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Antonietta Gentile,
Silvia Rossi,
Valeria Studer, Caterina Motta,
Valentina De Chiara,
Alessandra Musella,
Helena Sepman,
Diego Fresegna,
Gabriele Musumeci,
Giorgio Grasselli,
Nabila Haji,
Sagit Weiss,
Liat Hayardeny,
Georgia Mandolesi,
Diego Centonze
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ABSTRACT: Glutamate-mediated excitotoxicity is supposed to induce neurodegeneration in multiple sclerosis (MS). Glatiramer acetate (GA) is an immunomodulatory agent used in MS treatment with potential neuroprotective action. Aim of the present study was to investigate whether GA has effects on glutamate transmission alterations occurring in experimental autoimmune encephalomyelitis (EAE), to disclose a possible mechanism of GA-induced neuroprotection in this mouse model of MS. Single neuron electrophysiological recordings and immunofluorescence analysis of microglia activation were performed in the striatum of EAE mice, treated or not with GA, at different stages of the disease. GA treatment was able to reverse the tumor necrosis factor-α (TNF-α)-induced alterations of striatal glutamate-mediated excitatory postsynaptic currents (EPSCs) of EAE mice. Incubation of striatal slices of control animals with lymphocytes taken from EAE mice treated with GA failed to replicate such an anti-glutamatergic effect, while activated microglial cells stimulated with GA in vitro mimicked the effect of GA treatment of EAE mice. Consistently, EAE mice treated with GA had less microglial activation and less TNF-α expression than untreated EAE animals. Furthermore, direct application of GA to EAE slices replicated the in vivo protective activity of GA. Our results show that GA is neuroprotective against glutamate toxicity independently of its peripheral immunodulatory action, and through direct modulation of microglial activation and TNF-α release in the grey matter of EAE and possibly of MS brains.
Journal of Neuroimmune Pharmacology 01/2013; · 4.57 Impact Factor
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Francesca Ruffini,
Silvia Rossi,
Andrea Bergamaschi,
Elena Brambilla,
Annamaria Finardi, Caterina Motta,
Valeria Studer,
Francesca Barbieri,
Valentina De Chiara,
Liat Hayardeny,
Giancarlo Comi,
Diego Centonze,
Gianvito Martino
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ABSTRACT: BACKGROUND There are two generally accepted strategies for treating multiple sclerosis (MS), preventing central nervous system (CNS) damage indirectly through immunomodulatory interventions and/or repairing CNS damage by promoting remyelination. Both approaches also provide neuroprotection since they can prevent, indirectly or directly, axonal damage. OBJECTIVE Recent experimental and clinical evidence indicates that the novel immunomodulatory drug laquinimod can exert a neuroprotective role in MS. Whether laquinimod-mediated neuroprotection is exerted directly on neuronal cells or indirectly via peripheral immunomodulation is still unclear. METHODS C57Bl/6 experimental autoimmune encephalomyelitis (EAE) mice, immunised with myelin oligodendrocyte glycoprotein (MOG)35-55 peptide, were treated for 26 days with subcutaneous daily injections of laquinimod (from 1 to 25 mg/kg). Patch clamp electrophysiology was performed on acute brain striatal slices from EAE mice treated with daily (25 mg/kg) laquinimod and on acute brain striatal slices from control mice bathed with laquinimod (1-30 µM). RESULTS Both preventive and therapeutic laquinimod treatment fully prevented the alterations of GABAergic synapses induced by EAE, the first limiting also glutamatergic synaptic alterations. This dual effect might, in turn, have limited glutamatergic excitotoxicity, a phenomenon previously observed early during EAE and possibly correlated with later axonal damage. Furthermore, laquinimod treatment also preserved cannabinoid CB1 receptor sensitivity, normally lost during EAE. Finally, laquinimod per se was able to regulate synaptic transmission by increasing inhibitory post-synaptic currents and, at the same time, reducing excitatory post-synaptic currents. CONCLUSIONS Our data suggest a novel neuroprotective mechanism by which laquinimod might in vivo protect from neuronal damage occurring as a consequence of inflammatory immune-mediated demyelination.
Multiple Sclerosis 12/2012; · 4.26 Impact Factor
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Silvia Rossi,
Lucia Sacchetti,
Francesco Napolitano,
Valentina De Chiara, Caterina Motta,
Valeria Studer,
Alessandra Musella,
Francesca Barbieri,
Monica Bari,
Giorgio Bernardi,
Mauro Maccarrone,
Alessandro Usiello,
Diego Centonze
[show abstract]
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ABSTRACT: Interleukin-1β (IL-1β) is involved in mood alterations associated with inflammatory illnesses and with stress. The synaptic basis of IL-1β-induced emotional disturbances is still unknown. To address the possible involvement of the endocannabinoid system in IL-1β-induced anxiety, we performed behavioral and neurophysiological studies in mice exposed to stress or to intracerebroventricular injections of this inflammatory cytokine or of its antagonist. We found that a single intracerebroventricular injection of IL-1β caused anxiety in mice, and abrogated the sensitivity of cannabinoid CB1 receptors (CB1Rs) controlling GABA synapses in the striatum. Identical behavioral and synaptic results were obtained following social defeat stress, and intracerebroventricular injection of IL-1 receptor antagonist reverted both effects. IL-1β-mediated inhibition of CB1R function was secondary to altered cholesterol composition within membrane lipid rafts, and required intact function of the transient receptor potential vanilloid 1 (TRPV1) channel, another element of the endocannabinoid system. Membrane lipid raft disruption and inhibition of cholesterol synthesis, in fact, abrogated IL-1β-CB1R coupling, and TRPV1-/- mice were indeed insensitive to the synaptic and behavioral effects of both IL-1β and stress. On the other hand, cholesterol enrichment of striatal slices mimicked the synaptic effects of IL-1β on CB1Rs only in control mice, while the same treatment was ineffective in slices prepared from TRPV1-/- mice. The present investigation identifies a previously unrecognized interaction between a major proinflammatory cytokine and the endocannabinoid system in the pathophysiology of anxiety.
Journal of Neuroscience 10/2012; 32(40):13896-13905. · 7.11 Impact Factor
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Nabila Haji,
Georgia Mandolesi,
Antonietta Gentile,
Lucia Sacchetti,
Diego Fresegna,
Silvia Rossi,
Alessandra Musella,
Helena Sepman, Caterina Motta,
Valeria Studer,
Valentina De Chiara,
Giorgio Bernardi,
Piergiorgio Strata,
Diego Centonze
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ABSTRACT: Multiple sclerosis (MS) causes a variety of motor and sensory deficits and it is also associated with mood disturbances. It is unclear if anxiety and depression in MS entirely reflect a subjective reaction to a chronic disease causing motor disability or rather depend on specific effects of neuroinflammation in neuronal circuits. To answer this question, behavioral, electrophysiological, and immunofluorescence experiments were performed in mice with experimental autoimmune encephalomyelitis (EAE), which models MS in mice. First, we observed high anxiety indexes in EAE mice, preceding the appearance of motor defects. Then, we demonstrated that tumor necrosis factor α (TNF-α) has a crucial role in anxiety associated with neuroinflammation. In fact, intracerebroventricular (icv) administration of etanercept, an inhibitor of TNF-α signaling, resulted in anxiolytic-like effects in EAE-mice. Accordingly, icv injection of TNF-α induced per se overt anxious behavior in control mice. Moreover, we propose the striatum as one of the brain regions potentially involved in EAE anxious behavior. We observed that before disease onset EAE striatum presents elevated TNF-α levels and strong activated microglia, early signs of inflammation associated with alterations of striatal excitatory postsynaptic currents (EPSCs). Interestingly, etanercept corrected the synaptic defects of pre-symptomatic EAE mice while icv injection of TNF-α in non-EAE mice altered EPSCs, thus mimicking the synaptic effects of EAE. In conclusion, anxiety characterizes EAE course since the very early phases of the disease. TNF-α released from activated microglia mediates this effect likely through the modulation of striatal excitatory synaptic transmission.
Experimental Neurology 07/2012; 237(2):296-303. · 4.70 Impact Factor
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Silvia Rossi, Caterina Motta,
Valeria Studer,
Fabrizia Monteleone,
Valentina De Chiara,
Fabio Buttari,
Francesca Barbieri,
Giorgio Bernardi,
Luca Battistini,
Gary Cutter,
Olaf Stüve,
Marco Salvetti,
Diego Centonze
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ABSTRACT: Background: Multiple sclerosis (MS) patients discontinuing natalizumab treatment are at risk of disease reactivation. No clinical or surrogate parameters exist to identify patients at risk of post-natalizumab MS reactivation.Objective: To determine the role of natalizumab-induced lymphocytosis and of Akt polymorphisms in disease reactivation after natalizumab discontinuation.Methods: Peripheral leukocyte count and composition were monitored in 93 MS patients during natalizumab treatment, and in 56 of these subjects who discontinued the treatment. Genetic variants of the anti-apoptotic protein Akt were determined in all subjects because natalizumab modulates the apoptotic pathway and lymphocyte survival is regulated by the apoptotic cascade.Results: Natalizumab-induced peripheral lymphocytosis protected from post-natalizumab MS reactivation. Subjects who relapsed or had magnetic resonance imaging (MRI) worsening after treatment cessation, in fact, had milder peripheral lymphocyte increases during the treatment, largely caused by less marked T cell increase. Furthermore, subjects carrying a variant of the gene coding for Akt associated with reduced anti-apoptotic efficiency (rs2498804T) had lower lymphocytosis and higher risk of disease reactivation.Conclusion: This study identified one functionally meaningful genetic variant within the Akt signaling pathway that is associated with both lymphocyte count and composition alterations during natalizumab treatment, and with the risk of disease reactivation after natalizumab discontinuation.
Multiple Sclerosis 05/2012; · 4.26 Impact Factor
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[show abstract]
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ABSTRACT: Abnormal glutamate-dependent synaptic excitation contributes to neuronal damage in multiple sclerosis (MS). Little is known about the involvement of the GABA system in this disorder. Here we found that cerebrospinal fluid (CSF) from MS patients with enhanced brain lesions on magnetic resonance imaging inhibited GABA transmission in mouse brain slices. Enhanced IL-1β neuronal action was responsible for this effect, because IL-1β receptor antagonist blocked, and exogenous IL-1β mimicked the synaptic effect of inflamed CSF. Our results provide evidence that focal inflammation in MS perturbs the cytokine milieu within the circulating CSF, resulting in diffuse GABAergic alteration in neurons.
Multiple Sclerosis 03/2012; 18(11):1633-5. · 4.26 Impact Factor
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Silvia Rossi,
Roberto Furlan,
Valentina De Chiara, Caterina Motta,
Valeria Studer,
Francesco Mori,
Alessandra Musella,
Alessandra Bergami,
Luca Muzio,
Giorgio Bernardi,
Luca Battistini,
Gianvito Martino,
Diego Centonze
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ABSTRACT: The frequency of inflammatory episodes in the early stages of multiple sclerosis (MS) has been correlated with late neurodegeneration, but the mechanism by which inflammation gives rise to delayed neuronal damage is unknown. Increased activity of the neurotransmitter glutamate is thought to play a role in the inflammation-driven neurodegenerative process of MS, and therefore we tested whether inflammatory cytokines released during acute MS attacks have the property of enhancing glutamate-mediated transmission and excitotoxicity in central neurons.
We compared the effect of cerebrospinal fluid (CSF) from active and quiescent MS patients on glutamate-mediated excitatory postsynaptic currents (EPSCs) and excitotoxic damage in rodent brain slices. We also measured CSF concentrations of tumor necrosis factor-α, of interleukin-1β (IL-1β), and of IL-1 receptor antagonist (IL-1ra), and correlated cytokine levels with cortical excitability assessed in MS patients by means of paired-pulse transcranial magnetic stimulation (TMS).
CSF from MS patients with enhanced brain lesions at magnetic resonance imaging was able to increase spontaneous EPSC frequency and glutamate-mediated neuronal swelling in vitro, through a mechanism dependent on enhanced IL-1β signaling and increased glutamate α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor stimulation. Furthermore, IL-1β/IL-1ra ratio was significantly higher in the CSF of active MS subjects, and correlated with intracortical facilitation, an accredited TMS measure of glutamate transmission. Finally, we identified for the first time transient receptor potential vanilloid 1 channels as essential intermediates for the synaptic action of IL-1β on central glutamatergic synapses.
Our results provide compelling evidence of the synaptic mechanism linking inflammation and excitotoxic neurodegeneration in MS.
Annals of Neurology 01/2012; 71(1):76-83. · 11.09 Impact Factor
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Maura Castelli,
Mauro Federici,
Silvia Rossi,
Valentina De Chiara,
Francesco Napolitano,
Valeria Studer, Caterina Motta,
Lucia Sacchetti,
Rosaria Romano,
Alessandra Musella,
Giorgio Bernardi,
Alberto Siracusano,
Howard H Gu,
Nicola B Mercuri,
Alessandro Usiello,
Diego Centonze
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ABSTRACT: Abnormal dopamine (DA) transmission in the striatum plays a pivotal role in attention-deficit/hyperactivity disorder (ADHD). As striatal DA signalling modulates the endocannabinoid system (ECS), the present study was aimed at investigating cannabinoid CB1 receptor (CB1R) function in a model of ADHD obtained by triple point-mutation in the dopamine transporter (DAT) gene in mice, making them insensitive to cocaine [DAT cocaine-insensitive (DAT-CI) mice]. DAT-CI mice had a marked hyperactive phenotype, and neurophysiological recordings revealed that the sensitivity of CB1Rs controlling GABA-mediated synaptic currents [CB1Rs((GABA)) ] in the striatum was completely lost. In contrast, CB1Rs modulating glutamate transmission [CB1Rs((Glu)) ], and GABA(B) receptors were not affected in this model of ADHD. In DAT-CI mice, the blockade of CB1R((GABA)) function was complete even after cocaine or environmental manipulations activating the endogenous DA-dependent reward system, which are known to sensitize these receptors in control animals. Conversely, the hedonic property of sucrose was intact in DAT-CI mice, indicating normal sweet perception in these animals. Our results point to CB1Rs as novel molecular players in ADHD, and suggest that therapeutic strategies aimed at interfering with the ECS might prove effective in this disorder.
European Journal of Neuroscience 11/2011; 34(9):1369-77. · 3.63 Impact Factor
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Diego Centonze,
Roberto Floris,
Matteo Stefanini,
Silvia Rossi,
Sebastiano Fabiano,
Maura Castelli,
Simone Marziali,
Alessio Spinelli, Caterina Motta,
Francesco G Garaci,
Giorgio Bernardi,
Giovanni Simonetti
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ABSTRACT: It is still unclear whether chronic cerebrospinal venous insufficiency (CCSVI) is associated with multiple sclerosis (MS), because substantial methodological differences have been claimed by Zamboni to account for the lack of results of other groups. Furthermore, the potential role of venous malformations in influencing MS severity has not been fully explored. This information is particularly relevant, because uncontrolled surgical procedures are increasingly offered to MS patients to treat their venous stenoses.
In the present study, CCSVI was studied in 84 MS patients and in 56 healthy subjects by applying the Zamboni method for CCSVI identification.
We found no significant differences (p = 0.12) in CCSVI frequency between MS and control subjects. Furthermore, no differences were found between CCSVI-positive and CCSVI-negative patients in terms of relevant clinical variables such as disease duration, time between onset and first relapse, relapsing or progressive disease course, and risk of secondary progression course. Statistically significant differences were not found between CCSVI-positive and CCSVI-negative MS subjects by analyzing direct measures of disability such as mean Expanded Disability Status Scale (EDSS) (p = 0.07), mean progression index (p > 0.1), and mean MS severity score (p > 0.1). The percentage of subjects who reached EDSS 4.0 and 6.0 milestones was not different among CCSVI-negative and CCSVI-positive subjects, and no significant correlation was found between severity of disability and number of positive CCSVI criteria.
Our results indicate that CCSVI has no role in either MS risk or MS severity.
Annals of Neurology 07/2011; 70(1):51-8. · 11.09 Impact Factor
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Gabriele Musumeci,
Giorgio Grasselli,
Silvia Rossi,
Valentina De Chiara,
Alessandra Musella, Caterina Motta,
Valeria Studer,
Giorgio Bernardi,
Nabila Haji,
Helena Sepman,
Diego Fresegna,
Mauro Maccarrone,
Georgia Mandolesi,
Diego Centonze
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ABSTRACT: Transient receptor potential vanilloid 1 (TRPV1) channels are involved in several inflammatory diseases. However, their action is still controversial, and both pro-inflammatory and anti-inflammatory roles have been described. We used a strain of TRPV1-KO mice to characterize the role of these channels in experimental autoimmune encephalomyelitis (EAE), which models multiple sclerosis (MS) in mice. EAE mice showed higher lethality in the peak phase of the disease and a better recovery of the surviving animals in the chronic stages, compared to their wild-type (WT) counterparts. By means of whole-cell patch clamp experiments in corticostriatal brain slices, we found that the absence of TRPV1 channels exacerbated the defect of glutamate transmission occurring in the peak phase of EAE, and attenuated the alterations of GABA synapses in the chronic phase of EAE, thus paralleling the dual effects of TRPV1-KO on the motor deficits of EAE mice. Furthermore, in slices from non-EAE mice, we found that genetic or pharmacological blockade of TRPV1 channels enhanced the synaptic effects of tumor necrosis factor α (TNF-α) on glutamate-mediated excitatory postsynaptic currents, and prevented the action of interleukin 1β (IL-1β) on GABAergic inhibitory postsynaptic currents. Together, our results suggest that TRPV1 channels contrast TNF-α-mediated synaptic deficits in the peak phase of EAE and, in the chronic stages, enhance IL-1β-induced GABAergic defects. The opposing interplay with the synaptic actions of the two major pro-inflammatory cytokines might explain the bimodal effects of TRPV1 ablation on the motor deficits of EAE, and suggests that the inflammatory milieu determines whether TRPV1 channels exert preferentially aversive or protective effects on neurons during neuroinflammatory diseases.
Neurobiology of Disease 06/2011; 43(3):669-77. · 5.40 Impact Factor
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Silvia Rossi,
Roberto Furlan,
Valentina De Chiara,
Luca Muzio,
Alessandra Musella, Caterina Motta,
Valeria Studer,
Francesca Cavasinni,
Giorgio Bernardi,
Gianvito Martino,
Benjamin F Cravatt,
Beat Lutz,
Mauro Maccarrone,
Diego Centonze
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ABSTRACT: Cannabinoid CB1 receptors (CB1Rs) regulate the neurodegenerative damage of experimental autoimmune encephalomyelitis (EAE) and of multiple sclerosis (MS). The mechanism by which CB1R stimulation exerts protective effects is still unclear. Here we show that pharmacological activation of CB1Rs dampens the tumor necrosis factor α (TNFα)-mediated potentiation of striatal spontaneous glutamate-mediated excitatory postsynaptic currents (EPSCs), which is believed to cogently contribute to the inflammation-induced neurodegenerative damage observed in EAE mice. Furthermore, mice lacking CB1Rs showed a more severe clinical course and, in parallel, exacerbated alterations of sEPSC duration after induction of EAE, indicating that endogenous cannabinoids activate CB1Rs and mitigate the synaptotoxic action of TNFα in EAE. Consistently, we found that mice lacking the fatty acid amide hydrolase (FAAH), and thus expressing abnormally high brain levels of the endocannabinoid anandamide, developed a less severe EAE associated with preserved TNFα-induced sEPSC alterations. CB1Rs are important modulators of EAE pathophysiology, and might play a mechanistic role in the neurodegenerative damage of MS patients.
Brain Behavior and Immunity 04/2011; 25(6):1242-8. · 4.72 Impact Factor
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Silvia Rossi,
Fabio Buttari,
Valeria Studer, Caterina Motta,
Paolo Gravina,
Maura Castelli,
Vilma Mantovani,
Valentina De Chiara,
Alessandra Musella,
Stefania Fiore,
Silvia Masini,
Giorgio Bernardi,
Mauro Maccarrone,
Sergio Bernardini,
Diego Centonze
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ABSTRACT: Genetic and pharmacological inactivation of cannabinoid CB(1) receptors (CB(1)Rs) exacerbates disease course in experimental autoimmune encephalomyelitis, suggesting that CB(1)Rs might play a role in the neurodegenerative damage associated with multiple sclerosis (MS).
To see whether CNR1 gene polymorphism could influence disease progression in relapsing-remitting MS.
The genotype of 350 patients for the number of AAT repeats was characterized and correlation studies were performed with measures of disease severity and progression.
MS patients with the homozygous genotype for long AAT repeats in the CNR1 gene had more severe disease and higher risk of progression. These subjects had significantly higher scores on both the progression index and the MS severity scale. Furthermore, the percentage of patients with MS functional composite score progression or Bayesian Risk Estimate for MS (BREMS) score ≥ 2 (considered at very high risk of secondary progression) was significantly higher in the AAT long group than in the short group, while the frequency of patients with BREMS score ≤-0.63 (very likely to remain progression-free) was not significantly different between the two groups, although lower in the long group. Finally, the frequency of patients prescribed a second-line treatment was significantly higher among subjects of the AAT long group, providing a further, indirect indication of higher disease severity.
The results of the present investigation point to CB(1)R as an important modulator of disease severity in relapsing MS subjects.
Multiple Sclerosis 12/2010; 17(3):281-8. · 4.26 Impact Factor
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Francesco Mori,
Silvia Rossi,
Giulia Sancesario,
Claudia Codec|[agrave,
Giorgia Mataluni,
Fabrizia Monteleone,
Fabio Buttari,
Hajime Kusayanagi,
Maura Castelli, Caterina Motta,
Valeria Studer,
Giorgio Bernardi,
Giacomo Koch,
Sergio Bernardini,
Diego Centonze
[show abstract]
[hide abstract]
ABSTRACT: Cognitive dysfunction is of frequent observation in multiple sclerosis (MS). It is associated with gray matter pathology, brain atrophy, and altered connectivity, and recent evidence showed that acute inflammation can exacerbate mental deficits independently of the primary functional system involved. In this study, we measured cerebrospinal fluid (CSF) levels of amyloid-β1−42 and τ protein in MS and in clinically isolated syndrome patients, as both proteins have been associated with cognitive decline in Alzheimer's disease (AD). In AD, amyloid-β1–42 accumulates in the brain as insoluble extracellular plaques, possibly explaining why soluble amyloid-β1–42 is reduced in the CSF of these patients. In our sample of MS patients, amyloid-β1–42 levels were significantly lower in patients cognitively impaired (CI) and were inversely correlated with the number of Gadolinium-enhancing (Gd+) lesions at the magnetic resonance imaging (MRI). Positive correlations between amyloid-β1–42 levels and measures of attention and concentration were also found. Furthermore, abnormal neuroplasticity of the cerebral cortex, explored with θ burst stimulation (TBS), was observed in CI patients, and a positive correlation was found between amyloid-β1–42 CSF contents and the magnitude of long-term potentiation-like effects induced by TBS. No correlation was conversely found between τ protein concentrations and MRI findings, cognitive parameters, and TBS effects in these patients. Together, our results indicate that in MS, central inflammation is able to alter amyloid-β metabolism by reducing its concentration in the CSF and leading to impairment of synaptic plasticity and cognitive function.Keywords: cognition; inflammation; LTP; τ protein; transcranial magnetic stimulation
Neuropsychopharmacology 10/2010; 36(3):559-568. · 7.99 Impact Factor
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Silvia Rossi,
Valentina De Chiara,
Alessandra Musella,
Lucia Sacchetti,
Cristina Cantarella,
Maura Castelli,
Francesca Cavasinni, Caterina Motta,
Valeria Studer,
Giorgio Bernardi,
Benjamin F Cravatt,
Mauro Maccarrone,
Alessandro Usiello,
Diego Centonze
[show abstract]
[hide abstract]
ABSTRACT: The endocannabinoid anandamide (AEA) plays a crucial role in emotional control, and inhibition of its degradation by the fatty acid amide hydrolase (FAAH) has a potent antianxiety effect. The mechanism by which the magnification of AEA activity reduces anxiety is still largely undetermined. By using FAAH mutant mice and both intraperitoneal and intracerebroventricular administration of the FAAH inhibitor (3'-(aminocarbonyl)[1,1'-biphenyl]-3-yl)-cyclohexylcarbamate (URB597), we found that enhanced AEA signaling reversed, via central cannabinoid CB1 receptors (CB1Rs), the anxious phenotype of mice exposed to social defeat stress. This behavioral effect was associated with preserved activity of CB1Rs regulating GABA transmission in the striatum, whereas these receptors were dramatically down-regulated by stress in control animals. The hypothalamic-pituitary-adrenal (HPA) axis was not involved in the antistress effects of FAAH inhibition, although the HPA axis is a biological target of endogenous AEA. We also provided some physiological indications that striatal CB1Rs regulating GABA synapses are not the receptor targets of FAAH inhibition, which rather resulted in the stimulation of striatal CB1Rs regulating glutamate transmission. Collectively, our findings suggest that preservation of cannabinoid CB1 receptor function within the striatum is a possible synaptic correlate of the antianxiety effects of FAAH inhibition.
Molecular pharmacology 08/2010; 78(2):260-8. · 4.53 Impact Factor
