Sergio Tanganelli - Academia.edu (original) (raw)
Papers by Sergio Tanganelli
Journal of Alzheimer's disease : JAD, Jan 12, 2015
Considering the heterogeneity of pathological changes occurring in Alzheimer's disease (AD), ... more Considering the heterogeneity of pathological changes occurring in Alzheimer's disease (AD), a therapeutic approach aimed both to neuroprotection and to neuroinflammation reduction may prove effective. Palmitoylethanolamide (PEA) has attracted attention for its anti-inflammatory/neuroprotective properties observed in AD animal models. We evaluated the protective role of PEA against amyloid-β42 (Aβ42) toxicity on cell viability and glutamatergic transmission in primary cultures of cerebral cortex neurons and astrocytes from the triple-transgenic murine model of AD (3xTg-AD) and their wild-type littermates (non-Tg) mice. Aβ42 (0.5 μM; 24 h) affects the cell viability in cultured cortical neurons and astrocytes from non-Tg mice, but not in those from 3xTg-AD mice. These effects were counteracted by the pretreatment with PEA (0.1 μM). Basal glutamate levels in cultured neurons and astrocytes from 3xTg-AD mice were lower than those observed in cultured cells from non-Tg mice. Aβ42-ex...
Current protein & peptide science, 2014
This special issue is based on a mini-symposium in the area of neurosciences with the title "... more This special issue is based on a mini-symposium in the area of neurosciences with the title "Understanding the role of heteroreceptor complexes in the central nervous system" held at the Nobel Forum, Karolinska Institutet on December 17th, 2012, organized by Kjell Fuxe, Dasiel O. Borroto-Escuela and Luigi F. Agnati. It consists of seven mini-reviews in the field receptor heteromers. The early work on negative cooperativity and neuropeptide-monoamine receptor-receptor interactions in the central nervous system gave the first indications of the existence of homomers and heteromers of G-protein coupled receptors (GPCR), respectively, and the GPCR field began to expand from monomers into dimers and receptor mosaics (higher-order dimers). It was underlined that the existence of receptor heteromers with allosteric receptor-receptor interactions increases the diversity and bias of GPCR recognition and signalling. The molecular phenomenon of allosteric receptor-receptor interactio...
European Journal of Pharmacology, 1995
The acute or chronic administration of modafinil, (diphenyl-methyl-sulfinyl-2-acetamide, 30 mg/kg... more The acute or chronic administration of modafinil, (diphenyl-methyl-sulfinyl-2-acetamide, 30 mg/kg s.c.) decreased γ-aminobutyric acid (GABA) outflow from the cerebral cortex of freely moving guinea pigs and rats. In 5,7-dihydroxytryptamine intracerebroventricularly pretreated guinea pigs, the effect of modafinil on GABA outflow was reversed and the noradrenaline cortical levels increased. Prazosin (35,8 ng/kg i.p.) blocked the drug-induced increase in GABA efflux. In
... 14． Nida N. Farshori, Mudasir R. Banday, Zeeshan Zahoor, Abdul Rauf.DCC/DMAP mediated esterif... more ... 14． Nida N. Farshori, Mudasir R. Banday, Zeeshan Zahoor, Abdul Rauf.DCC/DMAP mediated esterification of hydroxy and non-hydroxy olefinic fatty acids with β-sitosterol: In vitro antimicrobial activity[J]. CCL, 2010,21(06): 646-650. ...
The effects of the principal psychoactive component of marijuana, ⌬ 9 -tetrahydrocannabinol (⌬ 9 ... more The effects of the principal psychoactive component of marijuana, ⌬ 9 -tetrahydrocannabinol (⌬ 9 -THC), on endogenous extracellular glutamate levels in primary cultures of rat cerebral cortex neurons were investigated. Locally applied ⌬ 9 -THC (0.03, 3, 300, and 1,000 nM) concentration-dependently increased basal extracellular glutamate levels (ϩ18% Ϯ 11%, ϩ54% Ϯ 10%, ϩ90% Ϯ 14%, ϩ149% Ϯ 33% vs. basal). The facilitatory effects of ⌬ 9 -THC (3 and 300 nM) on cortical glutamate were fully counteracted in the presence of the selective CB 1 receptor antagonist SR141716A (10 nM) and by replacement of the normal Krebs-Ringer bicarbonate buffer with a low-Ca 2ϩ (0.2 mM) medium. ⌬ 9 -THC application also induced an enhancement in K ϩ -evoked glutamate levels. These findings suggest that an increase in cortical glutamatergic transmission mediated by local CB 1 receptor activation may underlie some of the psychoactive and behavioral effects of acute marijuana consumption.
This review is focused on the D2 heteroreceptor complexes within the ventral striatum with their ... more This review is focused on the D2 heteroreceptor complexes within the ventral striatum with their receptor-receptor interactions and relevance for the treatment of schizophrenia. A "guide-andclasp" manner for receptor-receptor interactions is proposed where "adhesive guides" may be amino acid triplet homologies, which were determined for different kinds of D2 heteroreceptor complexes. The first putative D2 heteroreceptor complex to be discovered in relation to schizophrenia was the A2A-D2 heteroreceptor complex where antagonistic A2A-D2 receptorreceptor interactions were demonstrated after A2A agonist treatment in the ventral striatum. The A2A agonist CGS 21680 with atypical antipsychotic properties may at least in part act by increasing b-arrestin2 signaling over the D2 protomer in the A2A-D2 heteroreceptor complex in the ventral striatum. The antagonistic NTS1-D2 interactions in the NTS1-D2 heteroreceptor complex Progress in Brain Research, Volume 211, ISSN 0079-6123, http://dx.
Frontiers in Endocrinology, 2014
Allosteric receptor-receptor interactions in GPCR heteromers appeared to introduce an intermolecu... more Allosteric receptor-receptor interactions in GPCR heteromers appeared to introduce an intermolecular allosteric mechanism contributing to the diversity and bias in the protomers. Examples of dopamine D2R heteromerization are given to show how such allosteric mechanisms significantly change the receptor protomer repertoire leading to diversity and biased recognition and signaling. In 1980s and 1990s, it was shown that neurotensin (NT) through selective antagonistic NTR-D2 like receptor interactions increased the diversity of DA signaling by reducing D2R-mediated dopamine signaling over D1R-mediated dopamine signaling. Furthermore, D2R protomer appeared to bias the specificity of the NTR orthosteric binding site toward neuromedin N vs. NT in the heteroreceptor complex. Complex CCK2R-D1R-D2R interactions in possible heteroreceptor complexes were also demonstrated further increasing receptor diversity. In D2R-5-HT2AR heteroreceptor complexes, the hallucinogenic 5-HT2AR agonists LSD and DOI were recently found to exert a biased agonist action on the orthosteric site of the 5-HT2AR protomer leading to the development of an active conformational state different from the one produced by 5-HT. Furthermore, as recently demonstrated allosteric A2A-D2R receptor-receptor interaction brought about not only a reduced affinity of the D2R agonist binding site but also a biased modulation of the D2R protomer signaling in A2A-D2R heteroreceptor complexes. A conformational state of the D2R was induced, which moved away from Gi/o signaling and instead favored β-arrestin2-mediated signaling.These examples on allosteric receptor-receptor interactions obtained over several decades serve to illustrate the significant increase in diversity and biased recognition and signaling that develop through such mechanisms.
NeuroReport, 1997
The antinarcoleptic drug modafinil [(diphenyl-methyl)-sulfinyl-2-acetamide; Modiodal] dose-depend... more The antinarcoleptic drug modafinil [(diphenyl-methyl)-sulfinyl-2-acetamide; Modiodal] dose-dependently inhibits the activity of GABA neurons in the cerebral cortex and in the nucleus accumbens, as well as in sleep-related brain areas such as the medial preoptic area and the posterior hypothalamus. This study examined the effects of modafinil (30-300 mg/kg, i.p.) on dialysate glutamate and GABA levels in the ventromedial (VMT) and ventrolateral (VLT) thalamus and hippocampal formation (Hip) of the awake rat. The results show a maximal increase in glutamate release in these brain regions at the 100 mg/kg dose, associated with a lack of effect on GABA release. Thus modafinil may increase excitatory glutamatergic transmission in these regions, altering the balance between glutamate and GABA transmission.
Neuropharmacology, 2014
The tryptophan metabolite kynurenic acid (KYNA) is an endogenous antagonist of the α7 nicotinic a... more The tryptophan metabolite kynurenic acid (KYNA) is an endogenous antagonist of the α7 nicotinic acetylcholine receptor (α7nAChR) and, at higher concentrations, inhibits ionotropic glutamate receptors. Increases in KYNA levels are seen in brain and cerebrospinal fluid in individuals with schizophrenia (SZ) and may be causally related to cognitive deficits in SZ and other psychiatric diseases. As dysfunction of circuits involving GABAergic neurons in the prefrontal cortex (PFC) likely plays a role in the cognitive impairments seen in these disorders, we examined the effects of KYNA on extracellular GABA in this brain area. Applied to awake rats for 2 h by reverse dialysis, KYNA concentration-dependently and reversibly reduced extracellular GABA levels, with 300 nM KYNA causing a nadir of ∼45% of baseline concentrations. This effect was not duplicated by reverse dialysis of the selective glycineB receptor antagonist 7-Cl-KYNA (100 nM) or the AMPA/kainate receptor antagonist CNQX (100 μM), and was prevented by co-application of galantamine (5 μM), a positive allosteric modulator of the α7nAChR. Conversely, inhibition of endogenous KYNA formation by reverse dialysis of (S)-4-(ethylsulfonyl)benzoylalanine (ESBA; 5 mM) reversibly increased GABA levels in the PFC, reaching a peak of ∼160% of baseline concentrations. Co-infusion of 30 nM KYNA neutralized this effect. Taken together, these results demonstrate a role for endogenous KYNA in the bi-directional control of GABAergic neurotransmission in the PFC. Pharmacological manipulation of KYNA may therefore be useful in the treatment of GABAergic impairments in SZ and other brain disorders involving the PFC.
Naunyn-Schmiedeberg's Archives of Pharmacology, 1990
The interaction of locally perfused cholecystokinin-8 (sulphated) with systemically administered ... more The interaction of locally perfused cholecystokinin-8 (sulphated) with systemically administered apomorphine was studied on the release of dopamine and its metabolites using microdialysis in the neostriatum of the halothane-anaesthetized male rat. Dialysate levels of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid were assayed by high performance liquid chromatography in combination with electrochemical detection. Perfusion with cholecystokinin-8 (100 microM but not 1 microM or 10 nM) increased the dialysate levels of dopamine without affecting those of DOPAC or HVA. At low concentrations (1 microM and 10 nM but not 1 nM), cholecystokinin-8 counteracted the inhibitory effect of apomorphine (0.05 mg/kg, s.c.) on dopamine release. This counteraction was antagonized by perfusion with the cholecystokinin-8 antagonist proglumide (3 microM). At this concentration, proglumide perfused alone was without effect on basal or apomorphine-reduced levels of dopamine. The results indicate a facilitatory effect of cholecystokinin-8 on dopamine release in rat neostriatum only at high concentrations. At lower concentrations, cholecystokinin-8 appears to modulate dopamine release by an inhibitory effect on dopamine autoreceptors possibly involving an intramembrane interaction between presynaptic cholecystokinin-8 receptors and dopamine autoreceptors.
Journal of Neuroscience Research, 2002
The present in vivo microdialysis study evaluates the possible existence of a differential regula... more The present in vivo microdialysis study evaluates the possible existence of a differential regulation of serotonergic transmission by the antinarcoleptic drug modafinil [(diphenyl-methyl)-sulfinyl-2-acetamide; Modiodal] among various brain regions of the awake rat. The results show that, in the cerebral cortex, the central amygdala, and the dorsal raphe nucleus, modafinil in the dose range of 10 -100 mg/kg i.p. dose-dependently increases dialysate serotonin (5-HT) levels. In other brain areas, such as the medial preoptic area and the posterior hypothalamus, the modafinil-induced increase in dialysate 5-HT levels is observed only at tenfold higher doses (100 mg/kg), 10 -30 mg/kg being ineffective. Together these data suggest that, in the frontal cortex, the amygdala, and the dorsal raphe, modafinil is more potent in enhancing extracellular 5-HT levels and presumably 5-HT transmission than in the medial preoptic area and the posterior hypothalamus. In view of the role of ascending 5-HT pathways in arousal and depression, it seems likely that the antinarcoleptic drug modafinil may also have an antidepressant potential in addition to its wakefulnesspromoting action, both actions involving enhancement of 5-HT neurotransmission.
Journal of Neurochemistry, 2003
Two c-hydroxybutyric acid (GHB) analogues, transc-hydroxycrotonic acid (t-HCA) and c-(p-methoxybe... more Two c-hydroxybutyric acid (GHB) analogues, transc-hydroxycrotonic acid (t-HCA) and c-(p-methoxybenzyl)c-hydroxybutyric acid (NCS-435) displaced [ 3 H]GHB from GHB receptors with the same affinity as GHB but, unlike GHB, failed to displace [ 3 H]baclofen from GABA B receptors. The effect of the GHB analogues, GHB and baclofen, on G protein activity and hippocampal extracellular glutamate levels was compared. While GHB and baclofen stimulated 5¢-O-(3-[ 35 S]thiotriphospate) [ 35 S]GTPcS binding both in cortex homogenate and cortical slices, t-HCA and NCS-435 were ineffective up to 1 mM concentration. GHB and baclofen effect was suppressed by the GABA B antagonist CGP 35348 but not by the GHB receptor antagonist NCS-382. Perfused into rat hippocampus, 500 nM and 1 mM GHB increased and decreased extracellular glutamate levels, respectively. GHB stimulation was suppressed by NCS-382, while GHB inhibition by CGP 35348. t-HCA and NCS-435 (0.1-1000 lM) locally perfused into hippocampus increased extracellular glutamate; this effect was inhibited by NCS-382 (10 lM) but not by CGP 35348 (500 lM). The results indicate that GHB-induced G protein activation and reduction of glutamate levels are GABA B -mediated effects, while the increase of glutamate levels is a GHB-mediated effect. Neither t-HCA nor NCS-435 reproduced GHB sedative/hypnotic effect in mice, confirming that this effect is GABA B -mediated. The GHB analogues constitute important tools for understanding the physiological role of endogenous GHB and its receptor.
Journal of Neural Transmission, 2010
Previous studies have indicated that cocaine binding sites contain both high- and low-affinity bi... more Previous studies have indicated that cocaine binding sites contain both high- and low-affinity binding components and have actions not related to dopamine uptake inhibition. Therefore, it has been studied if concentrations of cocaine in the range of 0.1-100 nM can affect not only dopamine uptake but also the quinpirole-induced inhibition of the K(+)-evoked [(3)H]-dopamine efflux from rat striatal synaptosomes. It was found that quinpirole-induced inhibition of K(+)-evoked [(3)H]-dopamine efflux was significantly enhanced by cocaine at 1 and 10 nM but not at 0.1 nM with cocaine alone being inactive and 1 nM cocaine lacking effects on [(3)H]-dopamine uptake in rat striatal synaptosomes. The results indicate the existence of a novel allosteric agonist action of cocaine in low concentrations, not affecting dopamine uptake, at striatal D(2) autoreceptors modulating striatal dopamine transmission.
European Journal of Pharmacology, 1996
The present in vivo microdialysis study demonstrated that the subcutaneous injection of modafinil... more The present in vivo microdialysis study demonstrated that the subcutaneous injection of modafinil (diphenyl-methyl-sulfinyl-2-acetamide) in doses of 30-300 mg/kg dose dependently increased dopamine release from the intermediate level of the nucleus accumbens along the rostro-caudal axis of the halothane anaesthetized rat. The effect of modafinil in a dose of 100 mg/kg was counteracted by the local perfusion in the nucleus accumbens with the GABAB receptor antagonist phaclofen (beta-p-chlorophenyl-gamma-aminopropyl-phosphonic acid) (50 microM), the GABAA agonist muscimol (3-hydroxy-5-aminomethyl-isoxazolol) (10 microM) and the neuronal GABA reuptake inhibitor SKF89976A (4,4-diphenyl-3-butenyl-nipecotic acid) (0.1 microM), whereas it was increased by the GABAB receptor agonist (-)-baclofen [beta-(p-chlorophenyl-gamma-aminobutyric acid)] (10 microM). In addition, the modafinil-induced increase of dopamine release was associated with a significant reduction of accumbens GABA release. These results suggest that the dopamine releasing action of modafinil in the rat nucleus accumbens is secondary to its ability to reduce local GABAergic transmission, which leads to a reduction of GABAA receptor signaling on the dopamine terminals.
Brain Research Reviews, 2008
Functional studies have provided evidence supporting the concept that the tridecapeptide neuroten... more Functional studies have provided evidence supporting the concept that the tridecapeptide neurotensin (NT) acts in the central nervous system as a classical neurotransmitter and/or as an important modulator of neuronal signalling. The role of NT in the regulation of the striatal amino acidergic transmission, mainly by antagonising D2 receptor function, will be analysed. In addition, in different rat brain regions, including the basal ganglia, the contribution of NT receptors in modulating and reinforcing glutamate signalling will be shown including the involvement of interactions between NT and NMDA receptors. Since the enhancement of glutamate transmission and in particular the excessive activation of NMDA receptors, has been postulated to be an important factor in the induction of glutamate-mediated neuronal damage, the involvement of NT in the glutamate-induced neurodegenerative effects will be discussed. Moving from these observations and in order to further investigate this issue, results from preliminary behavioural, functional and biochemical experiments will be presented on the putative neuroprotective effect obtained by the blockade of NT receptor 1 (NTS1) via the systemic administration of the selective NTS1 antagonist SR48692 in an in vivo animal model of Parkinson's disease [unilateral nigral 6-hydroxydopamine (6-OHDA) induced lesion of the nigrostriatal pathway].
Journal of Neural Transmission, 2007
In 1980=81 Agnati and Fuxe introduced the concept of intramembrane receptor-receptor interactions... more In 1980=81 Agnati and Fuxe introduced the concept of intramembrane receptor-receptor interactions and presented the first experimental observations for their existence in crude membrane preparations. The second step was their introduction of the receptor mosaic hypothesis of the engram in 1982. The third step was their proposal that the existence of intramembrane receptor-receptor interactions made possible the integration of synaptic (WT) and extrasynaptic (VT) signals. With the discovery of the intramembrane receptor-receptor interactions with the likely formation of receptor aggregates of multiple receptors, so called receptor mosaics, the entire decoding process becomes a branched process already at the receptor level in the surface membrane. Recent developments indicate the relevance of cooperativity in intramembrane receptor-receptor interactions namely the presence of regulated cooperativity via receptor-receptor interactions in receptor mosaics (RM) built up of the same type of receptor (homo-oligomers) or of subtypes of the same receptor (RM type1). The receptor-receptor interactions will to a large extent determine the various conformational states of the receptors and their operation will be dependent on the receptor composition (stoichiometry), the spatial organization (topography) and order of receptor activation in the RM. The biochemical and functional integrative implications of the receptor-receptor interactions are outlined and longlived heteromeric receptor complexes with frozen RM in various nerve cell systems may play an essential role in learning, memory and retrieval processes. Intramembrane receptor-receptor interactions in the brain have given rise to novel strategies for treatment of Parkinson's disease (A2A and mGluR5 receptor antagonists), schizophrenia (A2A and mGluR5 agonists) and depression (galanin receptor antagonists). The A2A=D2, A2A=D3 and A2A=mGluR5 heteromers and heteromeric complexes with their possible participation in different types of RM are described in detail, especially in the cortico-striatal glutamate synapse and its extrasynaptic components, together with a postulated existence of A2A=D4 heteromers. Finally, the impact of intramembrane receptor-receptor interactions in molecular medicine is discussed outside the brain with focus on the endocrine, the cardiovascular and the immune systems.
Journal of Alzheimer's disease : JAD, Jan 12, 2015
Considering the heterogeneity of pathological changes occurring in Alzheimer's disease (AD), ... more Considering the heterogeneity of pathological changes occurring in Alzheimer's disease (AD), a therapeutic approach aimed both to neuroprotection and to neuroinflammation reduction may prove effective. Palmitoylethanolamide (PEA) has attracted attention for its anti-inflammatory/neuroprotective properties observed in AD animal models. We evaluated the protective role of PEA against amyloid-β42 (Aβ42) toxicity on cell viability and glutamatergic transmission in primary cultures of cerebral cortex neurons and astrocytes from the triple-transgenic murine model of AD (3xTg-AD) and their wild-type littermates (non-Tg) mice. Aβ42 (0.5 μM; 24 h) affects the cell viability in cultured cortical neurons and astrocytes from non-Tg mice, but not in those from 3xTg-AD mice. These effects were counteracted by the pretreatment with PEA (0.1 μM). Basal glutamate levels in cultured neurons and astrocytes from 3xTg-AD mice were lower than those observed in cultured cells from non-Tg mice. Aβ42-ex...
Current protein & peptide science, 2014
This special issue is based on a mini-symposium in the area of neurosciences with the title "... more This special issue is based on a mini-symposium in the area of neurosciences with the title "Understanding the role of heteroreceptor complexes in the central nervous system" held at the Nobel Forum, Karolinska Institutet on December 17th, 2012, organized by Kjell Fuxe, Dasiel O. Borroto-Escuela and Luigi F. Agnati. It consists of seven mini-reviews in the field receptor heteromers. The early work on negative cooperativity and neuropeptide-monoamine receptor-receptor interactions in the central nervous system gave the first indications of the existence of homomers and heteromers of G-protein coupled receptors (GPCR), respectively, and the GPCR field began to expand from monomers into dimers and receptor mosaics (higher-order dimers). It was underlined that the existence of receptor heteromers with allosteric receptor-receptor interactions increases the diversity and bias of GPCR recognition and signalling. The molecular phenomenon of allosteric receptor-receptor interactio...
European Journal of Pharmacology, 1995
The acute or chronic administration of modafinil, (diphenyl-methyl-sulfinyl-2-acetamide, 30 mg/kg... more The acute or chronic administration of modafinil, (diphenyl-methyl-sulfinyl-2-acetamide, 30 mg/kg s.c.) decreased γ-aminobutyric acid (GABA) outflow from the cerebral cortex of freely moving guinea pigs and rats. In 5,7-dihydroxytryptamine intracerebroventricularly pretreated guinea pigs, the effect of modafinil on GABA outflow was reversed and the noradrenaline cortical levels increased. Prazosin (35,8 ng/kg i.p.) blocked the drug-induced increase in GABA efflux. In
... 14． Nida N. Farshori, Mudasir R. Banday, Zeeshan Zahoor, Abdul Rauf.DCC/DMAP mediated esterif... more ... 14． Nida N. Farshori, Mudasir R. Banday, Zeeshan Zahoor, Abdul Rauf.DCC/DMAP mediated esterification of hydroxy and non-hydroxy olefinic fatty acids with β-sitosterol: In vitro antimicrobial activity[J]. CCL, 2010,21(06): 646-650. ...
The effects of the principal psychoactive component of marijuana, ⌬ 9 -tetrahydrocannabinol (⌬ 9 ... more The effects of the principal psychoactive component of marijuana, ⌬ 9 -tetrahydrocannabinol (⌬ 9 -THC), on endogenous extracellular glutamate levels in primary cultures of rat cerebral cortex neurons were investigated. Locally applied ⌬ 9 -THC (0.03, 3, 300, and 1,000 nM) concentration-dependently increased basal extracellular glutamate levels (ϩ18% Ϯ 11%, ϩ54% Ϯ 10%, ϩ90% Ϯ 14%, ϩ149% Ϯ 33% vs. basal). The facilitatory effects of ⌬ 9 -THC (3 and 300 nM) on cortical glutamate were fully counteracted in the presence of the selective CB 1 receptor antagonist SR141716A (10 nM) and by replacement of the normal Krebs-Ringer bicarbonate buffer with a low-Ca 2ϩ (0.2 mM) medium. ⌬ 9 -THC application also induced an enhancement in K ϩ -evoked glutamate levels. These findings suggest that an increase in cortical glutamatergic transmission mediated by local CB 1 receptor activation may underlie some of the psychoactive and behavioral effects of acute marijuana consumption.
This review is focused on the D2 heteroreceptor complexes within the ventral striatum with their ... more This review is focused on the D2 heteroreceptor complexes within the ventral striatum with their receptor-receptor interactions and relevance for the treatment of schizophrenia. A "guide-andclasp" manner for receptor-receptor interactions is proposed where "adhesive guides" may be amino acid triplet homologies, which were determined for different kinds of D2 heteroreceptor complexes. The first putative D2 heteroreceptor complex to be discovered in relation to schizophrenia was the A2A-D2 heteroreceptor complex where antagonistic A2A-D2 receptorreceptor interactions were demonstrated after A2A agonist treatment in the ventral striatum. The A2A agonist CGS 21680 with atypical antipsychotic properties may at least in part act by increasing b-arrestin2 signaling over the D2 protomer in the A2A-D2 heteroreceptor complex in the ventral striatum. The antagonistic NTS1-D2 interactions in the NTS1-D2 heteroreceptor complex Progress in Brain Research, Volume 211, ISSN 0079-6123, http://dx.
Frontiers in Endocrinology, 2014
Allosteric receptor-receptor interactions in GPCR heteromers appeared to introduce an intermolecu... more Allosteric receptor-receptor interactions in GPCR heteromers appeared to introduce an intermolecular allosteric mechanism contributing to the diversity and bias in the protomers. Examples of dopamine D2R heteromerization are given to show how such allosteric mechanisms significantly change the receptor protomer repertoire leading to diversity and biased recognition and signaling. In 1980s and 1990s, it was shown that neurotensin (NT) through selective antagonistic NTR-D2 like receptor interactions increased the diversity of DA signaling by reducing D2R-mediated dopamine signaling over D1R-mediated dopamine signaling. Furthermore, D2R protomer appeared to bias the specificity of the NTR orthosteric binding site toward neuromedin N vs. NT in the heteroreceptor complex. Complex CCK2R-D1R-D2R interactions in possible heteroreceptor complexes were also demonstrated further increasing receptor diversity. In D2R-5-HT2AR heteroreceptor complexes, the hallucinogenic 5-HT2AR agonists LSD and DOI were recently found to exert a biased agonist action on the orthosteric site of the 5-HT2AR protomer leading to the development of an active conformational state different from the one produced by 5-HT. Furthermore, as recently demonstrated allosteric A2A-D2R receptor-receptor interaction brought about not only a reduced affinity of the D2R agonist binding site but also a biased modulation of the D2R protomer signaling in A2A-D2R heteroreceptor complexes. A conformational state of the D2R was induced, which moved away from Gi/o signaling and instead favored β-arrestin2-mediated signaling.These examples on allosteric receptor-receptor interactions obtained over several decades serve to illustrate the significant increase in diversity and biased recognition and signaling that develop through such mechanisms.
NeuroReport, 1997
The antinarcoleptic drug modafinil [(diphenyl-methyl)-sulfinyl-2-acetamide; Modiodal] dose-depend... more The antinarcoleptic drug modafinil [(diphenyl-methyl)-sulfinyl-2-acetamide; Modiodal] dose-dependently inhibits the activity of GABA neurons in the cerebral cortex and in the nucleus accumbens, as well as in sleep-related brain areas such as the medial preoptic area and the posterior hypothalamus. This study examined the effects of modafinil (30-300 mg/kg, i.p.) on dialysate glutamate and GABA levels in the ventromedial (VMT) and ventrolateral (VLT) thalamus and hippocampal formation (Hip) of the awake rat. The results show a maximal increase in glutamate release in these brain regions at the 100 mg/kg dose, associated with a lack of effect on GABA release. Thus modafinil may increase excitatory glutamatergic transmission in these regions, altering the balance between glutamate and GABA transmission.
Neuropharmacology, 2014
The tryptophan metabolite kynurenic acid (KYNA) is an endogenous antagonist of the α7 nicotinic a... more The tryptophan metabolite kynurenic acid (KYNA) is an endogenous antagonist of the α7 nicotinic acetylcholine receptor (α7nAChR) and, at higher concentrations, inhibits ionotropic glutamate receptors. Increases in KYNA levels are seen in brain and cerebrospinal fluid in individuals with schizophrenia (SZ) and may be causally related to cognitive deficits in SZ and other psychiatric diseases. As dysfunction of circuits involving GABAergic neurons in the prefrontal cortex (PFC) likely plays a role in the cognitive impairments seen in these disorders, we examined the effects of KYNA on extracellular GABA in this brain area. Applied to awake rats for 2 h by reverse dialysis, KYNA concentration-dependently and reversibly reduced extracellular GABA levels, with 300 nM KYNA causing a nadir of ∼45% of baseline concentrations. This effect was not duplicated by reverse dialysis of the selective glycineB receptor antagonist 7-Cl-KYNA (100 nM) or the AMPA/kainate receptor antagonist CNQX (100 μM), and was prevented by co-application of galantamine (5 μM), a positive allosteric modulator of the α7nAChR. Conversely, inhibition of endogenous KYNA formation by reverse dialysis of (S)-4-(ethylsulfonyl)benzoylalanine (ESBA; 5 mM) reversibly increased GABA levels in the PFC, reaching a peak of ∼160% of baseline concentrations. Co-infusion of 30 nM KYNA neutralized this effect. Taken together, these results demonstrate a role for endogenous KYNA in the bi-directional control of GABAergic neurotransmission in the PFC. Pharmacological manipulation of KYNA may therefore be useful in the treatment of GABAergic impairments in SZ and other brain disorders involving the PFC.
Naunyn-Schmiedeberg's Archives of Pharmacology, 1990
The interaction of locally perfused cholecystokinin-8 (sulphated) with systemically administered ... more The interaction of locally perfused cholecystokinin-8 (sulphated) with systemically administered apomorphine was studied on the release of dopamine and its metabolites using microdialysis in the neostriatum of the halothane-anaesthetized male rat. Dialysate levels of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid were assayed by high performance liquid chromatography in combination with electrochemical detection. Perfusion with cholecystokinin-8 (100 microM but not 1 microM or 10 nM) increased the dialysate levels of dopamine without affecting those of DOPAC or HVA. At low concentrations (1 microM and 10 nM but not 1 nM), cholecystokinin-8 counteracted the inhibitory effect of apomorphine (0.05 mg/kg, s.c.) on dopamine release. This counteraction was antagonized by perfusion with the cholecystokinin-8 antagonist proglumide (3 microM). At this concentration, proglumide perfused alone was without effect on basal or apomorphine-reduced levels of dopamine. The results indicate a facilitatory effect of cholecystokinin-8 on dopamine release in rat neostriatum only at high concentrations. At lower concentrations, cholecystokinin-8 appears to modulate dopamine release by an inhibitory effect on dopamine autoreceptors possibly involving an intramembrane interaction between presynaptic cholecystokinin-8 receptors and dopamine autoreceptors.
Journal of Neuroscience Research, 2002
The present in vivo microdialysis study evaluates the possible existence of a differential regula... more The present in vivo microdialysis study evaluates the possible existence of a differential regulation of serotonergic transmission by the antinarcoleptic drug modafinil [(diphenyl-methyl)-sulfinyl-2-acetamide; Modiodal] among various brain regions of the awake rat. The results show that, in the cerebral cortex, the central amygdala, and the dorsal raphe nucleus, modafinil in the dose range of 10 -100 mg/kg i.p. dose-dependently increases dialysate serotonin (5-HT) levels. In other brain areas, such as the medial preoptic area and the posterior hypothalamus, the modafinil-induced increase in dialysate 5-HT levels is observed only at tenfold higher doses (100 mg/kg), 10 -30 mg/kg being ineffective. Together these data suggest that, in the frontal cortex, the amygdala, and the dorsal raphe, modafinil is more potent in enhancing extracellular 5-HT levels and presumably 5-HT transmission than in the medial preoptic area and the posterior hypothalamus. In view of the role of ascending 5-HT pathways in arousal and depression, it seems likely that the antinarcoleptic drug modafinil may also have an antidepressant potential in addition to its wakefulnesspromoting action, both actions involving enhancement of 5-HT neurotransmission.
Journal of Neurochemistry, 2003
Two c-hydroxybutyric acid (GHB) analogues, transc-hydroxycrotonic acid (t-HCA) and c-(p-methoxybe... more Two c-hydroxybutyric acid (GHB) analogues, transc-hydroxycrotonic acid (t-HCA) and c-(p-methoxybenzyl)c-hydroxybutyric acid (NCS-435) displaced [ 3 H]GHB from GHB receptors with the same affinity as GHB but, unlike GHB, failed to displace [ 3 H]baclofen from GABA B receptors. The effect of the GHB analogues, GHB and baclofen, on G protein activity and hippocampal extracellular glutamate levels was compared. While GHB and baclofen stimulated 5¢-O-(3-[ 35 S]thiotriphospate) [ 35 S]GTPcS binding both in cortex homogenate and cortical slices, t-HCA and NCS-435 were ineffective up to 1 mM concentration. GHB and baclofen effect was suppressed by the GABA B antagonist CGP 35348 but not by the GHB receptor antagonist NCS-382. Perfused into rat hippocampus, 500 nM and 1 mM GHB increased and decreased extracellular glutamate levels, respectively. GHB stimulation was suppressed by NCS-382, while GHB inhibition by CGP 35348. t-HCA and NCS-435 (0.1-1000 lM) locally perfused into hippocampus increased extracellular glutamate; this effect was inhibited by NCS-382 (10 lM) but not by CGP 35348 (500 lM). The results indicate that GHB-induced G protein activation and reduction of glutamate levels are GABA B -mediated effects, while the increase of glutamate levels is a GHB-mediated effect. Neither t-HCA nor NCS-435 reproduced GHB sedative/hypnotic effect in mice, confirming that this effect is GABA B -mediated. The GHB analogues constitute important tools for understanding the physiological role of endogenous GHB and its receptor.
Journal of Neural Transmission, 2010
Previous studies have indicated that cocaine binding sites contain both high- and low-affinity bi... more Previous studies have indicated that cocaine binding sites contain both high- and low-affinity binding components and have actions not related to dopamine uptake inhibition. Therefore, it has been studied if concentrations of cocaine in the range of 0.1-100 nM can affect not only dopamine uptake but also the quinpirole-induced inhibition of the K(+)-evoked [(3)H]-dopamine efflux from rat striatal synaptosomes. It was found that quinpirole-induced inhibition of K(+)-evoked [(3)H]-dopamine efflux was significantly enhanced by cocaine at 1 and 10 nM but not at 0.1 nM with cocaine alone being inactive and 1 nM cocaine lacking effects on [(3)H]-dopamine uptake in rat striatal synaptosomes. The results indicate the existence of a novel allosteric agonist action of cocaine in low concentrations, not affecting dopamine uptake, at striatal D(2) autoreceptors modulating striatal dopamine transmission.
European Journal of Pharmacology, 1996
The present in vivo microdialysis study demonstrated that the subcutaneous injection of modafinil... more The present in vivo microdialysis study demonstrated that the subcutaneous injection of modafinil (diphenyl-methyl-sulfinyl-2-acetamide) in doses of 30-300 mg/kg dose dependently increased dopamine release from the intermediate level of the nucleus accumbens along the rostro-caudal axis of the halothane anaesthetized rat. The effect of modafinil in a dose of 100 mg/kg was counteracted by the local perfusion in the nucleus accumbens with the GABAB receptor antagonist phaclofen (beta-p-chlorophenyl-gamma-aminopropyl-phosphonic acid) (50 microM), the GABAA agonist muscimol (3-hydroxy-5-aminomethyl-isoxazolol) (10 microM) and the neuronal GABA reuptake inhibitor SKF89976A (4,4-diphenyl-3-butenyl-nipecotic acid) (0.1 microM), whereas it was increased by the GABAB receptor agonist (-)-baclofen [beta-(p-chlorophenyl-gamma-aminobutyric acid)] (10 microM). In addition, the modafinil-induced increase of dopamine release was associated with a significant reduction of accumbens GABA release. These results suggest that the dopamine releasing action of modafinil in the rat nucleus accumbens is secondary to its ability to reduce local GABAergic transmission, which leads to a reduction of GABAA receptor signaling on the dopamine terminals.
Brain Research Reviews, 2008
Functional studies have provided evidence supporting the concept that the tridecapeptide neuroten... more Functional studies have provided evidence supporting the concept that the tridecapeptide neurotensin (NT) acts in the central nervous system as a classical neurotransmitter and/or as an important modulator of neuronal signalling. The role of NT in the regulation of the striatal amino acidergic transmission, mainly by antagonising D2 receptor function, will be analysed. In addition, in different rat brain regions, including the basal ganglia, the contribution of NT receptors in modulating and reinforcing glutamate signalling will be shown including the involvement of interactions between NT and NMDA receptors. Since the enhancement of glutamate transmission and in particular the excessive activation of NMDA receptors, has been postulated to be an important factor in the induction of glutamate-mediated neuronal damage, the involvement of NT in the glutamate-induced neurodegenerative effects will be discussed. Moving from these observations and in order to further investigate this issue, results from preliminary behavioural, functional and biochemical experiments will be presented on the putative neuroprotective effect obtained by the blockade of NT receptor 1 (NTS1) via the systemic administration of the selective NTS1 antagonist SR48692 in an in vivo animal model of Parkinson's disease [unilateral nigral 6-hydroxydopamine (6-OHDA) induced lesion of the nigrostriatal pathway].
Journal of Neural Transmission, 2007
In 1980=81 Agnati and Fuxe introduced the concept of intramembrane receptor-receptor interactions... more In 1980=81 Agnati and Fuxe introduced the concept of intramembrane receptor-receptor interactions and presented the first experimental observations for their existence in crude membrane preparations. The second step was their introduction of the receptor mosaic hypothesis of the engram in 1982. The third step was their proposal that the existence of intramembrane receptor-receptor interactions made possible the integration of synaptic (WT) and extrasynaptic (VT) signals. With the discovery of the intramembrane receptor-receptor interactions with the likely formation of receptor aggregates of multiple receptors, so called receptor mosaics, the entire decoding process becomes a branched process already at the receptor level in the surface membrane. Recent developments indicate the relevance of cooperativity in intramembrane receptor-receptor interactions namely the presence of regulated cooperativity via receptor-receptor interactions in receptor mosaics (RM) built up of the same type of receptor (homo-oligomers) or of subtypes of the same receptor (RM type1). The receptor-receptor interactions will to a large extent determine the various conformational states of the receptors and their operation will be dependent on the receptor composition (stoichiometry), the spatial organization (topography) and order of receptor activation in the RM. The biochemical and functional integrative implications of the receptor-receptor interactions are outlined and longlived heteromeric receptor complexes with frozen RM in various nerve cell systems may play an essential role in learning, memory and retrieval processes. Intramembrane receptor-receptor interactions in the brain have given rise to novel strategies for treatment of Parkinson's disease (A2A and mGluR5 receptor antagonists), schizophrenia (A2A and mGluR5 agonists) and depression (galanin receptor antagonists). The A2A=D2, A2A=D3 and A2A=mGluR5 heteromers and heteromeric complexes with their possible participation in different types of RM are described in detail, especially in the cortico-striatal glutamate synapse and its extrasynaptic components, together with a postulated existence of A2A=D4 heteromers. Finally, the impact of intramembrane receptor-receptor interactions in molecular medicine is discussed outside the brain with focus on the endocrine, the cardiovascular and the immune systems.