RESUMO
Anxiety disorders are the most common class of mental disorders present in the general population with an estimated lifetime prevalence of any anxiety disorder being approximately 15%, while the 12-month prevalence is more than 10%. They are classified into simple phobias, social phobias, obsessive-compulsive disorder (OCD) and panic attacks. Anxiety disorders are more prevalent in females than males and respond to pharmacological and non-pharmacological (behavioral) treatments. Anxiety disorders are complex with genetic and environmental factors interacting to produce the final psychopathology. There are many tests used to detect behaviors that indicate heightened anxiety in rodents however there are few pathological models of anxiety in rodents. Most compound testing is performed on naive, non-pathologically anxious, male animals which is a potential limitation to current strategies since these animals do not reflect the anxious patient. This article briefly describes some of the most common anxiety tests used in rodent research and concludes with a short perspective on areas the field could concentrate on to improve the understanding and successful translation of novel targets into new therapies in the clinic.
Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Camundongos , Ratos , Animais , Ansiolíticos/uso terapêutico , Descoberta de DrogasRESUMO
The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties from the IUPHAR database. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full. This compilation of the major pharmacological targets is divided into seven areas of focus: G protein-coupled receptors, ligand-gated ion channels, ion channels, catalytic receptors, nuclear hormone receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets. It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors & Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates.
Assuntos
Bases de Dados de Produtos Farmacêuticos , Terapia de Alvo Molecular , Farmacologia , Humanos , Ligantes , Preparações Farmacêuticas/químicaRESUMO
There is growing evidence that 5-HT3 receptor blockade will benefit patients with fatigue. Further research is needed to determine the mechanism underlying this widespread clinically important symptom and therapies may be derived from targeting the 5-HT system.
Assuntos
Fadiga/tratamento farmacológico , Antagonistas da Serotonina/uso terapêutico , Animais , Química Encefálica , Humanos , Ratos , Antagonistas da Serotonina/análiseRESUMO
The present study generated a polyclonal antibody (AP86/3) that recognises a peptide sequence of the h5-HT(3B) receptor subunit. Western blot analysis of homogenates prepared from cell lines expressing either homomeric (h5-HT(3A)) or heteromeric (h5-HT(3A/3B)) receptors, as well as immunocytochemical studies with the same cell lines, indicated that AP86/3 recognised, selectively, the 5-HT(3B) subunit. Immunohistochemical labelling was also apparent in cells in the rat hippocampus that displayed the distribution and morphology of interneurones.
Assuntos
Anticorpos/metabolismo , Hipocampo/citologia , Hipocampo/imunologia , Receptores de Serotonina/imunologia , Receptores de Serotonina/metabolismo , Animais , Reações Antígeno-Anticorpo , Linhagem Celular , Humanos , Soros Imunes/metabolismo , Imuno-Histoquímica , Masculino , Coelhos , Ratos , Ratos Wistar , Receptores 5-HT3 de SerotoninaRESUMO
The present study determined the detailed pharmacological profile of heterologously expressed human (h) homomeric 5-HT3A receptors in direct comparison to heteromeric h5-HT3A/3B receptors. The very minor differences in their respective pharmacological profiles indicates that the 5-HT3B receptor subunit alters, predominantly, the biophysical rather than the pharmacological properties of the 5-HT3 receptor.
Assuntos
Receptores de Serotonina/biossíntese , Sequestradores de Radicais Livres/farmacologia , Humanos , Ativação do Canal Iônico , Rim/citologia , Rim/efeitos dos fármacos , Rim/metabolismo , Receptores de Serotonina/classificação , Receptores 5-HT3 de Serotonina , Serotonina/farmacologiaRESUMO
Cellular localization of dopamine D(1)-like receptors was accomplished on target-specified sympathoadrenal preganglionic neurones using the radioligand [(3)H]SCH23390. Sympathoadrenal neurones were retrogradely labelled with cholera B subunit conjugated to horseradish peroxidase and were detected in segments T(1) to T(13) with a predominance at T(8)/T(9). Binding of the selective D(1)-like radioligand [(3)H]SCH23390 was associated with the retrogradely labelled sympathoadrenal neurones in longitudinal/horizontal sections of thoracic spinal cord. D(1)-like receptor localization on target-specific neurones was determined in more than half of the spinal cord sections and was associated predominantly with the cell soma and principal proximal dendrites in the intermediolateral cell column of the spinal grey matter. D(2)-like receptor localization was not associated with retrogradely labelled sympathoadrenal neurones but a higher degree of specific binding was noted in more medial aspects of the spinal grey matter. This is the first successful demonstration of receptor localization combining two quite different techniques and provides conclusive anatomical evidence for D(1)-like receptor localization on sympathetic preganglionic neurones that project to the adrenal medulla.
Assuntos
Medula Suprarrenal/inervação , Fibras Adrenérgicas/metabolismo , Benzazepinas/metabolismo , Antagonistas de Dopamina/metabolismo , Receptores de Dopamina D1/metabolismo , Medula Espinal/metabolismo , Animais , Animais Recém-Nascidos , Autorradiografia/métodos , Feminino , Ratos , Ratos Wistar , Espiperona/metabolismo , Vértebras TorácicasRESUMO
It is now nearly 5 years since the last of the currently recognised 5-HT receptors was identified in terms of its cDNA sequence. Over this period, much effort has been directed towards understanding the function attributable to individual 5-HT receptors in the brain. This has been helped, in part, by the synthesis of a number of compounds that selectively interact with individual 5-HT receptor subtypes--although some 5-HT receptors still lack any selective ligands (e.g. 5-ht1E, 5-ht5A and 5-ht5B receptors). The present review provides background information for each 5-HT receptor subtype and subsequently reviews in more detail the functional responses attributed to each receptor in the brain. Clearly this latter area has moved forward in recent years and this progression is likely to continue given the level of interest associated with the actions of 5-HT. This interest is stimulated by the belief that pharmacological manipulation of the central 5-HT system will have therapeutic potential. In support of which, a number of 5-HT receptor ligands are currently utilised, or are in clinical development, to reduce the symptoms of CNS dysfunction.
Assuntos
Química Encefálica/fisiologia , Transtornos do Humor/tratamento farmacológico , Receptores de Serotonina/fisiologia , Antagonistas da Serotonina/uso terapêutico , Agonistas do Receptor de Serotonina/uso terapêutico , Animais , Humanos , Receptores de Serotonina/análise , Receptores de Serotonina/efeitos dos fármacos , Homologia de Sequência de Aminoácidos , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
Using the technique of in vitro receptor autoradiography, we have determined the distribution of the [3H]-(S)-zacopride labelled 5-HT3 receptor in porcine brain. Highest densities of 5-HT3 receptor-associated [3H]-(S)-zacopride binding were detected in areas of porcine spinal cord, nodose ganglion, trigeminal nerve nucleus, area postrema and cerebral cortex, with relatively lower levels in other brain regions (e.g. hippocampus, caudate-putamen). The distribution of [3H]-(S)-zacopride binding in porcine forebrain provides further evidence for inter-species differences with respect to the differential expression of the 5-HT3 receptor in the forebrain.
Assuntos
Benzamidas/metabolismo , Encéfalo/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/metabolismo , Animais , Autorradiografia , Encéfalo/anatomia & histologia , SuínosRESUMO
The present study investigated the ability of mGlu (metabotropic glutamate) receptor to modulate dopamine release in the striatum of freely moving rats assessed using the microdialysis technique. The group I and II mGlu receptor agonist (1S,3R)-ACPD (1-amino-cyclopentane-1,3-dicarboxylate; 1-3 mM) increased dopamine release (367% of basal levels) which was prevented by the non-selective mGlu receptor antagonist, (+)-MCPG (alpha-methyl-4-carboxyphenylglycine; 10 mM). The group I mGlu receptor agonist, DHPG (3,5-dihydroxyphenylglycine; 0.3-1 mM), also increased dopamine release (maximum increase 229%) which was also antagonised by (+)-MCPG (10 mM). In contrast, the group II mGlu receptor agonist, DCG-IV (2-(2,3-dicarboxycyclopropyl)glycine; 3-50 microM), induced a more modest increase in dopamine release (156% of basal levels). Combined administration of DHPG (1 mM) and DCG-IV (50 microM) maximally increased dopamine release by 252% of basal levels which was antagonised completely by (+)-MCPG (10 mM). Such findings indicate that group I (and possibly group II) mGlu receptors facilitate rat striatal dopamine release in vivo.
Assuntos
Comportamento Animal/efeitos dos fármacos , Cicloleucina/análogos & derivados , Dopamina/metabolismo , Receptores de Glutamato Metabotrópico/fisiologia , Córtex Visual/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Cicloleucina/farmacologia , Interações Medicamentosas , Eletroquímica , Feminino , Microdiálise , Ratos , Ratos Wistar , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Receptores de Glutamato Metabotrópico/classificação , Córtex Visual/efeitos dos fármacosRESUMO
The ability of 2,2,2-trichloroethanol (TCE) and related alcohols to modify the 5-hydroxytryptamine3 (5-HT3) receptor-mediated depolarisation of the rat isolated cervical vagus nerve were investigated by extracellular electrophysiological recording using the 'grease gap' technique. TCE at millimolar concentrations increased the magnitude of the 5-HT3 receptor-mediated depolarisations of the rat vagus nerve by a number of agonists (5-HT, phenylbiguanide (PBG), quipazine). Concentration response curves generated for the 5-HT3 receptor agonists. 5-HT and PBG, in the absence and presence of TCE (5 mM) indicated that the potentiation in agonist-induced depolarisation was due to an increase in both agonist potency and apparent efficacy. Following apparent complete 5-HT3 receptor desensitisation (induced by either 5-HT or PBG; 100 microM for 90 min), application of TCE (5 mM) in the continued presence of either agonist induced a depolarisation of the vagus nerve. In addition to TCE, a number of related alcohols (tribromoethanol, isopentanol and 5-chloropentanol but not ethanol) at millimolar concentrations also potentiated depolarisation of the vagus nerve induced by 5-HT. Combined application of both TCE (0.1-20 mM) and isopentanol (20 mM) indicated that the potentiation of the 5-HT3 receptor-mediated depolarisation by these alcohols was not additive. The present studies indicate that the 5-HT3 receptor expressed on the cervical vagus nerve is susceptible to allosteric modulation by a number of alcohols including the anaesthetic agent TCE. Such an interaction may have relevance to the nausea and vomiting experienced by some patients following recovery from general anaesthesia.
Assuntos
Etilenocloroidrina/análogos & derivados , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/fisiologia , Nervo Vago/efeitos dos fármacos , Nervo Vago/ultraestrutura , Animais , Cloridrinas/farmacologia , Interações Medicamentosas , Etanol/análogos & derivados , Etanol/farmacologia , Etilenocloroidrina/farmacologia , Feminino , Técnicas In Vitro , Indóis/farmacologia , Pentanóis/farmacologia , Ratos , Ratos Wistar , Receptores 5-HT3 de Serotonina , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Sulfonamidas/farmacologia , Nervo Vago/fisiologiaRESUMO
The 5-HT3 receptor complex is a ligand-gated ion channel, and is therefore likely to comprise multiple subunits in common with other members of this superfamily. To date, however, only one 5-HT3 receptor subunit, plus an alternatively spliced variant, have been identified. In this article, Stephanie Fletcher and Nicholas Barnes review some of the extensive data in the literature that suggest the presence of other 5-HT3 receptor subunits. This is particularly relevant given the recent demonstration that the 5-HT3 receptor purified from pig brain contains a non-5-HT3A-like protein(s).
Assuntos
Receptores de Serotonina/química , Antagonistas da Serotonina/farmacologia , Regulação Alostérica , Animais , Córtex Cerebral/metabolismo , Eletrofisiologia , Cobaias , Peso Molecular , Neuroblastoma , Neurônios/metabolismo , Receptores de Serotonina/isolamento & purificação , Receptores 5-HT3 de Serotonina , Suínos , Células Tumorais CultivadasRESUMO
Considerable evidence exists for an involvement of serotonergic mechanisms in the control of alcohol consumption. In the present study, an extensive 5-hydroxytryptamine (5-HT3) receptor autoradiographical investigation was performed using two genetically selected rat strains, alcohol preferring (P) and Alko alcohol (AA) alcohol-preferring rats, as well as the corresponding alcohol nonpreferring (NP) and Alko nonalcohol (ANA) alcohol-nonpreferring rats. The aim was to determine if there are any differences in 5-HT3 binding levels that may illuminate mechanisms of alcohol preference in these animals. For quantitating 5-HT3 binding sites, [3H]S(-)zacopride (0.5 nM) was used. Non-specific binding was measured in the presence of granisetron 10(-6) M. The [3H]S(-)zacopride binding density was measured in two subregions of the amygdaloid nucleus, frontal cortex, piriform cortex, cingulate laminae, parietal anterior cortex, parietal medial cortex, hippocampus CA1, hippocampus CA3, and entorhinal cortex. In all the brain areas investigated, the results showed no differences between AA and ANA rats. In P rats, compared to NP controls, there was a 30% lower 5-HT3 binding level in the lateral nucleus and the posteromedial cortical nucleus of the amygdala. These findings suggest that the expression of high alcohol preference in genetically selected P and AA rats is not associated with a general alteration of central 5-HT3 receptors, although a lower 5-HT3 receptor level in the amygdala of P rats may contribute to the phenotype of this strain of animals.
Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Encéfalo/metabolismo , Receptores de Serotonina/metabolismo , Consumo de Bebidas Alcoólicas/genética , Animais , Autorradiografia , Benzamidas/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Masculino , Ratos , Ratos Endogâmicos/genética , Antagonistas da Serotonina/metabolismo , Distribuição TecidualRESUMO
The present investigation utilised monoclonal antibodies directed against subunits of the nicotinic acetylcholine receptor in immunoblot and immunoprecipitation studies, which failed to demonstrate that the native 5-hydroxytryptamine3 (5-HT3) receptor complex purified from porcine brain contains the alpha1, alpha3, alpha4, alpha5, alpha7 or beta2 subunits of the nicotinic acetylcholine receptor.
Assuntos
Química Encefálica , Receptores Nicotínicos/química , Receptores de Serotonina/química , Animais , Immunoblotting , Receptores 5-HT3 de Serotonina , SuínosRESUMO
The aim of the present study was to establish a radioligand binding assay to selectively label the native 5-HT7 receptor expressed in rat brain. In rat whole brain (minus cerebellum and striatum) homogenate, (+/-)-pindolol (10 microM)-insensitive [3H]5-CT ([3H]5-carboxamidotryptamine; 0.5 nM) specific binding (defined by 5-HT, 10 microM) displayed a pharmacological profile similar to the recombinant 5-HT7 receptor, although the Hill coefficients for competition curves generated by methiothepin, ritanserin, sumatriptan, clozapine and pimozide were significantly less than unity. In homogenates of rat hypothalamus, (+/-)-pindolol (10 microM)-insensitive [3H]5-CT recognition sites also resembled, pharmacologically, the 5-HT7 receptor, although pimozide still generated Hill coefficients significantly less than unity. Subsequent studies were performed in the additional presence of WAY100635 (100 nM) to prevent [3H]5-CT binding to residual, possibly, 5-HT1A sites. Competition for this [3H]5-CT binding indicated the labelling in whole rat brain homogenate of a homogenous population of sites with the pharmacological profile of the 5-HT7 receptor. Saturation studies also indicated that (+/-)-pindolol (10 microM)/WAY 100635 (100 nM)-insensitive [3H]5-CT binding to homogenates of whole rat brain was saturable and to an apparently homogenous population of sites which were labelled with nanomolar affinity (Bmax=33.2+/-0.7 fmol mg(-1) protein, pKd=8.78+/-0.05, mean+/-S.E.M., n=3). The development of this 5-HT7 receptor binding assay will aid investigation of the rat native 5-HT7 receptor.
Assuntos
Encéfalo/metabolismo , Receptores de Serotonina/metabolismo , Serotonina/análogos & derivados , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Ligação Competitiva , Clozapina/farmacologia , Indóis/farmacologia , Cinética , Masculino , Pindolol/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Wistar , Receptores de Serotonina/análise , Proteínas Recombinantes/metabolismo , Serotonina/farmacocinética , Serotonina/farmacologia , Sulfonamidas/farmacologia , TrítioRESUMO
The neurochemical consequences of aversive behavior based on novelty, rat social interaction, have been assessed in various rat brain regions utilizing high-performance liquid chromatography coupled with an electrochemical detector (HPLC-ECD) technique. The present studies indicated that compared to animals from the home cage, those exposed to the high-light aversive unfamiliar test condition, had significantly increased levels of 5-hydroxyindoleacetic acid (5-HIAA), the metabolite of 5-hydroxytryptamine (5-HT), in the tested brain regions including amygdala, entorhinal cortex, frontal cortex, temporal cortex, tuberculum olfactorium, hippocampus, nucleus accumbens, and striatum. The levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), the metabolites of dopamine (DA), were increased in tuberculum olfactorium, nucleus accumbens, and striatum. When compared to the low-light familiar test condition (LF), the levels, following exposure to the highlight unfamiliar situation, of 5-HIAA were significantly increased in the amygdala, entorhinal cortex, tuberculum olfactorium, hippocampus, and nucleus accumbens, while the 5-HIAA levels remained unchanged in the frontal cortex, temporal cortex, and striatum. The DOPAC and HVA levels were also increased by the HU situation in the amygdala, tuberculum olfactorium, and nucleus accumbens. An increase was also found for the levels of DA in the amygdala. Such effects were prevented by diazepam or the 5-HT3 receptor antagonist ondansetron. It is concluded that the aversive test condition of the social interaction test (HU) increases 5-HT and DA turnover throughout the rat brain. Such effects might be related to the sensitivity to novel anxiolytic drug of the social interaction test.
Assuntos
Química Encefálica/fisiologia , Dopamina/metabolismo , Serotonina/metabolismo , Animais , Ansiolíticos/farmacologia , Química Encefálica/efeitos dos fármacos , Catecolaminas/metabolismo , Diazepam/farmacologia , Meio Ambiente , Indóis/metabolismo , Relações Interpessoais , Luz , Masculino , Atividade Motora/efeitos dos fármacos , Ondansetron/farmacologia , Ratos , Antagonistas da Serotonina/farmacologiaRESUMO
Increasing evidence indicates that the 5-HT3 receptor antagonist R(+)-zacopride labels an additional site in brain tissue that is not sensitive to 5-HT (non-5-HT R(+)-zacopride site, R(+)-site). Since the levels of R(+)-sites in the brain are relatively low, the present studies explored the use of [125I]R(+)-zacopride to label the R(+)-site; the incorporation of an [125I] atom considerably increasing the specific activity of the radioligand relative to [3H]R(+)-zacopride that has been utilised previously. Competition experiments with [125I]R(+)-zacopride (1.0 nM) binding to rat whole brain homogenates, in the presence of the 5-HT3 receptor antagonist granisetron (1.0 microM), identified that R(+)-zacopride and prazosin bound to two sites (pIC50: 7.59 and 5.28, respectively, for R(+)-zacopride; 6.75 and 4.42, respectively, for prazosin) whereas S(-)-zacopride and mianserin possessed relatively low affinity (pIC50: 4.37 and 3.80, respectively) while (-)sulpiride and 5-HT failed to compete for [125I]R(+)-zacopride binding at concentrations up to 10 microM. Autoradiographic radioligand binding studies using [125I]R(+)-zacopride (0.5 nM) identified a heterogeneous distribution of specific binding sites (defined by unlabelled R(+)-zacopride, 1.0 microM) throughout the rat brain. In the presence of a saturating concentration of granisetron (1.0 microM), highest levels of specific [125I]R(+)-zacopride, binding sites (defined by R(+)-zacopride, 1.0 microM; R(+)-site), were detected in the olfactory tubercle, thalamus, corpus callosum, colliculus, dorsal and median raphe nucleus, spinal cord and the pons (8.0-13.0 fmol/mg). Moderate densities of R(+)-sites were located in the striatum, nucleus accumbens, substantia nigra, ventral tegmental area, globus pallidus, septal nuclei, frontal cortex and cerebellum (2.0-7.9 fmol/mg). In the hippocampus, amygdala and cortical areas. R(+)-site levels were low but detectable (0.1-1.9 fmol/mg). [125I]R(+)-zacopride labelled R(+)-sites were also detected in some rat peripheral tissues, for instance kidney cortex, adrenal gland and liver (2.4-6.8 fmol/mg). The present results indicate that specific non-5-HT [125I]R(+)-zacopride sites are heterogeneously distributed throughout the rat brain and are expressed in various peripheral tissues.
Assuntos
Benzamidas/metabolismo , Encéfalo/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Antagonistas da Serotonina/metabolismo , Animais , Autorradiografia , Ligação Competitiva , Técnicas In Vitro , Radioisótopos do Iodo , Masculino , Mianserina/metabolismo , Prazosina/metabolismo , Ligação Proteica , Ensaio Radioligante , Ratos , Ratos Wistar , Receptores de Serotonina/metabolismo , Receptores 5-HT3 de Serotonina , Serotonina/metabolismo , Estereoisomerismo , Sulpirida/metabolismo , Distribuição TecidualRESUMO
On the basis of our previous series of experiments we had postulated that the increased anxiety that occurred during diazepam withdrawal was mediated by increased 5-HT release in the hippocampus. The present series of experiments provide evidence for a major role of the median raphé nucleus (MRN) dorsal hippocampal pathway. Rats were treated once daily for 21 days with diazepam (2 mg/kg IP) and then tested after 24 h withdrawal in the social interaction test of anxiety. Relative to chronically vehicle treated animals, those withdrawn from diazepam were significantly more anxious and had significantly greater K(+)-evoked release of [3H]-5-hydroxytryptamine (5-HT) from slices of dorsal and of ventral regions of the hippocampus. Estimation of extracellular concentrations of 5-HT within the dorsal hippocampus, using in-vivo microdialysis, showed doubling in the levels of 5-HT in the rats withdrawn from chronic diazepam treatment. This just failed to reach significance, but 33% of the rats showed dramatic increases (650%). It was not possible to test these animals in the social interaction test, but it is proposed that only the diazepam-withdrawn rats with raised extracellular levels of 5-HT would have displayed increased anxiety. 5-HT1A receptor agonists injected into the MRN decrease the MRN firing rate, and hence the release of 5-HT in the dorsal hippocampus. As a further test of our hypothesis, we examined the effects of MRN injection of the 5-HT1A receptor agonist, 8-OH DPAT, on animals withdrawn from diazepam and tested in the low light familiar condition of the social interaction test. 8-OH DPAT (50-200 ng) dose-dependently reversed the anxiogenic effect of diazepam withdrawal, while having no effects in chronic vehicle-treated animals. These results provide clear evidence that the MRN-dorsal hippocampal 5-HT pathway is at least one of the pathways playing an important role in mediating diazepam withdrawal-induced anxiety.
Assuntos
Diazepam/efeitos adversos , Hipocampo/fisiopatologia , Vias Neurais/fisiopatologia , Núcleos da Rafe/fisiopatologia , Síndrome de Abstinência a Substâncias/fisiopatologia , Animais , Hipocampo/química , Relações Interpessoais , Masculino , Núcleos da Rafe/química , Ratos , Serotonina/análise , Serotonina/metabolismoRESUMO
There is considerable evidence for an involvement of serotonergic mechanisms in the control of alcohol consumption. In the present study, an extensive 5-HT2A receptor autoradiographic investigation was carried out in two genetically selected rat strains, P and AA alcohol-preferring rats, respectively, as well as in the corresponding NP and ANA alcohol-nonpreferring rats. The aim was to determine if there is any common pattern in 5-HT2A binding site densities that may illuminate mechanisms of alcohol preference in these animals. For quantitating 5-HT2A binding sites, [3H]ketanserin (2 nM) was used. Nonspecific binding was measured in the presence of methysergide 10(-6) M. Results demonstrated a lower level (from 50 to 70%) of 5-HT2A binding sites in the layer IV of prefrontal cortex, frontal cortex, parietal cortex of P rats compared to NP controls. Similarly, in the claustrum, 5-HT2A binding density of P rats was 50% lower than that of NP rats, although this failed to achieve statistical significance. No difference was detected in the other areas investigated, including the olfactory tubercles, nucleus accumbens, caudate putamen, pyriform cortex, ventral tegmental area, temporal cortex, and entorhinal cortex. In AA rats, [3H]ketanserin binding density measured in these brain areas was very similar to that observed in ANA nonpreferring controls, and statistical analysis did not reveal any significant difference between the two rat lines. The present study confirms previous reports demonstrating lower densities of 5-HT2A binding sites in the P rats and provides the first autoradiographic evidence showing that such an alteration does not occur in AA rats. These findings suggest that the expression of high alcohol preference in genetically selected P and AA rats is not associated with a shared neurochemical alteration of the 5-HT2A receptor system.