring, peri-gestational BAD did not affect behavioral reactivity in the open field and anxiety-like behavior in the elevated plus maze. Rather, BAD dams offspring displayed higher despair-behavior and lower social interaction with respect to control- and HAD dams progeny. Notably, only binge drinking exposure increased offspring vulnerability to alcohol abuse and relapse following forced abstinence. This is the first report showing that binge-like alcohol consumption from pre-conceptional until weaning induces relevant consequences in the affective phenotype of both the mothers and the offspring, and that such effects include heightened alcohol abuse vulnerability in the offspring. These findings highlight the need for more incisive public education campaigns about detrimental consequences of peri-gestational alcohol exposure.

2017 | Front Behav Neurosci   IF 2.6
Acetaldehyde, Motivation and Stress: Behavioral Evidence of an Addictive menage a trois.
Brancato A, Lavanco G, Cavallaro A, Plescia F, Cannizzaro C

Acetaldehyde (ACD) contributes to alcohol's psychoactive effects through its own rewarding properties. Recent studies shed light on the behavioral correlates of ACD administration and the possible interactions with key neurotransmitters for motivation, reward and stress-related response, such as dopamine and endocannabinoids. This mini review article critically examines ACD psychoactive properties, focusing on behavioral investigations able to unveil ACD motivational effects and their pharmacological modulation in vivo. Similarly to alcohol, rats spontaneously drink ACD, whose presence is detected in the brain following chronic self-administration paradigm. ACD motivational properties are demonstrated by operant paradigms tailored to model several drug-related behaviors, such as induction and maintenance of operant self-administration, extinction, relapse and punishment resistance. ACD-related addictive-like behaviors are sensitive to pharmacological manipulations of dopamine and endocannabinoid signaling. Interestingly, the ACD-dopamine-endocannabinoids relationship also contributes to neuroplastic alterations of the NPYergic system, a stress-related peptide critically involved in alcohol abuse. The understanding of the menage-a-trois among ACD, reward- and stress-related circuits holds promising potential for the development of novel pharmacological approaches aimed at reducing alcohol abuse.

2017 | front psychiatry   IF 3.2
Homer2 and Alcohol: A Mutual Interaction.
Castelli V, Brancato A, Cavallaro A, Lavanco G, Cannizzaro C

The past two decades of data derived from addicted individuals and preclinical animal models of addiction implicate a role for the excitatory glutamatergic transmission within the mesolimbic structures in alcoholism. The cellular localization of the glutamatergic receptor subtypes, as well as their signaling efficiency and function, are highly dependent upon discrete functional constituents of the postsynaptic density, including the Homer family of scaffolding proteins. The consequences of repeated alcohol administration on the expression of the Homer family proteins demonstrate a crucial and active role, particularly for the expression of Homer2 isoform, in regulating alcohol-induced behavioral and cellular neuroplasticity. The interaction between Homer2 and alcohol can be defined as a mutual relation: alcohol consumption enhances the expression of Homer2 protein isoform within the nucleus accumbens and the extended amygdala, cerebral areas where, in turn, Homer2 is able to mediate the development of the 'pro-alcoholic' behavioral phenotype, as a consequence of the morpho-functional synaptic adaptations. Such findings are relevant for the detection of the strategic molecular components that prompt alcohol-induced functional and behavioral disarrangement as targets for future innovative treatment options.

01/12/2016 | J Neurosci Methods   IF 2.8
The use of the Emotional-Object Recognition as an assay to assess learning and memory associated to an aversive stimulus in rodents.
Brancato A, Lavanco G, Cavallaro A, Plescia F, Cannizzaro C

BACKGROUND: Emotionally salient experiences induce the formation of explicit memory traces, besides eliciting automatic or implicit emotional memory in rodents. This study aims at investigating the implementation of a novel task for studying the formation of limbic memory engrams as a result of the acquisition- and retrieval- of fear-conditioning - biased declarative memory traces, measured by animal discrimination of an 'emotional-object'. Moreover, by using this new method we investigated the potential interactions between stimulation of cannabinoid transmission and integration of emotional information and cognitive functioning. NEW METHOD: The Emotional-Object Recognition task is composed of 3 following sessions: habituation; cued fear-conditioned learning; emotional recognition. Rats are exposed to Context 'B chamber' for habituation and cued fear-conditioning, and tested in Context 'A chamber' for emotional-object recognition. RESULTS: Cued fear-conditioning induces a reduction in emotional-object exploration time during the Emotional-Object Recognition task in controls. The activation of cannabinoid signalling impairs limbic memory formation, with respect to vehicle. COMPARISON TO EXISTING METHODS: The Emotional-Object Recognition test overcomes several limitations of commonly employed methods that explore declarative-, spatial memory and fear-conditioning in a non-integrated manner. It allows the assessment of unbiased cognitive indicators of emotional learning and memory. CONCLUSIONS: The Emotional-Object Recognition task is a valuable tool for investigating whether, and at what extent, specific drugs or pathological conditions that interfere with the individual affective/emotional homeostasis, can modulate the formation of emotionally salient explicit memory traces, thus jeopardizing control and regulation of animal behavioural strategy.

01/09/2016 | Behav Brain Res   IF 2.8
Effects of DA-Phen, a dopamine-aminoacidic conjugate, on alcohol intake and forced abstinence.
Sutera FM, De Caro V, Cannizzaro C, Giannola LI, Lavanco G, Plescia F

The mesolimbic dopamine (DA) system plays a key role in drug reinforcement and is involved in the development of alcohol addiction. Manipulation of the DAergic system represents a promising strategy to control drug-seeking behavior. Previous studies on 2-amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (DA-Phen) showed in vivo effects as a DA-ergic modulator. This study was aimed at investigate DA-Phen effects on operant behavior for alcohol seeking behavior, during reinstatement following subsequent periods of alcohol deprivation. For this purpose, male Wistar rats were tested in an operant paradigm of self-administration; behavioral reactivity and anxiety like-behavior during acute abstinence were evaluated. A characterization of DA-Phen CNS targeting by its quantification in the brain was also carried out. Our findings showed that DA-Phen administration was able to reduce relapse in alcohol drinking by 50% and reversed the alterations in behavioral reactivity and emotionality observed during acute abstinence. In conclusion, DA-Phen can reduce reinstatement of alcohol drinking in an operant-drinking paradigm following deprivation periods and reverse abstinence-induced behavioral phenotype. DA-Phen activity seems to be mediated by the modulation of the DAergic transmission. However further studies are needed to characterize DA-Phen pharmacodynamic and pharmacokinetic properties, and its potential therapeutic profile in alcohol addiction.

2016 | Front Behav Neurosci   IF 2.6
Continuous and Intermittent Alcohol Free-Choice from Pre-gestational Time to Lactation: Focus on Drinking Trajectories and Maternal Behavior.
Brancato A, Plescia F, Lavanco G, Cavallaro A, Cannizzaro C

BACKGROUND: Alcohol consumption during pregnancy and lactation induces detrimental consequences, that are not limited to the direct in utero effects of the drug on fetuses, but extend to maternal care. However, the occurrence and severity of alcohol toxicity are related to the drinking pattern and the time of exposure. The present study investigated in female rats long-term alcohol drinking trajectories, by a continuous and intermittent free-choice paradigm, during pre-gestational time, pregnancy, and lactation; moreover, the consequences of long-term alcohol consumption on the response to natural reward and maternal behavior were evaluated. METHODS: Virgin female rats were exposed to home-cage two-bottle continuous- or intermittent 'alcohol (20% v/v) vs. water' choice regimen along 12 weeks and throughout pregnancy and lactation. Animals were tested for saccharin preference, and maternal behavior was assessed by recording dams' undisturbed spontaneous home-cage behavior in the presence of their offspring. RESULTS: Our results show that the intermittent alcohol drinking-pattern induced an escalation in alcohol intake during pre-gestational time and lactation more than the continuous access, while a reduction in alcohol consumption was observed during pregnancy, contrarily to the drinking trajectories of the continuous access-exposed rats. Long-term voluntary alcohol intake induced a decreased saccharin preference in virgin female rats and a significant reduction in maternal care, with respect to control dams, although the intermittent drinking produced a greater impairment than the continuous-access paradigm. CONCLUSION: The present data indicate that both alcohol-drinking patterns are associated to modifications in the drinking trajectories of female rats, in pre-gestational time, during pregnancy and lactation. Moreover, long-lasting alcohol intake can affect sensitivity to natural rewarding stimuli and maternal behavior and sensitivity to natural rewarding stimuli in a pattern-related manner. This study underlies the importance of modeling human alcohol habit and its consequences on the mother-infant dyad, in order to prevent detrimental effects on offspring development and maturation.