RESUMO
Several psychoactive drugs may induce addiction. Despite distinct pharmacological targets, all have the common property to stimulate the brain reward circuitry, which results in an increase of dopamine release in the nucleus accumbens. The stimulation induced by drugs of abuse is much more important in intensity and duration than the stimulation induced by natural rewards. The positive reinforcement resulting from this stimulation promotes repeated drug intake, which induces cellular and molecular adaptations in the brain reward circuit and other regions associated with this circuit. Enduring changes are more particularly observed in regions involved in pleasure, motivation, memory, conditioning, executive functions, judgement and self-control. A tolerance to the reinforcing effects of natural rewards is observed in parallel to a hypersensitivity to the motivational effects of drugs and drug-associated stimuli. Behaviour focuses more and more exclusively on drug research and drug consumption. Drug privation can induce a negative emotional state, withdrawal signs and craving which are key elements of relapse
Assuntos
Comportamento Aditivo/fisiopatologia , Encéfalo/fisiopatologia , Dopamina/metabolismo , Humanos , Neurobiologia , Neuropsicologia , Estresse Psicológico/fisiopatologiaRESUMO
Treatment of addiction is extremely eomplex Identification of neurobiological mechanisms involved in this disease has made it possible to identify interesting pharmacological targets in the reward circuit and regions associated with this circuit. Current treatments are based on interactions with the acute effects of the drug on dopaminergic transmission, on the reactivation of the reward circuit in the absence of drug, on the reduction of withdrawal symptoms, or on inter-Sactions with systems associated with the reward circuit. In these systems, neurotransmitters such as GABA, glutamate and endogenous opioids play a crucial role in the development of addiction. In this article, we focus on the pharmacological management of addiction to alcohol, nicotine and opiates.
Assuntos
Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Agonistas de Dopamina/uso terapêutico , GABAérgicos/uso terapêutico , Humanos , Vias Neurais/fisiopatologia , Neurotransmissores/fisiologia , Reforço Psicológico , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/psicologiaRESUMO
There are multiple pharmacological targets in the central nervous system. After reviewing the synaptic physiology and the major neurotransmitter molecules, this article describes the main strategies used in neuropharmacology. The concept of specificity in the central nervous system is discussed, and allows a distinction between drugs according to the degree of specificity of their action. A catalogue of pharmacological targets is presented with therapeutic examples, and an emphasis on new agents having an original mechanism of action or acting on new targets.
Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/fisiologia , Humanos , Sinapses/fisiologia , Sinapses/ultraestruturaRESUMO
BACKGROUND AND PURPOSE: The identification of potent and selective radioligands for the mapping of 5-HT receptors is interesting both for clinical and experimental research. The aim of this study was to compare the potency of a new putative 5-HT(1A) receptor antagonist, p-DMPPF, (4-(2-hydroxyphenyl)-1-[2'-[N-(2''-pyridinyl)-p-fluorobenzamido]ethyl]piperazine) with that of the well-known 5-HT(1A) antagonists, WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide) and its fluorobenzoyl analogue, p-MPPF (4-(2-methoxyphenyl)-1-[2'-[N-(2''-pyridinyl)-p-fluorobenzamido]ethyl]piperazine). EXPERIMENTAL APPROACH: Single cell extracellular recordings of dorsal raphe (DR) neurones were performed in rat brain slices. The potency of each compound at antagonizing the effect of the 5-HT(1A) agonist, 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)-tetraline], was quantified using the Schild equation. The pharmacological profile of p-DMPPF was defined using competition binding assays. KEY RESULTS: Consistently with a 5-HT(1A) receptor antagonist profile, incubation of slices with an equimolar (10 nM) concentration of each compound markedly reduced the inhibitory effect of 8-OH-DPAT on the firing rate of DR neurones, causing a significant rightward shift in its concentration-response curve. The rank order of potency of the antagonists was WAY-100635>p-DMPPF>or=p-MPPF. The sensitivity of DR neurones to the inhibitory effect of 8-OH-DPAT was found to be heterogeneous. The binding experiments demonstrated that p-DMPPF is highly selective for 5-HT(1A) receptors, with a K(i) value of 7 nM on these receptors. CONCLUSIONS AND IMPLICATIONS: The potency of the new compound, p-DMPPF, as a 5-HT(1A) antagonist is similar to that of p-MPPF in our electrophysiological assay. Its selectivity towards 5-HT(1A) receptors makes it a good candidate for clinical development.
Assuntos
Benzamidas/farmacologia , Piperazinas/farmacologia , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Aminopiridinas/farmacologia , Animais , Ligação Competitiva/efeitos dos fármacos , Eletrofisiologia , Técnicas In Vitro , Cinética , Masculino , Neurônios/efeitos dos fármacos , Ligação Proteica , Piridinas/farmacologia , Ensaio Radioligante , Núcleos da Rafe/citologia , Núcleos da Rafe/efeitos dos fármacos , Ratos , Ratos Wistar , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
Small conductance calcium-activated potassium (SK) channels are found in many types of neurons as well as in some other cell types. These channels are selective for K(+) and open when intracellular Ca(2+) rises to omega 500 nM. In neurons, this occurs during and after an action potential. Activation of SK channels hyperpolarizes the membrane, thus reducing cell excitability for several tens or hundreds of milliseconds. This phenomenon is called a afterhyperpolarization (AHP). Three subtypes of SK channels (SK1, SK2, SK3) have been cloned and exhibit a differential localization in the brain. SK channels may play a role in physiological and pathological conditions. They may be involved in the control of memory and cognition. Moreover, they are heavily expressed in the basal ganglia (in particular in the substantia nigra, pars compacta) and in the limbic system, suggesting that they may modulate motricity and emotional behaviour. Based on these facts, SK channel subtypes may be a suitable target for developing novel therapeutic agents, but more work is needed to validate these targets. Hence, there is a great need for selective ligands. Moreover, although the risk of peripheral side-effects for SK channel modulators appears to be low, some questions remain to be investigated. Currently, different molecules are known as SK channel modulators. Apamin is a very potent peptidic agent; it produces a strong blockade of these targets which is only very slowly reversible and it has limited selectivity. Dequalinium was found to be an effective blocker. Different chemical modulations on the dequalinium structure led to the discovery of highly potent bis-quinolinium derivatives such as UCL 1684. Other bis-(2-amino-benzimidazole) derivatives are in development. On the other hand, quaternary salts of bicuculline were reported to be effective in inhibiting AHPs. More recent developments on structurally-related molecules revealed that methyl-laudanosine is a new interesting tool for exploring SK channel pharmacology. Finally, a family of compounds has been shown to facilitate SK channel opening. Such compounds may be useful in treating disorders involving neuronal hyperexcitability.
Assuntos
Neurônios/metabolismo , Canais de Potássio Cálcio-Ativados , Canais de Potássio/fisiologia , Animais , Condutividade Elétrica , Eletrofisiologia , Humanos , Ligantes , Canais de Potássio/efeitos dos fármacos , Canais de Potássio Ativados por Cálcio de Condutância BaixaRESUMO
Intracellular recordings were made from neurones, presumed to be dopaminergic, in the rat midbrain slice preparation. Bicuculline methiodide (BMI) and methochloride (BMC) reversibly blocked the slow, apamin-sensitive component of the afterhyperpolarization in these cells. The IC50 for this effect was about 26 microM. In comparison, BMC antagonized the input resistance decrease evoked by muscimol (3 microM) with an IC50 of 7 microM. The base of bicuculline was less potent in blocking the slow afterhyperpolarization. SR95531 (2-[carboxy-3'-propyl]-3-amino-6-paramethoxy-phenyl-pyridaziniu m bromide), another competitive GABA(A) antagonist, and picrotoxin, a non-competitive GABA(A) antagonist, also blocked the action of muscimol (IC50s: 2 and 12 microM respectively), but had no effect on the afterhyperpolarization at a concentration of up to 100 microM. Moreover, 100 microM SR95531 did not affect the blockade of the afterhyperpolarization by BMC. This blockade persisted in the presence of tetrodotoxin and was apparently not due to a reduction of calcium entry, suggesting that it involved a direct action on the channels which mediate this afterhyperpolarization. These results strongly suggest that quaternary salts of bicuculline act on more than one target in the central nervous system. Thus, the involvement of GABA(A) receptors in a given effect cannot be proven solely on the basis of its blockade by these agents.
Assuntos
Bicuculina/farmacologia , Dopamina/fisiologia , Antagonistas GABAérgicos/farmacologia , Neurônios/efeitos dos fármacos , Animais , Bicuculina/química , Estimulação Elétrica , Eletrofisiologia , Antagonistas de Receptores de GABA-A , Técnicas In Vitro , Masculino , Potenciais da Membrana/fisiologia , Técnicas de Patch-Clamp , Piridazinas/farmacologia , Ratos , Ratos WistarRESUMO
The effect of rilmenidine (S 3341) and clonidine on the firing rate of locus ceruleus (LC) and dorsal raphe (DR) cells was studied in vivo after systemic and microiontophoretic administration. The effect of the 2 drugs was also studied in vitro on brain slices containing LC cells. Rilmenidine and clonidine inhibited the firing of LC and DR neurons. Complementary experiments performed with yohimbine and prazosin demonstrated that the effect of LC is related to an agonistic action on alpha 2 somatodendritic receptors, whereas the effect observed on DR cells is indirect. On LC cells, clonidine is 30 to 60 times as potent as rilmenidine. These observations may be related to less sedative effects of rilmenidine than of clonidine.
Assuntos
Agonistas alfa-Adrenérgicos/farmacologia , Locus Cerúleo/efeitos dos fármacos , Oxazóis/farmacologia , Núcleos da Rafe/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Agonistas alfa-Adrenérgicos/administração & dosagem , Animais , Clonidina/administração & dosagem , Clonidina/farmacologia , Técnicas In Vitro , Infusões Intravenosas , Iontoforese , Locus Cerúleo/fisiologia , Dietilamida do Ácido Lisérgico/farmacologia , Masculino , Oxazóis/administração & dosagem , Prazosina/farmacologia , Núcleos da Rafe/fisiologia , Ratos , Ratos Endogâmicos , RilmenidinaRESUMO
The inclusion of a drug into cyclodextrin generally results in the modification of its physical and chemical properties and sometimes can increase its oral bioavailability. The aim of this study was to compare the effects of the fluoxetine HCl/gamma-cyclodextrin complex to that of traditional fluoxetine HCl. In the forced swimming test in mice, fluoxetine HCl/gamma-cyclodextrin was more effective than fluoxetine HCl, the ED30s being, respectively, 9.5 and 16.9 mg/kg PO. Both compounds (10 mg/kg PO) were able to reduce the firing rate of dorsal raphe neurons in the rat. However, between-groups comparisons showed no significant differences between fluoxetine HCl treated animals and the vehicle group, while fluoxetine HCl/gamma-cyclodextrin appeared significantly more effective than vehicle from minute 25 of the measurement period. In healthy volunteers, the relative oral bioavailability, calculated as the ratio AUC 0-infinity fluoxetine HCl/gamma-cyclodextrin on AUC 0-infinity fluoxetine HCl (20 mg PO), was equal to 249.9%. The three experiments taken together suggest that the complexation of fluoxetine HCl into gamma-cyclodextrin increases its pharmacological efficacy in animals, this effect being related to an enhancement of its oral bioavailability as demonstrated in human healthy subjects.
Assuntos
Ciclodextrinas/administração & dosagem , Fluoxetina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , gama-Ciclodextrinas , Adolescente , Adulto , Animais , Disponibilidade Biológica , Fluoxetina/análogos & derivados , Fluoxetina/farmacocinética , Fluoxetina/farmacologia , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Estudos Prospectivos , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/fisiologia , Ratos , Ratos Wistar , NataçãoRESUMO
It has been suggested that hydrogen peroxide is involved in cascades of pathological events affecting neural cells. The aim of this study was therefore to examine whether this molecule is able by itself to modify membrane properties of pyramidal neurons in the CA1 region of the rat hippocampus. Intracellular recordings in the slice preparation showed that 3.3 mM hydrogen peroxide hyperpolarized all neurons tested (n = 41) by 11 +/- 3 mV. This effect persisted in the presence of tetrodotoxin. It developed slowly, was reversible and reproducible. In the presence of tetrodotoxin, the extrapolated reversal potential of this effect was -95 +/- 5 mV in 2.5 mM external potassium. This value was not significantly different from the one obtained with the GABAB agonist baclofen (10 microM) (-98 +/- 5 mV). It shifted when the concentration of external potassium was increased to 10.5 mM (from -96 +/- 5 to -62 +/- 4 mV), in close agreement with the Nernst equation potassium ions. The hyperpolarization was significantly reduced (by 65 +/- 22%) by the potassium channel blocker barium (100 microM). We suggest that hydrogen peroxide is able to induce an increase in potassium conductance in rat CA1 pyramidal neurons. The exact mechanism by which it produces this effect (direct action on channels or indirect effect) remains to be determined.
Assuntos
Peróxido de Hidrogênio/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Oxidantes/farmacologia , Potássio/fisiologia , Células Piramidais/fisiologia , Animais , Baclofeno/farmacologia , Bário/farmacologia , Condutividade Elétrica , Eletrofisiologia , Agonistas dos Receptores de GABA-B , Hipocampo/citologia , Hipocampo/fisiologia , Masculino , Bloqueadores dos Canais de Potássio , Células Piramidais/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
The influence of acute administration of stereoisomers of fenfluramine and norfenfluramine on the firing rate of central monoaminergic neurons was investigated in rats anaesthetized with chloral hydrate. The firing rate of dorsal raphe (DR) and locus coeruleus (LC) neurons was inhibited. The parent drugs were more active on DR neurons than on LC neurons, and the converse was true for the demethylated metabolites. In both cases the d isomers were more active than the l isomers. No effect was observed on the electrical activity of A10 dopaminergic neurons. These differences in potency and selectivity could have therapeutic implications.
Assuntos
Fibras Colinérgicas/efeitos dos fármacos , Fenfluramina/farmacologia , Condução Nervosa/efeitos dos fármacos , Animais , Fibras Colinérgicas/fisiologia , Eletrodos Implantados , Eletrofisiologia , Fenfluramina/administração & dosagem , Infusões Intravenosas , Masculino , Norfenfluramina/farmacologia , Ratos , Ratos Endogâmicos , Fatores de TempoRESUMO
The spontaneous firing rate of the noradrenergic neurons of the locus coeruleus and of the serotonergic neurons of the dorsal raphe was recorded with extracellular microelectrodes in chloral hydrate-anesthetized rats. A quantitative comparison of the effect of five tricyclic antidepressants, of tranylcypromine and of mianserin on the spontaneous activity of these two types of cells was performed. All drugs tested, except mianserin reduced the frequency of discharge of the noradrenergic neurons. Intravenous perfusion of the drugs allowed the doses required for inhibition of firing to 50% of the baseline rate (ID50) to be determined. Secondary aminated antidepressants (desipramine and nortriptyline) were more potent inhibitors than their tertiary aminated analogues (imipramine, chlorimipramine and amitriptyline). All drugs tested, except desipramine decreased the rate of firing of the serotonergic cells. In this case, the tertiary aminated antidepressants were much more potent than their secondary analogues. Mianserin was only active at very high doses. These results are in good agreement with the relative potencies of the tricyclic antidepressants for blocking the uptake of noradrenaline and serotonin into central and peripheral neurons.
Assuntos
Antidepressivos/farmacologia , Tronco Encefálico/efeitos dos fármacos , Locus Cerúleo/efeitos dos fármacos , Núcleos da Rafe/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Antidepressivos Tricíclicos/farmacologia , Técnicas In Vitro , Masculino , Mianserina/farmacologia , Ratos , Tranilcipromina/farmacologiaRESUMO
JL3, 10-(4-methylpiperazin-1-yl)pyrido[4,3-b][1,4]benzothiazepine, has potent antidepressant-like activity in Porsolt's test in mice. Therefore, its influence on the electrical activity of central monoaminergic neurons was investigated in rats anaesthetized with chloral hydrate. JL3 induced a marked decrease of the firing rate of dorsal raphe serotonergic neurons (ID50 = 3.87 +/- 0.57 mg kg-1) and of locus coeruleus noradrenergic neurons (ID50 = 2.63 +/- 0.35 mg kg-1). The drug did not modify the electrical activity of A10 dopaminergic neurons. JL3 does not block amine uptake but it has affinity for 5-HT1A and 5-HT2 receptors. It is speculated that serotonergic mechanisms could play a role in the electrophysiological effects of JL3.
Assuntos
Antidepressivos/farmacologia , Núcleos da Rafe/efeitos dos fármacos , Tiazepinas/farmacologia , Animais , Relação Dose-Resposta a Droga , Eletrofisiologia , Humanos , Locus Cerúleo/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Using in vitro electrophysiological procedures, we confirm the inhibitory effect of 10-(4-methylpiperazin-1-yl)pyrido[4,3-b][1, 4]benzothiazepine (JL 3), on dorsal raphe serotonergic (IC(50)=14 microM) and noradrenergic neurons (IC(50)=4.5 microM). The effect on dorsal raphe neurons was reduced by N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl- cyclohexanecarboxamide (WAY-100635), suggesting the importance of 5-HT(1A) receptor stimulation. Yohimbine, and ritanserin, to a lesser extent, blocked the inhibitory effect of JL 3 on locus coeruleus neurons indicating that alpha(2)-adrenoceptors and 5-HT(2A) receptors may be implicated in the effects. Because of its negligible alpha(2)-adrenoceptor affinity, the effect of JL 3 on locus coeruleus neurons, would have to be indirect. JL 3 may interfere with the norepinephrine transporter site (IC(50)=0.34 microM). JL 3 tended to reinforce the hypertensive effect of norepinephrine, while it strongly inhibited the hypertensive effect of tyramine, further indicating an interaction at the norepinephrine transporter site level.
Assuntos
Antidepressivos/farmacologia , Neurônios/efeitos dos fármacos , Receptores Adrenérgicos/metabolismo , Receptores de Serotonina/metabolismo , Tiazepinas/farmacologia , Inibidores da Captação Adrenérgica/farmacologia , Animais , Interações Medicamentosas , Técnicas In Vitro , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/metabolismo , Masculino , Neurônios/metabolismo , Norepinefrina/farmacologia , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/metabolismo , Ratos , Ratos Wistar , Tiramina/farmacologiaRESUMO
The principal neurochemical property of tricyclic antidepressants is the blockade of noradrenaline (NA) and/or 5-hydroxytryptamine (5-HT) uptake into monoaminergic nerve endings. Electrophysiological studies show that these drugs also decrease the firing rate of the noradrenergic neurones of the locus coeruleus (L.C.) and of the serotonergic neurones of the dorsal raphe (D.R.). In order to assess the relation between the two phenomena, the influence of five tricyclic antidepressants on NA and 5-HT uptake was studied in vitro. The concentrations required to produce a 50% inhibition (IC50) were determined and correlated with the respective doses required to reduce to 50% (ID50) the firing rate of L.C. and D.R. neurones. Ex vivo experiments were also performed to study the influence of the tricyclic antidepressants on NA and 5-HT uptake when administered i.v. at the doses decreasing to 50% the firing rate of L.C. and D.R. cells. The inhibition of the NA uptake by tricyclic antidepressants can account, at least in part, for the inhibition of the firing rate of L.C. neurones observed after acute i.v. administration. In the case of serotonergic neurons, the results do not allow a firm conclusion.
Assuntos
Antidepressivos Tricíclicos/farmacologia , Encéfalo/efeitos dos fármacos , Norepinefrina/metabolismo , Serotonina/metabolismo , Absorção , Animais , Eletrofisiologia , Feminino , Técnicas In Vitro , Cinética , Locus Cerúleo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Núcleos da Rafe/efeitos dos fármacos , Ratos , Ratos EndogâmicosRESUMO
BHT 920 was originally described as a dopamine autoreceptor agonist. In this study, the effect of this compound on the firing rate of noradrenergic locus coeruleus, serotonergic dorsal raphe and dopaminergic ventral tegmental area neurons was examined both in the anaesthetized rat and in rat brain slices. Extracellular recordings were performed in cells whose identity was determined by electrophysiological, pharmacological and histological criteria. In vivo, BHT 920 inhibited the firing of locus coeruleus neurons (ID50: 14.5 +/- 4.7 micrograms/kg, mean +/- SEM) and ventral tegmental area neurons (ID50: 7 +/- 3 micrograms/kg) at very low doses. As a comparison, the ID50 of clonidine on locus coeruleus cells was 5.5 +/- 0.6 microgram/kg and the ID50 of apomorphine on ventral tegmental area neurons was 13 +/- 3 micrograms/kg. BHT 920 also decreased the firing of dorsal raphe cells, but this effect was obtained at higher doses (ID50: 57 +/- 11 micrograms/kg). The in vitro study confirmed the results obtained in vivo. BHT 920 potently inhibited the firing of locus coeruleus cells (IC50: 71 +/- 28 nM) and was less potent than clonidine (IC50: 5.3 +/- 0.98 nM). The compound also inhibited the firing of ventral tegmental area neurons at very low concentrations (IC50: 21 +/- 3.3 nM), being more potent than apomorphine (IC50: 56 +/- 29 nM). BHT 920 only slightly decreased the firing rate of dorsal raphe neurons at 50 microM, showing that the drug has little direct effect on these cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Agonistas alfa-Adrenérgicos/farmacologia , Azepinas/farmacologia , Monoaminas Biogênicas/fisiologia , Encéfalo/efeitos dos fármacos , Dopaminérgicos/farmacologia , Neurônios/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Apomorfina/farmacologia , Clonidina/farmacologia , Dioxanos/farmacologia , Idazoxano , Técnicas In Vitro , Locus Cerúleo/efeitos dos fármacos , Masculino , Núcleos da Rafe/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Sulpirida/farmacologia , Tegmento Mesencefálico/efeitos dos fármacosRESUMO
After heart disease, cancer and stroke, Alzheimer's disease (AD) is the fourth major cause of death in the developed countries. Due to demographic changes, this situation will further worsen in the future. With the use of molecular biology techniques, important progress has recently been made in the understanding of the molecular changes leading to some forms of this disabling illness. The first step was the partial sequencing of the amyloid protein accumulating in the senile plaques and vascular deposits characteristic of AD. This allowed the cloning of a cDNA coding for a long amyloid precursor protein (APP). During the last few years, independent reports have described the presence of several reproducible point mutations in specific codons of APP in early onset familial Alzheimer patients. These mutations are responsible for an abnormal processing of APP, leading to the formation of pathological beta/A4 amyloid deposits. beta/A4 has been shown to possess neurotrophic properties in embryonic neurones and to be a potent neurotoxic agent in differentiated hippocampal neurones. More recently, modifications of intracellular calcium, activation of kinases, free radical generation and anomalies in potassium channels have been described as possible mechanisms of beta/A4 toxicity. Some forms of Apo-E lipoprotein may be an additional risk factor. Hence, it now seems possible to elaborate a coherent theory to explain the cascade of events leading to the development of AD. Genetically induced point mutations or environmental factors may produce a modification of the APP metabolism and processing. As a consequence, abnormal deposits of beta/A4 are formed. They may exert direct or indirect neurotoxic actions. A degeneration of cholinergic, catecholaminergic and other neurones follows, leading to the well known cognitive and behavioural changes of AD.
Assuntos
Doença de Alzheimer/fisiopatologia , Precursor de Proteína beta-Amiloide/fisiologia , Doença de Alzheimer/tratamento farmacológico , Precursor de Proteína beta-Amiloide/efeitos dos fármacos , Animais , HumanosRESUMO
Electrophysiological studies were performed in order to compare the influence of tianeptine and clomipramine on the firing rate of central locus coeruleus noradrenergic neurons, raphe dorsalis serotoninergic neurons, and hippocampus CA1 pyramidal cells. The interaction of tianeptine and clomipramine with the response of CA1 cells to iontophoretically applied 5-HT or GABA was also investigated. The i.v. perfusion of tianeptine decreased the firing rate of locus coeruleus neurons (ID50 = 1.74 +/- 0.2 mg/kg), did not modify the firing rate of raphe dorsalis neurons, and increased the firing rate of CA1 pyramidal cells (ED50 = 0.68 +/- 0.17 mg/kg). The tianeptine inhibiting dose 50 for noradrenergic neuron firing rate was 2.5 times higher than the activating dose for hippocampus pyramidal cells, and 6 times higher than the inhibiting dose for selective noradrenaline uptake inhibitors as desipramine. In comparison, the i.v. infusion of clomipramine decreased the firing rate of locus coeruleus, raphe dorsalis, and CA1 neurons. The iontophoretic application of tianeptine did not modify the response of CA1 cells to 5-HT or GABA but decreased the recovery time after 5-HT and GABA. The iontophoretic application of clomipramine potentiated the response of CA1 cells to 5-HT but not to GABA and increased the recovery time after 5-HT and GABA. Tianeptine appears to have an original electrophysiological profile in agreement with an increase in serotonin uptake: this profile distinguishes tianeptine from classical antidepressants such as clomipramine.
Assuntos
Antidepressivos Tricíclicos/farmacologia , Hipocampo/efeitos dos fármacos , Locus Cerúleo/efeitos dos fármacos , Núcleos da Rafe/efeitos dos fármacos , Tiazepinas/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Antidepressivos Tricíclicos/administração & dosagem , Clomipramina/farmacologia , Infusões Intravenosas , Masculino , Neurônios/efeitos dos fármacos , Norepinefrina/metabolismo , Ratos , Ratos Endogâmicos , Serotonina/metabolismo , Tiazepinas/administração & dosagemRESUMO
OBJECTIVES: To estimate costs associated with dementia and its severity and to identify main cost determinants. DESIGN: One-year prospective cohort study. SETTING: 231 general practitioners (GPs) and 15 specialist clinics throughout Belgium. SUBJECTS: 605 patients aged > or = 65 years (219 referent patients, 218 demented patients at home and 168 demented patients in institution). OUTCOME MEASURES: Medical costs (visits to GPs/specialists, physiotherapy, hospitalisation, nursing, incontinence, medication) and non-medical costs (special equipment, services, professional help and caregiving). RESULTS: Total monthly costs amounted to 368.50 Euro dollar for referent patients, 445.56 Euro dollar for demented patients at home and 2301.7 Euro dollar for demented patients in institutions. Highest costs were measured in patients with severe dementia (556.88 Euro dollar at home, 2465.28 Euro dollar in institutions). In demented patients at home, 60% of costs were accounted for by the health system, with hospitalisation and medication being the main cost components (36% and 20%). In demented patients in institution, 46% of the costs were accounted for by the health system, with residential costs and nursing being the main cost components (42% and 32%). In multivariate covariance analysis, the main determinants of costs for demented patients at home were physical dependence and co-morbidity (neoplasm, cardiovascular disease). The adjusted difference between demented and referent patients was 25 Euro dollar per month. CONCLUSIONS: A large fraction of the costs observed in dementia is explained by the association of dementia with physical dependence, co-morbidity and need for caregiving. From an economic point of view, the results support the caring for patients at home.
Assuntos
Efeitos Psicossociais da Doença , Demência/economia , Serviços de Assistência Domiciliar/economia , Hospitalização/economia , Idoso , Idoso de 80 Anos ou mais , Bélgica/epidemiologia , Transtornos Cognitivos/economia , Estudos de Coortes , Custos e Análise de Custo , Demência/epidemiologia , Custos Diretos de Serviços , Feminino , Humanos , Masculino , Casas de Saúde/economia , Estudos ProspectivosRESUMO
Histoenzymologic analysis of human and animal epileptogenic foci has shown enzymatic changes in certain reactive astrocytes. Histochemical examination of these astrocytes in animals has led to clear differentiation between the classic, perilesional reactive astrocyte, constituting a medium for cicatrical glioses and the reactive astrocyte present in experimental epileptogenic foci. We have called the latter the "activated astrocyte". Analysis of 154 human cerebral tumours revealed activated astrocytes in the cortex of all patients with epileptic antecedents. No epileptic attacks were observed in patients where the cortex was invaded by the tumour but no activated astrocytes were present. Analysis of ten cases of non tumoral focal epilepsy confirmed the presence of activated astrocytes in the focus in all cases where the scar was resected surgically. The production of epileptogenic foci in animals shows the close relation between activated astrocytes and the epileptogenic focus. It even seems that the enzymatic changes in the astrocytes precedes the first electrical signs. The authors arguse against the hypothesis that the activated astrocytes are the result of attacks. Until the morphological criteria of the epilectic neuron have been defined the activated astrocyte constitutes the only morphological evidence of the epileptogenic focus.
Assuntos
Astrócitos/enzimologia , Epilepsia/enzimologia , Oxirredutases/análise , Fosforilases/análise , Animais , Epilepsias Parciais/enzimologia , Histocitoquímica , Humanos , Masculino , RatosRESUMO
OBJECTIVE: To study the impact of cognitive impairment and severity of dementia on the quality of life (QoL) of patients and their caregivers. DESIGN: Descriptive cross-sectional study within the NAtional Dementia Economic Study. SETTING: 231 general practices and 15 specialist clinics in Belgium. SUBJECTS: 605 patients aged > or = 65 years: 106 referent subjects without cognitive impairment (R), 113 subjects with cognitive impairment and no dementia (CIND), 386 subjects with mild (83), mild/moderate (108), moderate (62) or severe (133) dementia (D1 to D4). OUTCOME MEASURES: QoL of patients: COOP/WONCA charts, Katz's Activities of Daily Living (ADL) scale, Lawton's Instrumental Activities of Daily Living (IADL) scale. QoL of caregivers: COOP/WONCA charts, SF-36 questionnaire, short-form Beck Depression Inventory, Sense of Competence questionnaire (SCQ). MAIN RESULTS: QoL of patients: For R, CIND and D1 to D4 patients, dependence for ADL reached 5%, 6%, 16%, 20%, 48% and 79%, respectively, and mean IADL scores were 5.6, 5.0, 3.4, 2.0, 0.6 and 0.1, respectively. QoL of caregivers: The main impact of caregiving was on mental health, with SF-36 MCS scores of 51.3, 47.7 and 45.4 for R, CIND and all D patients and respectively 32.6%, 31.3% and 42.5% depression prevalence. Sense of competence decreased with severity of patient's cognitive impairment. Caregivers of CIND patients always rated intermediate between R and D1 patients. Caregivers of D3 patients were the most affected ones. CONCLUSION: The data suggest that improving the cognitive status of patients and providing assistance to caregivers would be complementary ways of action to support caregiving of patients living at home.