Roberto Coccurello | Consiglio Nazionale delle Ricerche (CNR) (original) (raw)

Papers by Roberto Coccurello

Research paper thumbnail of Brief maternal separation affects brain α 1 -adrenoceptors and apoptotic signaling in adult mice

Exposure to adversity during early life is a risk factor for the development of different mood an... more Exposure to adversity during early life is a risk factor for the development of different mood and psychiatric disorders, including depressive-like behaviors. Here, neonatal mice were temporarily but repeatedly (day 1 to day 13) separated from mothers and placed in a testing environment containing a layer of odorless clean bedding (CB). We assessed in adult animals the impact of this early experience on binding sites and mRNA expression of α 1-adrenergic receptor subtypes, heat shock proteins (HSPs) and proapoptotic and antiapoptotic members of the Bcl-2 family proteins in different brain regions involved in processing of olfactory information and rewarding stimuli. We found that repeated exposure to CB experience produced anhedonic-like behavior in terms of reduced saccharin intake and α 1-adrenoceptor downregulation in piriform and somatosensory cortices, hippocampus, amygdala and discrete thalamic nuclei. We also found a selective decrease of α 1B-adrenoceptor binding sites in the cingulate cortex and hippocampus and an increase of hippocampal α 1A and α 1B receptor, but not of α 1D-adrenoceptor, mRNA levels. Moreover, while a significant decrease of antiapoptotic heat shock proteins Hsp72 and Hsp90 was identified in the prefrontal cortex, a parallel increase of antiapoptotic members of Bcl-2 family proteins was found at the hippocampal level. Together, these data provide evidence that the early exposure to CB experience produced enduring downregulation of α 1-adrenoceptors in the prefrontal– limbic forebrain/limbic midbrain network, which plays a key role in the processing of olfactory information and reaction to rewarding stimuli. Finally, these data show that CB experience can " prime " the hippocampal circuitry and promote the expression of antiapoptotic factors that can confer potential neuroprotection to subsequent adversity.

Research paper thumbnail of Impairing effect of amphetamine and concomitant ionotropic glutamate receptors blockade in the ventral striatum on spatial learning in mice

Rationale Accumulating evidence supports the involvement of the ventral striatum (VS) in spatial ... more Rationale Accumulating evidence supports the involvement of the ventral striatum (VS) in spatial information processing. The multiple cortical glutamatergic and mesolimbic dopaminergic (DAergic) afferences on the same neurons in the ventral striatum provide the neuroanatomical substrate for glutamate and dopamine functional interaction. However, there is little evidence in the literature on how this interaction affects the ability to encode spatial information.

Research paper thumbnail of Oleoylethanolamide: A Novel Potential Pharmacological Alternative to Cannabinoid Antagonists for the Control of Appetite

The initial pharmaceutical interest for the endocannabinoid system as a target for antiobesity th... more The initial pharmaceutical interest for the endocannabinoid system as a target for antiobesity therapies has been restricted by the severe adverse effects of the CB1 antagonist rimonabant. This study points at oleoylethanolamide (OEA), a monounsaturated analogue, and functional antagonist of anandamide, as a potential and safer antiobesity alternative to CB1 antagonism. Mice treated with equal doses (5 or 10 mg/kg, i.p.) of OEA or rimonabant were analyzed for the progressive expression of spontaneous behaviors (eating, grooming, rearing, locomotion, and resting) occurring during the development of satiety, according to the paradigm called behavioral satiety sequence (BSS). Both drugs reduced food (wet mash) intake to a similar extent. OEA treatment decreased eating activity within the first 30 min and caused a temporary increase of resting time that was not accompanied by any decline of horizontal, vertical and total motor activity. Besides decreasing eating activity, rimonabant caused a marked increase of the time spent grooming and decreased horizontal motor activity, alterations that might be indicative of aversive nonmotivational effects on feeding. These results support the idea that OEA suppresses appetite by stimulating satiety and that its profile of action might be predictive of safer effects in humans as a novel antiobesity treatment.

Research paper thumbnail of European Journal of Nutrition Increased intake of energy-dense diet and negative energy balance in a mouse model of chronic psychosocial defeat

Methods In our model of subordinate (defeated), mice (CPD) cohabitated in constant sensory contac... more Methods In our model of subordinate (defeated), mice (CPD) cohabitated in constant sensory contact with dominants, being forced to interact on daily basis, and were offered ad libitum access either to an HFD or to a control diet (CD). Control mice (of the same strain as CPD mice) were housed in pairs and left unstressed in their home cage (UN). In all these mice, we evaluated body weight, different adipose depots, energy metabolism, caloric intake, and neuropeptide expression. Results CPD mice increased the intake of HFD and reduced body weight in the presence of enhanced lipid oxidation. Resting energy expenditure and interscapular brown adipose tissue (iBAT) were increased in CPD mice, whereas epididymal adipose tissue increased only in HFDfed unstressed mice. Propiomelanocortin mRNA levels in hypothalamic arcuate nucleus increased only in HFD-fed unstressed mice. Oxytocin mRNA levels in the paraventricular nucleus and neuropeptide Y mRNA levels within the arcuate were increased only in CD-fed CPD mice. In the arcuate, CART was increased in HFD-fed UN mice and in CD-fed CPD mice, while HFD intake suppressed CART increase in defeated animals. In the basolateral amygdala, CART expression was increased only in CPD animals on HFD.

Research paper thumbnail of Expert Review of Clinical Pharmacology The bright side of psychoactive substances: cannabinoid-based drugs in motor diseases

Downloaded by [La Trobe University] at 09:09 07 July 2016

Research paper thumbnail of The Endocannabinoid-Like Derivative Oleoylethanolamide at the Gut–Brain Interface: A “Lipid Way” to Control Energy Intake and Body Weight

Cannabinoids in Health and Disease, 2016

In the last three decades, we witnessed a concomitant major increase in lifespan and a worldwide ... more In the last three decades, we witnessed a concomitant major increase in lifespan and a worldwide increasing incidence of chronic diseases such as obesity and type 2 diabetes. Disruption of energy homeostasis and systemic inflammation appear as common traits of these epidemic human diseases. The conventional endocannabinoid (eCB) system encompasses two G-protein–coupled receptors (GPCRs), their endogenous ligands (anandamide and 2-AG), and the enzymes essential for eCB biosynthesis and hydro‐ lytic inactivation. Nonetheless, the family of eCB-like derivatives is growing constant‐ ly including other N-acylethanolamines (NAEs) and 2-monoacylglycerols (2-MAGs) that do not bind canonical CB receptors rather other orphan G-protein–coupled receptors or peroxisome proliferator-activated nuclear receptors (PPARs). Here, we focus on the recent knowledge gathered on one such PPAR endocannabinoid ligand, oleoylethanolamide (OEA), from the identification of its synthesis in the small intestine to its anorexiant function with particular emphasis on our discovery of the main brain neurotransmitters system involved in its satiating effects.

Research paper thumbnail of Chronic treatment with the mGlu5R antagonist MPEP reduces the functional effects of the mGlu5R agonist CHPG in the striatum of 6-hydroxydopamine-lesioned rats: Possible relevance to the effects of mGlu5R blockade in Parkinson's disease

Journal of Neuroscience Research, 2005

This study was designed to test whether chronic treatment with the metabotropic glutamate recepto... more This study was designed to test whether chronic treatment with the metabotropic glutamate receptor 5 (mGlu5R) antagonist MPEP showed antiparkinsonian effects in rats unilaterally lesioned with 6-hydroxydopamine (6-OHDA) (a "classic" model of Parkinson's disease, PD), and to evaluate whether chronic MPEP influenced the functional properties and/or the expression of striatal mGlu5Rs. Wistar rats were lesioned with 6-OHDA and then treated with MPEP (3 mg/kg/day, i.p.) or its vehicle over 2 weeks. Chronic MPEP did not induce measurable antiparkinsonian effects, since no differences were found between MPEP- and vehicle-treated animals in the pattern of L-DOPA-induced contralateral rotations. In corticostriatal slices taken from animals chronically treated with MPEP, the functional effects of the mGlu5R agonist CHPG were significantly reduced in the lesioned vs. the intact side, while no changes were found in slices taken from vehicle-treated rats. The binding of [3H]MPEP to striatal membranes showed that neither the maximal number of binding sites (Bmax) nor the dissociation constant (Kd) were changed by the lesion and/or by chronic MPEP. While chronic MPEP did not potentiate L-DOPA-induced turning in a classical model of PD, its ability to reduce mGlu5R-associated signal could help to explain the neuroprotective/antiparkinsonian effects observed in other models of PD.

Research paper thumbnail of Paternal alcohol exposure in mice alters brain NGF and BDNF and increases ethanol-elicited preference in male offspring

Addiction Biology, 2015

Ethanol (EtOH) exposure during pregnancy induces cognitive and physiological deficits in the offs... more Ethanol (EtOH) exposure during pregnancy induces cognitive and physiological deficits in the offspring. However, the role of paternal alcohol exposure (PAE) on offspring EtOH sensitivity and neurotrophins has not received much attention. The present study examined whether PAE may disrupt nerve growth factor (NGF) and/or brain-derived neurotrophic factor (BDNF) and affect EtOH preference/rewarding properties in the male offspring. CD1 sire mice were chronically addicted for EtOH or administered with sucrose. Their male offsprings when adult were assessed for EtOH preference by a conditioned place preference paradigm. NGF and BDNF, their receptors (p75 NTR , TrkA and TrkB), dopamine active transporter (DAT), dopamine receptors D1 and D2, pro-NGF and pro-BDNF were also evaluated in brain areas. PAE affected NGF levels in frontal cortex, striatum, olfactory lobes, hippocampus and hypothalamus. BDNF alterations in frontal cortex, striatum and olfactory lobes were found. PAE induced a higher susceptibility to the EtOH rewarding effects mostly evident at the lower concentration (0.5 g/kg) that was ineffective in non-PAE offsprings. Moreover, higher ethanol concentrations (1.5 g/kg) produced an aversive response in PAE animals and a significant preference in non-PAE offspring. PAE affected also TrkA in the hippocampus and p75 NTR in the frontal cortex. DAT was affected in the olfactory lobes in PAE animals treated with 0.5 g/kg of ethanol while no differences were found on D1/D2 receptors and for pro-NGF or pro-BDNF. In conclusion, this study shows that: PAE affects NGF and BDNF expression in the mouse brain; PAE may induce ethanol intake preference in the male offspring.

Research paper thumbnail of Oleoylethanolamide: A Novel Potential Pharmacological Alternative to Cannabinoid Antagonists for the Control of Appetite

BioMed Research International, 2014

The initial pharmaceutical interest for the endocannabinoid system as a target for antiobesity th... more The initial pharmaceutical interest for the endocannabinoid system as a target for antiobesity therapies has been restricted by the severe adverse effects of the CB1 antagonist rimonabant. This study points at oleoylethanolamide (OEA), a monounsaturated analogue, and functional antagonist of anandamide, as a potential and safer antiobesity alternative to CB1 antagonism. Mice treated with equal doses (5 or 10 mg/kg, i.p.) of OEA or rimonabant were analyzed for the progressive expression of spontaneous behaviors (eating, grooming, rearing, locomotion, and resting) occurring during the development of satiety, according to the paradigm called behavioral satiety sequence (BSS). Both drugs reduced food (wet mash) intake to a similar extent. OEA treatment decreased eating activity within the first 30 min and caused a temporary increase of resting time that was not accompanied by any decline of horizontal, vertical and total motor activity. Besides decreasing eating activity, rimonabant caused a marked increase of the time spent grooming and decreased horizontal motor activity, alterations that might be indicative of aversive nonmotivational effects on feeding. These results support the idea that OEA suppresses appetite by stimulating satiety and that its profile of action might be predictive of safer effects in humans as a novel antiobesity treatment.

Research paper thumbnail of Satiety factor oleoylethanolamide recruits the brain histaminergic system to inhibit food intake

Proceedings of the National Academy of Sciences, 2014

Key factors driving eating behavior are hunger and satiety, which are controlled by a complex int... more Key factors driving eating behavior are hunger and satiety, which are controlled by a complex interplay of central neurotransmitter systems and peripheral stimuli. The lipid-derived messenger oleoylethanolamide (OEA) is released by enterocytes in response to fat intake and indirectly signals satiety to hypothalamic nuclei. Brain histamine is released during the appetitive phase to provide a high level of arousal in anticipation of feeding, and mediates satiety. However, despite the possible functional overlap of satiety signals, it is not known whether histamine participates in OEA-induced hypophagia. Using different experimental settings and diets, we report that the anorexiant effect of OEA is significantly attenuated in mice deficient in the histamine-synthesizing enzyme histidine decarboxylase (HDC-KO) or acutely depleted of histamine via interocerebroventricular infusion of the HDC blocker α-fluoromethylhistidine (α-FMH). α-FMH abolished OEA-induced early occurrence of satiety onset while increasing histamine release in the CNS with an H 3 receptor antagonist-increased hypophagia. OEA augmented histamine release in the cortex of fasted mice within a time window compatible to its anorexic effects. OEA also increased c-Fos expression in the oxytocin neurons of the paraventricular nuclei of WT but not HDC-KO mice. The density of c-Fos immunoreactive neurons in other brain regions that receive histaminergic innervation and participate in the expression of feeding behavior was comparable in OEA-treated WT and HDC-KO mice. Our results demonstrate that OEA requires the integrity of the brain histamine system to fully exert its hypophagic effect and that the oxytocin neuron-rich nuclei are the likely hypothalamic area where brain histamine influences the central effects of OEA.

Research paper thumbnail of Impairing effect of amphetamine and concomitant ionotropic glutamate receptors blockade in the ventral striatum on spatial learning in mice

Psychopharmacology, 2013

Rationale Accumulating evidence supports the involvement of the ventral striatum (VS) in spatial ... more Rationale Accumulating evidence supports the involvement of the ventral striatum (VS) in spatial information processing. The multiple cortical glutamatergic and mesolimbic dopaminergic (DAergic) afferences on the same neurons in the ventral striatum provide the neuroanatomical substrate for glutamate and dopamine functional interaction. However, there is little evidence in the literature on how this interaction affects the ability to encode spatial information.

Research paper thumbnail of Brief maternal separation affects brain α1-adrenoceptors and apoptotic signaling in adult mice

Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2014

Exposure to adversity during early life is a risk factor for the development of different mood an... more Exposure to adversity during early life is a risk factor for the development of different mood and psychiatric disorders, including depressive-like behaviors. Here, neonatal mice were temporarily but repeatedly (day 1 to day 13) separated from mothers and placed in a testing environment containing a layer of odorless clean bedding (CB). We assessed in adult animals the impact of this early experience on binding sites and mRNA expression of α 1 -adrenergic receptor subtypes, heat shock proteins (HSPs) and proapoptotic and antiapoptotic members of the Bcl-2 family proteins in different brain regions involved in processing of olfactory information and rewarding stimuli. We found that repeated exposure to CB experience produced anhedonic-like behavior in terms of reduced saccharin intake and α 1 -adrenoceptor downregulation in piriform and somatosensory cortices, hippocampus, amygdala and discrete thalamic nuclei. We also found a selective decrease of α 1B -adrenoceptor binding sites in the cingulate cortex and hippocampus and an increase of hippocampal α 1A and α 1B receptor, but not of α 1D -adrenoceptor, mRNA levels. Moreover, while a significant decrease of antiapoptotic heat shock proteins Hsp72 and Hsp90 was identified in the prefrontal cortex, a parallel increase of antiapoptotic members of Bcl-2 family proteins was found at the hippocampal level. Together, these data provide evidence that the early exposure to CB experience produced enduring downregulation of α 1 -adrenoceptors in the prefrontallimbic forebrain/limbic midbrain network, which plays a key role in the processing of olfactory information and reaction to rewarding stimuli. Finally, these data show that CB experience can "prime" the hippocampal circuitry and promote the expression of antiapoptotic factors that can confer potential neuroprotection to subsequent adversity.

Research paper thumbnail of The satiety signal oleoylethanolamide stimulates oxytocin neurosecretion from rat hypothalamic neurons

Peptides, 2013

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Research paper thumbnail of Postnatal Aversive Experience Impairs Sensitivity to Natural Rewards and Increases Susceptibility to Negative Events in Adult Life

Cerebral Cortex, 2013

Evidence shows that maternal care and postnatal traumatic events can exert powerful effects on br... more Evidence shows that maternal care and postnatal traumatic events can exert powerful effects on brain circuitry development but little is known about the impact of early postnatal experiences on processing of rewarding and aversive stimuli related to the medial prefrontal cortex (mpFC) function in adult life. In this study, the unstable maternal environment induced by repeated cross-fostering (RCF) impaired palatable food conditioned place preference and disrupted the natural preference for sweetened fluids in the saccharin preference test. By contrast, RCF increased sensitivity to conditioned place aversion (CPA) and enhanced immobility in the forced swimming test. Intracerebral microdialysis data showed that the RCF prevents mpFC dopamine (DA) outflow regardless of exposure to rewarding or aversive stimuli, whereas it induces a strong and sustained prefrontal norepinephrine (NE) release in response to different aversive experiences. Moreover, the selective mpFC NE depletion abolished CPA, thus indicating that prefrontal NE is required for motivational salience attribution to aversionrelated stimuli. These findings demonstrate that an unstable maternal environment impairs the natural propensity to seek pleasurable sources of reward, enhances sensitivity to negative events in adult life, blunts prefrontal DA outflow, and modulates NE release in the reverse manner depending on the exposure to rewarding or aversive stimuli.

Research paper thumbnail of Potential mechanisms of atypical antipsychotic-induced metabolic derangement: clues for understanding obesity and novel drug design

Pharmacology Therapeutics, Sep 1, 2010

Beside the therapeutic improvement over first-generation antipsychotics, the fact that prescripti... more Beside the therapeutic improvement over first-generation antipsychotics, the fact that prescription of atypical agents is also associated to the emergence of severe metabolic derangement in patients is not a mystery anymore. Body weight gain, dyslipidemia, adiposity, impaired glucose homeostasis, insulin and leptin resistance and new-onset type II diabetes are all part of a syndromic cluster of vast medical concern. Thus, clinical reports and rodent models of atypical antipsychotic-associated metabolic impairment have growth in parallel as separate territories. This review focuses on the attempt to take a snapshot of the present developing moment and to describe to what extent clinical data are reflected by the findings derived from animal studies. This aim is pursued through different steps that, starting from the criteria necessary to characterize the "atypicality" of atypical drugs, then explore the consistency among clinical and animal-based data. The endpoint of this survey consists in the analysis of the potential mechanisms underlying the metabolic derangement induced by this class of drugs. It is, indeed, our opinion that some atypical antipsychotics should be viewed as potent obesogenic factors that can be exploited as valuable tools to shed light into the elusive dilemma of obesity. For this reason, recently identified obesogenic and diabetogenic mechanisms are the background on which the present work is built and some novel forthcoming lines of investigation suggested.

Research paper thumbnail of 30 Days of Continuous Olanzapine Infusion Determines Energy Imbalance, Glucose Intolerance, Insulin Resistance, and Dyslipidemia in Mice

Journal of Clinical Psychopharmacology, Dec 1, 2009

The aim of this study was to model in mice the association between metabolic syndrome and the adm... more The aim of this study was to model in mice the association between metabolic syndrome and the administration of atypical antipsychotic (AAP). Two dosages (4 and 8 mg/kg per day) of olanzapine (OL) were infused in 36 female mice for 30 days by osmotic mini-pumps. This study was also designed to further extend the implications raised in other experiments by our model of AAP-induced metabolic dysregulation. Through the use of the osmotic mini-pumps, this model is aimed to circumvent the shorter (than in humans) half-life of AAPs in rodents and to chronically administer OL by a reliable and less disturbing method. Indirect calorimetry was used to evaluate metabolic rate (MR) and respiratory exchange ratio together with weight and caloric intake. Serum insulin, leptin, and glucose tolerance (oral glucose tolerance test) were assessed. Pancreatic beta cells insulin levels, periuterine and liver fat content were also analyzed. Olanzapine-infused mice exhibited a reduction of overall MR (kilojoule per hour) and resting MR and respiratory exchange ratio, with periuterine fat significantly enlarged. All metabolic alterations were detected at the highest dose, with major effects found on weight gain and hyperphagia. Impaired glucose metabolism, associated with hyperinsulinemia and hyperleptinemia were found. Insulin resistance was evidenced by the raise of HOMA-IR index. Increased insulin and lipid storage were detected at pancreatic and hepatic levels respectively. These findings illustrate the development of a cluster of risk factors (metabolic syndrome) and, for the first time, a decrease of energy expenditure (MR) due to chronic OL infusion.

Research paper thumbnail of Histone Modifications in a Mouse Model of Early Adversities and Panic Disorder: Role for Asic1 and Neurodevelopmental Genes

Scientific reports, 2016

Hyperventilation following transient, CO2-induced acidosis is ubiquitous in mammals and heritable... more Hyperventilation following transient, CO2-induced acidosis is ubiquitous in mammals and heritable. In humans, respiratory and emotional hypersensitivity to CO2 marks separation anxiety and panic disorders, and is enhanced by early-life adversities. Mice exposed to the repeated cross-fostering paradigm (RCF) of interference with maternal environment show heightened separation anxiety and hyperventilation to 6% CO2-enriched air. Gene-environment interactions affect CO2 hypersensitivity in both humans and mice. We therefore hypothesised that epigenetic modifications and increased expression of genes involved in pH-detection could explain these relationships. Medullae oblongata of RCF- and normally-reared female outbred mice were assessed by ChIP-seq for H3Ac, H3K4me3, H3K27me3 histone modifications, and by SAGE for differential gene expression. Integration of multiple experiments by network analysis revealed an active component of 148 genes pointing to the mTOR signalling pathway and n...

Research paper thumbnail of S6 Functional Interactions Between Metabotropic Glutamate and Adenosine A2A Receptors in Parkinsonian Rats

Research paper thumbnail of B89 Effects of the A2A Receptor Antagonist KW-6002 on Vigilance and Motor Performance in Aged Rats and Animal Models for Early- to Late-Stage Parkinson??S Disease

Research paper thumbnail of Paternal alcohol exposure in mice alters brain NGF and BDNF and increases ethanol-elicited preference in male offspring

Ethanol (EtOH) exposure during pregnancy induces cognitive and physiological deficits in the offs... more Ethanol (EtOH) exposure during pregnancy induces cognitive and physiological deficits in the offspring. However, the role of paternal alcohol exposure (PAE) on offspring EtOH sensitivity and neurotrophins has not received much attention. The present study examined whether PAE may disrupt nerve growth factor (NGF) and/or brain-derived neurotrophic factor (BDNF) and affect EtOH preference/rewarding properties in the male offspring. CD1 sire mice were chronically addicted for EtOH or administered with sucrose. Their male offsprings when adult were assessed for EtOH preference by a conditioned place preference paradigm. NGF and BDNF, their receptors (p75 NTR , TrkA and TrkB), dopamine active transporter (DAT), dopamine receptors D1 and D2, pro-NGF and pro-BDNF were also evaluated in brain areas. PAE affected NGF levels in frontal cortex, striatum, olfactory lobes, hippocampus and hypothalamus. BDNF alterations in frontal cortex, striatum and olfactory lobes were found. PAE induced a higher susceptibility to the EtOH rewarding effects mostly evident at the lower concentration (0.5 g/kg) that was ineffective in non-PAE offsprings. Moreover, higher ethanol concentrations (1.5 g/kg) produced an aversive response in PAE animals and a significant preference in non-PAE offspring. PAE affected also TrkA in the hippocampus and p75 NTR in the frontal cortex. DAT was affected in the olfactory lobes in PAE animals treated with 0.5 g/kg of ethanol while no differences were found on D1/D2 receptors and for pro-NGF or pro-BDNF. In conclusion, this study shows that: PAE affects NGF and BDNF expression in the mouse brain; PAE may induce ethanol intake preference in the male offspring.

Research paper thumbnail of Brief maternal separation affects brain α 1 -adrenoceptors and apoptotic signaling in adult mice

Exposure to adversity during early life is a risk factor for the development of different mood an... more Exposure to adversity during early life is a risk factor for the development of different mood and psychiatric disorders, including depressive-like behaviors. Here, neonatal mice were temporarily but repeatedly (day 1 to day 13) separated from mothers and placed in a testing environment containing a layer of odorless clean bedding (CB). We assessed in adult animals the impact of this early experience on binding sites and mRNA expression of α 1-adrenergic receptor subtypes, heat shock proteins (HSPs) and proapoptotic and antiapoptotic members of the Bcl-2 family proteins in different brain regions involved in processing of olfactory information and rewarding stimuli. We found that repeated exposure to CB experience produced anhedonic-like behavior in terms of reduced saccharin intake and α 1-adrenoceptor downregulation in piriform and somatosensory cortices, hippocampus, amygdala and discrete thalamic nuclei. We also found a selective decrease of α 1B-adrenoceptor binding sites in the cingulate cortex and hippocampus and an increase of hippocampal α 1A and α 1B receptor, but not of α 1D-adrenoceptor, mRNA levels. Moreover, while a significant decrease of antiapoptotic heat shock proteins Hsp72 and Hsp90 was identified in the prefrontal cortex, a parallel increase of antiapoptotic members of Bcl-2 family proteins was found at the hippocampal level. Together, these data provide evidence that the early exposure to CB experience produced enduring downregulation of α 1-adrenoceptors in the prefrontal– limbic forebrain/limbic midbrain network, which plays a key role in the processing of olfactory information and reaction to rewarding stimuli. Finally, these data show that CB experience can " prime " the hippocampal circuitry and promote the expression of antiapoptotic factors that can confer potential neuroprotection to subsequent adversity.

Research paper thumbnail of Impairing effect of amphetamine and concomitant ionotropic glutamate receptors blockade in the ventral striatum on spatial learning in mice

Rationale Accumulating evidence supports the involvement of the ventral striatum (VS) in spatial ... more Rationale Accumulating evidence supports the involvement of the ventral striatum (VS) in spatial information processing. The multiple cortical glutamatergic and mesolimbic dopaminergic (DAergic) afferences on the same neurons in the ventral striatum provide the neuroanatomical substrate for glutamate and dopamine functional interaction. However, there is little evidence in the literature on how this interaction affects the ability to encode spatial information.

Research paper thumbnail of Oleoylethanolamide: A Novel Potential Pharmacological Alternative to Cannabinoid Antagonists for the Control of Appetite

The initial pharmaceutical interest for the endocannabinoid system as a target for antiobesity th... more The initial pharmaceutical interest for the endocannabinoid system as a target for antiobesity therapies has been restricted by the severe adverse effects of the CB1 antagonist rimonabant. This study points at oleoylethanolamide (OEA), a monounsaturated analogue, and functional antagonist of anandamide, as a potential and safer antiobesity alternative to CB1 antagonism. Mice treated with equal doses (5 or 10 mg/kg, i.p.) of OEA or rimonabant were analyzed for the progressive expression of spontaneous behaviors (eating, grooming, rearing, locomotion, and resting) occurring during the development of satiety, according to the paradigm called behavioral satiety sequence (BSS). Both drugs reduced food (wet mash) intake to a similar extent. OEA treatment decreased eating activity within the first 30 min and caused a temporary increase of resting time that was not accompanied by any decline of horizontal, vertical and total motor activity. Besides decreasing eating activity, rimonabant caused a marked increase of the time spent grooming and decreased horizontal motor activity, alterations that might be indicative of aversive nonmotivational effects on feeding. These results support the idea that OEA suppresses appetite by stimulating satiety and that its profile of action might be predictive of safer effects in humans as a novel antiobesity treatment.

Research paper thumbnail of European Journal of Nutrition Increased intake of energy-dense diet and negative energy balance in a mouse model of chronic psychosocial defeat

Methods In our model of subordinate (defeated), mice (CPD) cohabitated in constant sensory contac... more Methods In our model of subordinate (defeated), mice (CPD) cohabitated in constant sensory contact with dominants, being forced to interact on daily basis, and were offered ad libitum access either to an HFD or to a control diet (CD). Control mice (of the same strain as CPD mice) were housed in pairs and left unstressed in their home cage (UN). In all these mice, we evaluated body weight, different adipose depots, energy metabolism, caloric intake, and neuropeptide expression. Results CPD mice increased the intake of HFD and reduced body weight in the presence of enhanced lipid oxidation. Resting energy expenditure and interscapular brown adipose tissue (iBAT) were increased in CPD mice, whereas epididymal adipose tissue increased only in HFDfed unstressed mice. Propiomelanocortin mRNA levels in hypothalamic arcuate nucleus increased only in HFD-fed unstressed mice. Oxytocin mRNA levels in the paraventricular nucleus and neuropeptide Y mRNA levels within the arcuate were increased only in CD-fed CPD mice. In the arcuate, CART was increased in HFD-fed UN mice and in CD-fed CPD mice, while HFD intake suppressed CART increase in defeated animals. In the basolateral amygdala, CART expression was increased only in CPD animals on HFD.

Research paper thumbnail of Expert Review of Clinical Pharmacology The bright side of psychoactive substances: cannabinoid-based drugs in motor diseases

Downloaded by [La Trobe University] at 09:09 07 July 2016

Research paper thumbnail of The Endocannabinoid-Like Derivative Oleoylethanolamide at the Gut–Brain Interface: A “Lipid Way” to Control Energy Intake and Body Weight

Cannabinoids in Health and Disease, 2016

In the last three decades, we witnessed a concomitant major increase in lifespan and a worldwide ... more In the last three decades, we witnessed a concomitant major increase in lifespan and a worldwide increasing incidence of chronic diseases such as obesity and type 2 diabetes. Disruption of energy homeostasis and systemic inflammation appear as common traits of these epidemic human diseases. The conventional endocannabinoid (eCB) system encompasses two G-protein–coupled receptors (GPCRs), their endogenous ligands (anandamide and 2-AG), and the enzymes essential for eCB biosynthesis and hydro‐ lytic inactivation. Nonetheless, the family of eCB-like derivatives is growing constant‐ ly including other N-acylethanolamines (NAEs) and 2-monoacylglycerols (2-MAGs) that do not bind canonical CB receptors rather other orphan G-protein–coupled receptors or peroxisome proliferator-activated nuclear receptors (PPARs). Here, we focus on the recent knowledge gathered on one such PPAR endocannabinoid ligand, oleoylethanolamide (OEA), from the identification of its synthesis in the small intestine to its anorexiant function with particular emphasis on our discovery of the main brain neurotransmitters system involved in its satiating effects.

Research paper thumbnail of Chronic treatment with the mGlu5R antagonist MPEP reduces the functional effects of the mGlu5R agonist CHPG in the striatum of 6-hydroxydopamine-lesioned rats: Possible relevance to the effects of mGlu5R blockade in Parkinson's disease

Journal of Neuroscience Research, 2005

This study was designed to test whether chronic treatment with the metabotropic glutamate recepto... more This study was designed to test whether chronic treatment with the metabotropic glutamate receptor 5 (mGlu5R) antagonist MPEP showed antiparkinsonian effects in rats unilaterally lesioned with 6-hydroxydopamine (6-OHDA) (a "classic" model of Parkinson's disease, PD), and to evaluate whether chronic MPEP influenced the functional properties and/or the expression of striatal mGlu5Rs. Wistar rats were lesioned with 6-OHDA and then treated with MPEP (3 mg/kg/day, i.p.) or its vehicle over 2 weeks. Chronic MPEP did not induce measurable antiparkinsonian effects, since no differences were found between MPEP- and vehicle-treated animals in the pattern of L-DOPA-induced contralateral rotations. In corticostriatal slices taken from animals chronically treated with MPEP, the functional effects of the mGlu5R agonist CHPG were significantly reduced in the lesioned vs. the intact side, while no changes were found in slices taken from vehicle-treated rats. The binding of [3H]MPEP to striatal membranes showed that neither the maximal number of binding sites (Bmax) nor the dissociation constant (Kd) were changed by the lesion and/or by chronic MPEP. While chronic MPEP did not potentiate L-DOPA-induced turning in a classical model of PD, its ability to reduce mGlu5R-associated signal could help to explain the neuroprotective/antiparkinsonian effects observed in other models of PD.

Research paper thumbnail of Paternal alcohol exposure in mice alters brain NGF and BDNF and increases ethanol-elicited preference in male offspring

Addiction Biology, 2015

Ethanol (EtOH) exposure during pregnancy induces cognitive and physiological deficits in the offs... more Ethanol (EtOH) exposure during pregnancy induces cognitive and physiological deficits in the offspring. However, the role of paternal alcohol exposure (PAE) on offspring EtOH sensitivity and neurotrophins has not received much attention. The present study examined whether PAE may disrupt nerve growth factor (NGF) and/or brain-derived neurotrophic factor (BDNF) and affect EtOH preference/rewarding properties in the male offspring. CD1 sire mice were chronically addicted for EtOH or administered with sucrose. Their male offsprings when adult were assessed for EtOH preference by a conditioned place preference paradigm. NGF and BDNF, their receptors (p75 NTR , TrkA and TrkB), dopamine active transporter (DAT), dopamine receptors D1 and D2, pro-NGF and pro-BDNF were also evaluated in brain areas. PAE affected NGF levels in frontal cortex, striatum, olfactory lobes, hippocampus and hypothalamus. BDNF alterations in frontal cortex, striatum and olfactory lobes were found. PAE induced a higher susceptibility to the EtOH rewarding effects mostly evident at the lower concentration (0.5 g/kg) that was ineffective in non-PAE offsprings. Moreover, higher ethanol concentrations (1.5 g/kg) produced an aversive response in PAE animals and a significant preference in non-PAE offspring. PAE affected also TrkA in the hippocampus and p75 NTR in the frontal cortex. DAT was affected in the olfactory lobes in PAE animals treated with 0.5 g/kg of ethanol while no differences were found on D1/D2 receptors and for pro-NGF or pro-BDNF. In conclusion, this study shows that: PAE affects NGF and BDNF expression in the mouse brain; PAE may induce ethanol intake preference in the male offspring.

Research paper thumbnail of Oleoylethanolamide: A Novel Potential Pharmacological Alternative to Cannabinoid Antagonists for the Control of Appetite

BioMed Research International, 2014

The initial pharmaceutical interest for the endocannabinoid system as a target for antiobesity th... more The initial pharmaceutical interest for the endocannabinoid system as a target for antiobesity therapies has been restricted by the severe adverse effects of the CB1 antagonist rimonabant. This study points at oleoylethanolamide (OEA), a monounsaturated analogue, and functional antagonist of anandamide, as a potential and safer antiobesity alternative to CB1 antagonism. Mice treated with equal doses (5 or 10 mg/kg, i.p.) of OEA or rimonabant were analyzed for the progressive expression of spontaneous behaviors (eating, grooming, rearing, locomotion, and resting) occurring during the development of satiety, according to the paradigm called behavioral satiety sequence (BSS). Both drugs reduced food (wet mash) intake to a similar extent. OEA treatment decreased eating activity within the first 30 min and caused a temporary increase of resting time that was not accompanied by any decline of horizontal, vertical and total motor activity. Besides decreasing eating activity, rimonabant caused a marked increase of the time spent grooming and decreased horizontal motor activity, alterations that might be indicative of aversive nonmotivational effects on feeding. These results support the idea that OEA suppresses appetite by stimulating satiety and that its profile of action might be predictive of safer effects in humans as a novel antiobesity treatment.

Research paper thumbnail of Satiety factor oleoylethanolamide recruits the brain histaminergic system to inhibit food intake

Proceedings of the National Academy of Sciences, 2014

Key factors driving eating behavior are hunger and satiety, which are controlled by a complex int... more Key factors driving eating behavior are hunger and satiety, which are controlled by a complex interplay of central neurotransmitter systems and peripheral stimuli. The lipid-derived messenger oleoylethanolamide (OEA) is released by enterocytes in response to fat intake and indirectly signals satiety to hypothalamic nuclei. Brain histamine is released during the appetitive phase to provide a high level of arousal in anticipation of feeding, and mediates satiety. However, despite the possible functional overlap of satiety signals, it is not known whether histamine participates in OEA-induced hypophagia. Using different experimental settings and diets, we report that the anorexiant effect of OEA is significantly attenuated in mice deficient in the histamine-synthesizing enzyme histidine decarboxylase (HDC-KO) or acutely depleted of histamine via interocerebroventricular infusion of the HDC blocker α-fluoromethylhistidine (α-FMH). α-FMH abolished OEA-induced early occurrence of satiety onset while increasing histamine release in the CNS with an H 3 receptor antagonist-increased hypophagia. OEA augmented histamine release in the cortex of fasted mice within a time window compatible to its anorexic effects. OEA also increased c-Fos expression in the oxytocin neurons of the paraventricular nuclei of WT but not HDC-KO mice. The density of c-Fos immunoreactive neurons in other brain regions that receive histaminergic innervation and participate in the expression of feeding behavior was comparable in OEA-treated WT and HDC-KO mice. Our results demonstrate that OEA requires the integrity of the brain histamine system to fully exert its hypophagic effect and that the oxytocin neuron-rich nuclei are the likely hypothalamic area where brain histamine influences the central effects of OEA.

Research paper thumbnail of Impairing effect of amphetamine and concomitant ionotropic glutamate receptors blockade in the ventral striatum on spatial learning in mice

Psychopharmacology, 2013

Rationale Accumulating evidence supports the involvement of the ventral striatum (VS) in spatial ... more Rationale Accumulating evidence supports the involvement of the ventral striatum (VS) in spatial information processing. The multiple cortical glutamatergic and mesolimbic dopaminergic (DAergic) afferences on the same neurons in the ventral striatum provide the neuroanatomical substrate for glutamate and dopamine functional interaction. However, there is little evidence in the literature on how this interaction affects the ability to encode spatial information.

Research paper thumbnail of Brief maternal separation affects brain α1-adrenoceptors and apoptotic signaling in adult mice

Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2014

Exposure to adversity during early life is a risk factor for the development of different mood an... more Exposure to adversity during early life is a risk factor for the development of different mood and psychiatric disorders, including depressive-like behaviors. Here, neonatal mice were temporarily but repeatedly (day 1 to day 13) separated from mothers and placed in a testing environment containing a layer of odorless clean bedding (CB). We assessed in adult animals the impact of this early experience on binding sites and mRNA expression of α 1 -adrenergic receptor subtypes, heat shock proteins (HSPs) and proapoptotic and antiapoptotic members of the Bcl-2 family proteins in different brain regions involved in processing of olfactory information and rewarding stimuli. We found that repeated exposure to CB experience produced anhedonic-like behavior in terms of reduced saccharin intake and α 1 -adrenoceptor downregulation in piriform and somatosensory cortices, hippocampus, amygdala and discrete thalamic nuclei. We also found a selective decrease of α 1B -adrenoceptor binding sites in the cingulate cortex and hippocampus and an increase of hippocampal α 1A and α 1B receptor, but not of α 1D -adrenoceptor, mRNA levels. Moreover, while a significant decrease of antiapoptotic heat shock proteins Hsp72 and Hsp90 was identified in the prefrontal cortex, a parallel increase of antiapoptotic members of Bcl-2 family proteins was found at the hippocampal level. Together, these data provide evidence that the early exposure to CB experience produced enduring downregulation of α 1 -adrenoceptors in the prefrontallimbic forebrain/limbic midbrain network, which plays a key role in the processing of olfactory information and reaction to rewarding stimuli. Finally, these data show that CB experience can "prime" the hippocampal circuitry and promote the expression of antiapoptotic factors that can confer potential neuroprotection to subsequent adversity.

Research paper thumbnail of The satiety signal oleoylethanolamide stimulates oxytocin neurosecretion from rat hypothalamic neurons

Peptides, 2013

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Research paper thumbnail of Postnatal Aversive Experience Impairs Sensitivity to Natural Rewards and Increases Susceptibility to Negative Events in Adult Life

Cerebral Cortex, 2013

Evidence shows that maternal care and postnatal traumatic events can exert powerful effects on br... more Evidence shows that maternal care and postnatal traumatic events can exert powerful effects on brain circuitry development but little is known about the impact of early postnatal experiences on processing of rewarding and aversive stimuli related to the medial prefrontal cortex (mpFC) function in adult life. In this study, the unstable maternal environment induced by repeated cross-fostering (RCF) impaired palatable food conditioned place preference and disrupted the natural preference for sweetened fluids in the saccharin preference test. By contrast, RCF increased sensitivity to conditioned place aversion (CPA) and enhanced immobility in the forced swimming test. Intracerebral microdialysis data showed that the RCF prevents mpFC dopamine (DA) outflow regardless of exposure to rewarding or aversive stimuli, whereas it induces a strong and sustained prefrontal norepinephrine (NE) release in response to different aversive experiences. Moreover, the selective mpFC NE depletion abolished CPA, thus indicating that prefrontal NE is required for motivational salience attribution to aversionrelated stimuli. These findings demonstrate that an unstable maternal environment impairs the natural propensity to seek pleasurable sources of reward, enhances sensitivity to negative events in adult life, blunts prefrontal DA outflow, and modulates NE release in the reverse manner depending on the exposure to rewarding or aversive stimuli.

Research paper thumbnail of Potential mechanisms of atypical antipsychotic-induced metabolic derangement: clues for understanding obesity and novel drug design

Pharmacology Therapeutics, Sep 1, 2010

Beside the therapeutic improvement over first-generation antipsychotics, the fact that prescripti... more Beside the therapeutic improvement over first-generation antipsychotics, the fact that prescription of atypical agents is also associated to the emergence of severe metabolic derangement in patients is not a mystery anymore. Body weight gain, dyslipidemia, adiposity, impaired glucose homeostasis, insulin and leptin resistance and new-onset type II diabetes are all part of a syndromic cluster of vast medical concern. Thus, clinical reports and rodent models of atypical antipsychotic-associated metabolic impairment have growth in parallel as separate territories. This review focuses on the attempt to take a snapshot of the present developing moment and to describe to what extent clinical data are reflected by the findings derived from animal studies. This aim is pursued through different steps that, starting from the criteria necessary to characterize the "atypicality" of atypical drugs, then explore the consistency among clinical and animal-based data. The endpoint of this survey consists in the analysis of the potential mechanisms underlying the metabolic derangement induced by this class of drugs. It is, indeed, our opinion that some atypical antipsychotics should be viewed as potent obesogenic factors that can be exploited as valuable tools to shed light into the elusive dilemma of obesity. For this reason, recently identified obesogenic and diabetogenic mechanisms are the background on which the present work is built and some novel forthcoming lines of investigation suggested.

Research paper thumbnail of 30 Days of Continuous Olanzapine Infusion Determines Energy Imbalance, Glucose Intolerance, Insulin Resistance, and Dyslipidemia in Mice

Journal of Clinical Psychopharmacology, Dec 1, 2009

The aim of this study was to model in mice the association between metabolic syndrome and the adm... more The aim of this study was to model in mice the association between metabolic syndrome and the administration of atypical antipsychotic (AAP). Two dosages (4 and 8 mg/kg per day) of olanzapine (OL) were infused in 36 female mice for 30 days by osmotic mini-pumps. This study was also designed to further extend the implications raised in other experiments by our model of AAP-induced metabolic dysregulation. Through the use of the osmotic mini-pumps, this model is aimed to circumvent the shorter (than in humans) half-life of AAPs in rodents and to chronically administer OL by a reliable and less disturbing method. Indirect calorimetry was used to evaluate metabolic rate (MR) and respiratory exchange ratio together with weight and caloric intake. Serum insulin, leptin, and glucose tolerance (oral glucose tolerance test) were assessed. Pancreatic beta cells insulin levels, periuterine and liver fat content were also analyzed. Olanzapine-infused mice exhibited a reduction of overall MR (kilojoule per hour) and resting MR and respiratory exchange ratio, with periuterine fat significantly enlarged. All metabolic alterations were detected at the highest dose, with major effects found on weight gain and hyperphagia. Impaired glucose metabolism, associated with hyperinsulinemia and hyperleptinemia were found. Insulin resistance was evidenced by the raise of HOMA-IR index. Increased insulin and lipid storage were detected at pancreatic and hepatic levels respectively. These findings illustrate the development of a cluster of risk factors (metabolic syndrome) and, for the first time, a decrease of energy expenditure (MR) due to chronic OL infusion.

Research paper thumbnail of Histone Modifications in a Mouse Model of Early Adversities and Panic Disorder: Role for Asic1 and Neurodevelopmental Genes

Scientific reports, 2016

Hyperventilation following transient, CO2-induced acidosis is ubiquitous in mammals and heritable... more Hyperventilation following transient, CO2-induced acidosis is ubiquitous in mammals and heritable. In humans, respiratory and emotional hypersensitivity to CO2 marks separation anxiety and panic disorders, and is enhanced by early-life adversities. Mice exposed to the repeated cross-fostering paradigm (RCF) of interference with maternal environment show heightened separation anxiety and hyperventilation to 6% CO2-enriched air. Gene-environment interactions affect CO2 hypersensitivity in both humans and mice. We therefore hypothesised that epigenetic modifications and increased expression of genes involved in pH-detection could explain these relationships. Medullae oblongata of RCF- and normally-reared female outbred mice were assessed by ChIP-seq for H3Ac, H3K4me3, H3K27me3 histone modifications, and by SAGE for differential gene expression. Integration of multiple experiments by network analysis revealed an active component of 148 genes pointing to the mTOR signalling pathway and n...

Research paper thumbnail of S6 Functional Interactions Between Metabotropic Glutamate and Adenosine A2A Receptors in Parkinsonian Rats

Research paper thumbnail of B89 Effects of the A2A Receptor Antagonist KW-6002 on Vigilance and Motor Performance in Aged Rats and Animal Models for Early- to Late-Stage Parkinson??S Disease

Research paper thumbnail of Paternal alcohol exposure in mice alters brain NGF and BDNF and increases ethanol-elicited preference in male offspring

Ethanol (EtOH) exposure during pregnancy induces cognitive and physiological deficits in the offs... more Ethanol (EtOH) exposure during pregnancy induces cognitive and physiological deficits in the offspring. However, the role of paternal alcohol exposure (PAE) on offspring EtOH sensitivity and neurotrophins has not received much attention. The present study examined whether PAE may disrupt nerve growth factor (NGF) and/or brain-derived neurotrophic factor (BDNF) and affect EtOH preference/rewarding properties in the male offspring. CD1 sire mice were chronically addicted for EtOH or administered with sucrose. Their male offsprings when adult were assessed for EtOH preference by a conditioned place preference paradigm. NGF and BDNF, their receptors (p75 NTR , TrkA and TrkB), dopamine active transporter (DAT), dopamine receptors D1 and D2, pro-NGF and pro-BDNF were also evaluated in brain areas. PAE affected NGF levels in frontal cortex, striatum, olfactory lobes, hippocampus and hypothalamus. BDNF alterations in frontal cortex, striatum and olfactory lobes were found. PAE induced a higher susceptibility to the EtOH rewarding effects mostly evident at the lower concentration (0.5 g/kg) that was ineffective in non-PAE offsprings. Moreover, higher ethanol concentrations (1.5 g/kg) produced an aversive response in PAE animals and a significant preference in non-PAE offspring. PAE affected also TrkA in the hippocampus and p75 NTR in the frontal cortex. DAT was affected in the olfactory lobes in PAE animals treated with 0.5 g/kg of ethanol while no differences were found on D1/D2 receptors and for pro-NGF or pro-BDNF. In conclusion, this study shows that: PAE affects NGF and BDNF expression in the mouse brain; PAE may induce ethanol intake preference in the male offspring.