Cellular distribution of the histamine H3 receptor in the basal ganglia : functional modulation of dopamine and glutamate neurotransmission

This is the author's version of a work that was accepted for publication in Basal ganglia. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Vol. 3 Núm. 2 (Jul. 2013)Altres ajuts: Red_de_Trastornos_Adictivos/RD06/0001/0015Histamine H3 receptors (H3R) are widely expressed in the brain where they participate in sleep-wake cycle and cognition among other functions. Despite their high expression in some regions of the basal ganglia, their functional role in this forebrain neural network remains unclear. The present findings provide in situ hybridization and immunohistochemical evidence for H3R expression in several neuronal populations of the rat basal ganglia but not in astrocytes (glial fibrillary acidic protein immunoreactive cells). We demonstrate the presence of H3R mRNA and protein in dopaminergic neurons (tyrosine hydroxylase positive) of the ventral tegmental area and substantia nigra. In the dorsal and ventral (nucleus accumbens) striatal complex we show H3R immunoreactivity in cholinergic (choline acetyltransferase immunoreactive) and GABAergic neurons (substance P, proenkephalin or dopamine D1 receptor positive) as well as in corticostriatal terminals (VGLUT1-immunoreactive). Double-labelling experiments in the medial prefrontal cortex show that H3R is expressed in D1R-positive interneurons and VGLUT1-positive corticostriatal output neurons. Our functional experiments confirm that H3R ligands modulate dopamine synthesis and the probability of glutamate release in the striatum from cortico-striatal afferents. The presence of H3R in such different neuronal populations and its involvement in the control of striatal dopaminergic and glutamatergic transmission ascribes a complex role to H3R in the function of the basal ganglia neural network

Spontaneous changes in brain striatal dopamine synthesis and storage dynamics ex vivo reveal end-product feedback-inhibition of tyrosine hydroxylase

Altres ajuts: acord transformatiu CRUE-CSICAltres ajuts: , The Michael J. Fox Foundation (ID15291), "la Caixa" Foundation (ID 100010434), under the agreement LCF/PR/HR17/52150003Synaptic events are important to define treatment strategies for brain disorders. In the present paper, freshly obtained rat brain striatal minces were incubated under different times and conditions to determine dopamine biosynthesis, storage, and tyrosine hydroxylase phosphorylation. Remarkably, we found that endogenous dopamine spontaneously accumulated during tissue incubation at 37 °C ex vivo while dopamine synthesis simultaneously decreased. We analyzed whether these changes in brain dopamine biosynthesis and storage were linked to dopamine feedback inhibition of its synthesis-limiting enzyme tyrosine hydroxylase. The aromatic-l-amino-acid decarboxylase inhibitor NSD-1015 prevented both effects. As expected, dopamine accumulation was increased with l-DOPA addition or VMAT2-overexpression, and dopamine synthesis decreased further with added dopamine, the VMAT2 inhibitor tetrabenazine or D2 auto-receptor activation with quinpirole, accordingly to the known synaptic effects of these treatments. Phosphorylation activation and inhibition of tyrosine hydroxylase on Ser31 and Ser40 with okadaic acid, Sp-cAMP and PD98059 also exerted the expected effects. However, no clear-cut association was found between dopamine feedback inhibition of its own biosynthesis and changes of tyrosine hydroxylase phosphorylation, assessed by Western blot and mass spectrometry. The later technique also revealed a new Thr30 phosphorylation in rat tyrosine hydroxylase. Our methodological assessment of brain dopamine synthesis and storage dynamics ex vivo could be applied to predict the in vivo effects of pharmacological interventions in animal models of dopamine-related disorders

Paper del receptor H3 d’histamina en la neurotransmissió dopaminèrgica i el desig d’autoadministració de cocaïna.

El nostre grup ha desenvolupat una tècnica directa per a la determinació radioisotòpica de la síntesi i l’alliberament de DA en cervell de rata. Les mostres s’incuben amb 3H-Tirosina i la 3H-Dopamina que es forma en el teixit és purificada posteriorment per HPLC. La determinació simultània amb la nostra tècnica de la síntesi i l’alliberament de dopamina fa que sigui una solució versàtil i permeti un processament de gran quantitat de mostres de manera automatitzada utilitzant el HPLC. Actualment la dependència a la cocaïna no té tractament farmacològic. S’utilitzen com a model animals de recaiguda per a la cerca de nous medicaments. El receptor H3 de histamina és relativament abundant en el cervell respecte altres teixits i en particular el nucli accumbens i l’estriat. Estudis previs suggereixen que l’antagonista/agonista invers del receptor H3 facilita l’alliberament de dopamina reforçant els efectes subjectius dels psicoestimulants. El nostre grup ha demostrat que l’agonista del receptor H3 d’ histamina disminueix la cerca de cocaïna en un test d’extinció i recaiguda en un model animal d’autoadministració. El pretractament del agonista H3 d’histamina disminueix la resposta en una prova d’extinció i recaiguda.We have developed a straightforward radioisotopic determination of dopamine synthesis in brain striatal tissue preparations. Brain miniprisms are incubated with 3H-tyrosine, and 3H-dopamine formed is purified by HPLC. We tested our method with prototypical stimulators (dbcAMP, okadaic acid) and inhibitors (3-I-tyrosine, GABA) of tyrosine hydroxylase activity as well as with dopamine D2 autoreceptor agonists. Dopamine release to the incubation buffer was simultaneously determined in some experiments in order to better characterize dopaminergic neuronal mechanisms. We tested our method on determinations of 3H-dopamine release after K+ depolarization, inhibition of dopamine uptake or metabolism. Effects of psychotropic drugs nicotine and cocaine are also described. Cocaine dependence has no pharmacological treatment. Relapse models in animals are used as a screen for new medications. Histamine H3 receptors are relatively abundant in brain respect to other tissues, and particularly in the nucleus accumbens and striatum. Previous studies suggest that H3 antagonists/inverse agonists could facilitate dopamine release, reinforcement and/or the subjective effects of psychostimulants. Here we show that histamine H3 receptor agonists decrease cocaine seeking in tests of extinction and reinstatement of cocaine self-administration. Rats were subjected to cocaine self-administration under a FR5 schedule, followed by a reinforcement dose-response, progressive ratio, extinction and reinstatement tests elicited by two doses of cocaine priming

Paper del receptor H₃ d'histamina en la neurotransmissió dopaminèrgica i el desig d'autoadministració de cocaïna

El nostre grup ha desenvolupat una tècnica directa per a la determinació radioisotòpica de la síntesi i l'alliberament de DA en cervell de rata. Les mostres s'incuben amb 3H-Tirosina i la 3H-Dopamina que es forma en el teixit és purificada posteriorment per HPLC. La determinació simultània amb la nostra tècnica de la síntesi i l'alliberament de dopamina fa que sigui una solució versàtil i permeti un processament de gran quantitat de mostres de manera automatitzada utilitzant el HPLC. Actualment la dependència a la cocaïna no té tractament farmacològic. S'utilitzen com a model animals de recaiguda per a la cerca de nous medicaments. El receptor H3 de histamina és relativament abundant en el cervell respecte altres teixits i en particular el nucli accumbens i l'estriat. Estudis previs suggereixen que l'antagonista/agonista invers del receptor H3 facilita l'alliberament de dopamina reforçant els efectes subjectius dels psicoestimulants. El nostre grup ha demostrat que l'agonista del receptor H3 d' histamina disminueix la cerca de cocaïna en un test d'extinció i recaiguda en un model animal d'autoadministració. El pretractament del agonista H3 d'histamina disminueix la resposta en una prova d'extinció i recaigudaWe have developed a straightforward radioisotopic determination of dopamine synthesis in brain striatal tissue preparations. Brain miniprisms are incubated with 3H-tyrosine, and 3H-dopamine formed is purified by HPLC. We tested our method with prototypical stimulators (dbcAMP, okadaic acid) and inhibitors (3-I-tyrosine, GABA) of tyrosine hydroxylase activity as well as with dopamine D2 autoreceptor agonists. Dopamine release to the incubation buffer was simultaneously determined in some experiments in order to better characterize dopaminergic neuronal mechanisms. We tested our method on determinations of 3H-dopamine release after K+ depolarization, inhibition of dopamine uptake or metabolism. Effects of psychotropic drugs nicotine and cocaine are also described. Cocaine dependence has no pharmacological treatment. Relapse models in animals are used as a screen for new medications. Histamine H3 receptors are relatively abundant in brain respect to other tissues, and particularly in the nucleus accumbens and striatum. Previous studies suggest that H3 antagonists/inverse agonists could facilitate dopamine release, reinforcement and/or the subjective effects of psychostimulants. Here we show that histamine H3 receptor agonists decrease cocaine seeking in tests of extinction and reinstatement of cocaine self-administration. Rats were subjected to cocaine self-administration under a FR5 schedule, followed by a reinforcement dose-response, progressive ratio, extinction and reinstatement tests elicited by two doses of cocaine priming

Cellular distribution of the histamine H3 receptor in the basal ganglia : functional modulation of dopamine and glutamate neurotransmission

This is the author's version of a work that was accepted for publication in Basal ganglia. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Vol. 3 Núm. 2 (Jul. 2013)Histamine H3 receptors (H3R) are widely expressed in the brain where they participate in sleep-wake cycle and cognition among other functions. Despite their high expression in some regions of the basal ganglia, their functional role in this forebrain neural network remains unclear. The present findings provide in situ hybridization and immunohistochemical evidence for H3R expression in several neuronal populations of the rat basal ganglia but not in astrocytes (glial fibrillary acidic protein immunoreactive cells). We demonstrate the presence of H3R mRNA and protein in dopaminergic neurons (tyrosine hydroxylase positive) of the ventral tegmental area and substantia nigra. In the dorsal and ventral (nucleus accumbens) striatal complex we show H3R immunoreactivity in cholinergic (choline acetyltransferase immunoreactive) and GABAergic neurons (substance P, proenkephalin or dopamine D1 receptor positive) as well as in corticostriatal terminals (VGLUT1-immunoreactive). Double-labelling experiments in the medial prefrontal cortex show that H3R is expressed in D1R-positive interneurons and VGLUT1-positive corticostriatal output neurons. Our functional experiments confirm that H3R ligands modulate dopamine synthesis and the probability of glutamate release in the striatum from cortico-striatal afferents. The presence of H3R in such different neuronal populations and its involvement in the control of striatal dopaminergic and glutamatergic transmission ascribes a complex role to H3R in the function of the basal ganglia neural network

Cocaine disrupts histamine H3 receptor modulation of dopamine D1 receptor signaling: σ1-D1-H3 receptor complexes as key targets for reducing cocaine’s effects

The general effects of cocaine are not well understood at the molecular level. What is known is that dopamine D1 receptor plays an important role. Here we show that a key mechanism may be cocaine’s blockade of the histamine H3 receptor-mediated inhibition of D1 receptor function. This blockade requires the σ1 receptor and occurs upon cocaine binding to σ1-D1-H3 receptor complexes. The cocaine-mediated disruption leaves an uninhibited D1 receptor that activates Gs, freely recruits β-arrestin, increases p-ERK 1/2 levels and induces cell death when over activated. Using in vitro assays with transfected cells and in ex vivo experiments using both rats acutely treated or self-administered with cocaine along with mice depleted of σ1 receptor, we show that blockade of σ1 receptor by an antagonist restores the protective H3 receptor-mediated brake on D1 receptor signaling and prevents the cell death from elevated D1 receptor signaling. These findings suggest that a combination therapy of σ1R antagonists with H3 receptor agonists could serve to reduce some effects of cocaine

Pla d’actuació per prevenir els efectes de les onades de calor sobre la salut (POCS 2021): informe de les actuacions realitzades i dels resultats obtinguts 

Calor elevada; Mesures de prevenció; ResultatsCalor elevada; Medidas de prevención; ResultadosHigh heat; Preventive measures; ResultsEl Pla d'actuació per prevenir els efectes de les onades de calor sobre la salut (POCS) a Catalunya és un pla estacional que s'activa anualment de l'1 de juny fins al 30 de setembre. Està coordinat per l'Agència de Salut Pública de Catalunya (ASPCAT) i el Servei Català de la Salut i compta amb la participació de més d'una quinzena d'entitats. L’informe presenta les actuacions realitzades i dels resultats obtinguts en relació al pla d’actuació per prevenir els efectes de les onades de calor sobre la salut (POCS) durant l'estiu de l'any 2021

Cocaine disrupts histamine H₃ receptor modulation of dopamine D₁ receptor signaling : σ₁-D₁-H₃ receptor complexes as key targets for reducing cocaine's effects

The general effects of cocaine are not well understood at the molecular level. What is known is that the dopamine D₁ receptor plays an important role. Here we show that a key mechanism may be cocaine's blockade of the histamine H₃ receptor-mediated inhibition of D₁ receptor function. This blockade requires the σ₁ receptor and occurs upon cocaine binding to σ₁-D₁-H₃ receptor complexes. The cocainemediated disruption leaves an uninhibited D₁ receptor that activates Gs , freely recruits β-arrestin, increases p-ERK 1/2 levels, and induces cell death when over activated. Using in vitro assays with transfected cells and in ex vivo experiments using both rats acutely treated or self-administered with cocaine along with mice depleted of σ₁ receptor, we show that blockade of σ₁ receptor by an antagonist restores the protective H₃ receptor-mediated brake on D₁ receptor signaling and prevents the cell death from elevated D₁ receptor signaling. These findings suggest that a combination therapy of σ₁R antagonists with H₃ receptor agonists could serve to reduce some effects of cocaine

Cocaine disrupts histamine H3 receptor modulation of dopamine D1 receptor signaling: σ1-D1-H3 receptor complexes as key targets for reducing cocaine's effects

The general effects of cocaine are not well understood at the molecular level. What is known is that the dopamine D1 receptor plays an important role. Here we show that a key mechanism may be cocaine's blockade of the histamine H3 receptor-mediated inhibition of D1 receptor function. This blockade requires the σ1 receptor and occurs upon cocaine binding to σ1-D1-H3 receptor complexes. The cocaine-mediated disruption leaves an uninhibited D1 receptor that activates Gs, freely recruits β-arrestin, increases p-ERK 1/2 levels, and induces cell death when over activated. Using in vitro assays with transfected cells and in ex vivo experiments using both rats acutely treated or self-administered with cocaine along with mice depleted of σ1 receptor, we show that blockade of σ1 receptor by an antagonist restores the protective H3 receptor-mediated brake on D1 receptor signaling and prevents the cell death from elevated D1 receptor signaling. These findings suggest that a combination therapy of σ1R antagonists with H3 receptor agonists could serve to reduce some effects of cocaine

Cocaine disrupts histamine H3 receptor modulation of dopamine D1 receptor signaling: σ1-D1-H3 receptor complexes as key targets for reducing cocaine's effects

The general effects of cocaine are not well understood at the molecular level. What is known is that the dopamine D1 receptor plays an important role. Here we show that a key mechanism may be cocaine's blockade of the histamine H3 receptor-mediated inhibition of D1 receptor function. This blockade requires the σ1 receptor and occurs upon cocaine binding to σ1-D1-H3 receptor complexes. The cocaine-mediated disruption leaves an uninhibited D1 receptor that activates Gs, freely recruits β-arrestin, increases p-ERK 1/2 levels, and induces cell death when over activated. Using in vitro assays with transfected cells and in ex vivo experiments using both rats acutely treated or self-administered with cocaine along with mice depleted of σ1 receptor, we show that blockade of σ1 receptor by an antagonist restores the protective H3 receptor-mediated brake on D1 receptor signaling and prevents the cell death from elevated D1 receptor signaling. These findings suggest that a combination therapy of σ1R antagonists with H3 receptor agonists could serve to reduce some effects of cocaine