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07/03/2019 | JCI Insight   IF 6
The motivation for exercise over palatable food is dictated by cannabinoid type-1 receptors.
Muguruza C, Redon B, Fois GR, Hurel I, Scocard A, Nguyen C, Stevens C, Soria-Gomez E, Varilh M, Cannich A, Daniault J, Busquets-Garcia A, Pelliccia T, Caille S, Georges F, Marsicano G, Chaouloff F

The lack of intrinsic motivation to engage in, and adhere to, physical exercise has major health consequences. However, the neurobiological bases of exercise motivation are still unknown. This study aimed at examining whether the endocannabinoid system (ECS) is involved in this process. To do so, we developed an operant conditioning paradigm wherein mice unlocked a running wheel with nose pokes. Using pharmacological tools and conditional mutants for cannabinoid type-1 (CB1) receptors, we provide evidence that CB1 receptors located on GABAergic neurons are both necessary and sufficient to positively control running motivation. Conversely, this receptor population proved dispensable for the modulation of running duration per rewarded sequence. Although the ECS mediated the motivation for another reward, namely palatable food, such a regulation was independent from CB1 receptors on GABAergic neurons. In addition, we report that the lack of CB1 receptors on GABAergic neurons decreases the preference for running over palatable food when mice were proposed an exclusive choice between the two rewards. Beyond providing a paradigm that enables motivation processes for exercise to be dissected either singly or in concurrence, this study is the first to our knowledge to identify a neurobiological mechanism that might contribute to sedentary behavior.


11/2014 | Neuropharmacology   IF 4.4
Evaluation of 5-HT2A and mGlu2/3 receptors in postmortem prefrontal cortex of subjects with major depressive disorder: Effect of antidepressant treatment.
Muguruza C, Miranda-Azpiazu P, Diez-Alarcia R, Morentin B, Gonzalez-Maeso J, Callado LF, Meana JJ

Several studies have demonstrated alterations in serotonin 5-HT2A (5-HT2AR) and glutamate metabotropic mGlu2 (mGlu2R) receptors in depression, but never in the same sample population. Recently it has been shown that both receptors form a functional receptor heterocomplex that is altered in schizophrenia. The present study evaluates the gene expression and protein density of 5-HT2AR and mGlu2/3R in the postmortem prefrontal cortex of subjects with major depressive disorder (n = 14) compared with control subjects (n = 14) in a paired design. No significant differences between subjects with depression and controls in the relative mRNA levels of the genes HTR2A, GRM2 and GRM3 were observed. The 5-HT2AR density evaluated by [(3)H]ketanserin binding was significantly lower in antidepressant-treated subjects (Bmax = 313 +/- 17 fmol/mg protein; p < 0.05) compared to controls (Bmax = 360 +/- 12 fmol/mg protein) but not in antidepressant-free subjects (Bmax = 394 +/- 16 fmol/mg protein; p > 0.05). In rats, chronic treatment with citalopram (10 mg/kg/day) and mirtazapine (5 mg/kg/day) decreased mRNA expression and 5-HT2AR density whereas reboxetine (20 mg/kg/day) modified only mRNA expression. The mGlu2/3R density evaluated by [(3)H]LY341495 binding was not significantly different between depression and control subjects. The present results demonstrate no changes in expression and density of both 5-HT2AR and mGlu2/3R in the postmortem prefrontal cortex of subjects with major depressive disorder under basal conditions. However, antidepressant treatment induces a decrease in 5-HT2AR density. This finding suggests that 5-HT2AR down-regulation may be a mechanism for antidepressant effect.

23/07/2014 | Eur J Med Chem   IF 4.8
Guanidine-based alpha2-adrenoceptor ligands: Towards selective antagonist activity.
O'Donovan DH, Muguruza C, Callado LF, Rozas I

Depression has been linked to a selective increase in the high affinity conformation of the alpha2-adrenergic autoreceptors (alpha2-ARs) in the human brain as well as to an overexpression of alpha2-ARs in the hippocampus and cerebral cortex. Thus, the development of novel alpha2-AR antagonists represents an attractive source of new antidepressants. This paper describes the design, synthesis and pharmacological evaluation of 30 new guanidinium and 2-iminoimidazolidinium as potential alpha2-AR antagonists. In order to design this new series of alpha2-AR antagonists, a pharmacophore model was developed using the GALAHAD software. This study suggested that increased substitution in the space surrounding the cationic guanidine moiety might lead selectively to antagonist activity. Following the preparation of compounds incorporating this feature and competitive radioligand binding, [(35)S]GTPgammaS functional assays revealed that this structural modification affords exclusively alpha2-AR antagonists, in contrast with the analogous unsubstituted compounds in which a mixture of antagonist/agonist activities was previously observed.

08/2013 | Eur Neuropsychopharmacol   IF 4.5
Dysregulated 5-HT(2A) receptor binding in postmortem frontal cortex of schizophrenic subjects.
Muguruza C, Moreno JL, Umali A, Callado LF, Meana JJ, Gonzalez-Maeso J

Previous postmortem and neuroimaging studies have repeatedly suggested alterations in serotonin 5-HT(2A) receptor (5-HT(2A)R) binding associated with the pathophysiology of schizophrenia. These studies were performed with ligands, such as ketanserin, altanserin and LSD, that may bind with high-affinity to different structural or functional conformations of the 5-HT(2A)R. Interpretation of results may also be confounded by chronic antipsychotic treatment and suicidal behavior in the schizophrenia group. We quantified 5-HT(2A)R density by radioligand binding assays in postmortem prefrontal cortex of antipsychotic-free (n=29) and antipsychotic-treated (n=16) schizophrenics, suicide victims with other psychiatric diagnoses (n=13), and individually matched controls. [(3)H]Ketanserin binding, and its displacement by altanserin or the LSD-like agonist DOI, was assayed. Results indicate that the number of [(3)H]ketanserin binding sites to the 5-HT(2A)R was increased in antipsychotic-free (128 +/- 11%), but not in antipsychotic-treated (92 +/- 12%), schizophrenic subjects. In suicide victims, [(3)H]ketanserin binding did not differ as compared to controls. Aging correlated negatively with [(3)H]ketanserin binding in schizophrenia, suicide victims and controls. The fraction of high-affinity sites of DOI displacing [(3)H]ketanserin binding to the 5-HT(2A)R was increased in antipsychotic-free schizophrenic subjects. Functional uncoupling of heterotrimeric G proteins led to increased fraction of high-affinity sites of altanserin displacing [(3)H]ketanserin binding to the 5-HT(2A)R in schizophrenic subjects, but not in controls. Together, these results suggest that the active conformation of the 5-HT(2A)R is up-regulated in prefrontal cortex of antipsychotic-free schizophrenic subjects, and may provide a pharmacological explanation for discordant findings previously obtained.

08/2013 | Schizophr Res   IF 4.6
Quantification of endocannabinoids in postmortem brain of schizophrenic subjects.
Muguruza C, Lehtonen M, Aaltonen N, Morentin B, Meana JJ, Callado LF

Numerous studies have implicated the endocannabinoid system in the pathophysiology of schizophrenia. Endocannabinoids have been measured in blood and cerebrospinal fluid in schizophrenic patients but, to the date, there are no published reports dealing with measurements of endocannabinoid levels in schizophrenics' brain tissue. In the present study, postmortem brain samples from 19 subjects diagnosed with schizophrenia (DSM-IV) and 19 matched controls were studied. In specific brain regions, levels of four endocannabinoids (2-arachidonoylglycerol (2-AG), arachidonoylethanolamine (anandamide, AEA), dihomo-gamma-linolenoylethanolamine (LEA), and docosahexaenoylethanolamine (DHEA)) and two cannabimimetic compounds (palmitoyl-ethanolamine (PEA) and oleoyl-ethanolamine (OEA)) were measured using quantitative liquid chromatography with triple quadrupole mass spectrometric detection. Suffering from schizophrenia significantly affects the brain levels of 2-AG (p<0.001), AEA (p<0.0001), DHEA (p<0.0001), LEA (p<0.01) and PEA (p<0.05). In schizophrenic subjects, the three studied brain regions (cerebellum: 130+/-18%; p=0.16; hippocampus: 168+/-28%, p<0.01; prefrontal cortex: 237+/-45%, p<0.05) showed higher 2-AG levels when compared to matched controls. Conversely, AEA levels were lower in all brain regions of schizophrenic subjects (cerebellum: 66+/-7%, p<0.01; hippocampus: 66+/-7%, p<0.01; prefrontal cortex: 75+/-10%, p=0.07). Statistically significant lower levels of DHEA were also found in cerebellum (60+/-6%, p<0.001) and hippocampus (68+/-7%, p<0.05) of schizophrenic subjects. PEA (71+/-6%, p<0.05) and LEA (72+/-6%, p<0.05) levels were also found to be lower in cerebellum. No significant differences were found in OEA levels. Our results evidence specific alterations in the levels of some endocannabinoids in different brain regions of schizophrenic subjects. Furthermore, these data evidence the involvement of the endocannabinoid system in the pathophysiology of schizophrenia.

02/2013 | Neuropharmacology   IF 4.4
Antidepressant-like properties of three new alpha2-adrenoceptor antagonists.
Muguruza C, Rodriguez F, Rozas I, Meana JJ, Uriguen L, Callado LF

Evidence suggests that depression is associated with an increase in the high-affinity conformation of the alpha2-adrenoceptors in human brain. Such enhanced alpha2-adrenoceptor activity could explain the deficit in central noradrenergic transmission described in the aetiology of depression. Thus, administration of alpha2-adrenoceptor antagonists augments noradrenaline levels and provides an effective therapeutic approach for the treatment of depressive disorders. In previous studies, we have characterized three new synthesized guanidine and 2-aminoimidazoline aromatic derivatives (8b, 17b and 20b) as alpha2-adrenoceptor antagonists that are able to increase extracellular concentration of noradrenaline in rat brain. The purpose of the present study was to evaluate the in vivo antidepressant-like properties of these three new alpha2-adrenoceptor antagonists. For that aim, compounds were tested on the tail suspension test (TST) and forced swim test (FST), two classically widely-used behavioural paradigms for the evaluation of antidepressant-like activity. Compound 8b significantly reduced the immobility time at 10, 20 and 40 mg/kg doses in both TST and FST. Compound 17b reduced the immobility time at 40 mg/kg in both TST and FST. Compound 20b showed a significant decrease in the immobility time at 20 mg/kg in the TST. As drugs of reference, fluoxetine induced a significant antidepressant-like effect in both TST and FST, while mirtazapine induced a significant antidepressant-like effect only in the FST. Additionally, none of the tested compounds increased locomotor activity or displayed anxiolytic-like properties. These results suggest that these new synthesized alpha2-adrenoceptor antagonists may be useful as potential antidepressant drugs.

28/12/2012 | J Biol Chem   IF 4.1
Identification of three residues essential for 5-hydroxytryptamine 2A-metabotropic glutamate 2 (5-HT2A.mGlu2) receptor heteromerization and its psychoactive behavioral function.
Moreno JL, Muguruza C, Umali A, Mortillo S, Holloway T, Pilar-Cuellar F, Mocci G, Seto J, Callado LF, Neve RL, Milligan G, Sealfon SC, Lopez-Gimenez JF, Meana JJ, Benson DL, Gonzalez-Maeso J

Serotonin and glutamate G protein-coupled receptor (GPCR) neurotransmission affects cognition and perception in humans and rodents. GPCRs are capable of forming heteromeric complexes that differentially alter cell signaling, but the role of this structural arrangement in modulating behavior remains unknown. Here, we identified three residues located at the intracellular end of transmembrane domain four that are necessary for the metabotropic glutamate 2 (mGlu2) receptor to be assembled as a GPCR heteromer with the serotonin 5-hydroxytryptamine 2A (5-HT(2A)) receptor in the mouse frontal cortex. Substitution of these residues (Ala-677(4.40), Ala-681(4.44), and Ala-685(4.48)) leads to absence of 5-HT(2A).mGlu2 receptor complex formation, an effect that is associated with a decrease in their heteromeric ligand binding interaction. Disruption of heteromeric expression with mGlu2 attenuates the psychosis-like effects induced in mice by hallucinogenic 5-HT(2A) agonists. Furthermore, the ligand binding interaction between the components of the 5-HT(2A).mGlu2 receptor heterocomplex is up-regulated in the frontal cortex of schizophrenic subjects as compared with controls. Together, these findings provide structural evidence for the unique behavioral function of a GPCR heteromer.