RESUMO
Synaptic roles for neurofilament (NF) proteins have rarely been considered. Here, we establish all four NF subunits as integral resident proteins of synapses. Compared with the population in axons, NF subunits isolated from synapses have distinctive stoichiometry and phosphorylation state, and respond differently to perturbations in vivo. Completely eliminating NF proteins from brain by genetically deleting three subunits (α-internexin, NFH and NFL) markedly depresses hippocampal long-term potentiation induction without detectably altering synapse morphology. Deletion of NFM in mice, but not the deletion of any other NF subunit, amplifies dopamine D1-receptor-mediated motor responses to cocaine while redistributing postsynaptic D1-receptors from endosomes to plasma membrane, consistent with a specific modulatory role of NFM in D1-receptor recycling. These results identify a distinct pool of synaptic NF subunits and establish their key role in neurotransmission in vivo, suggesting potential novel influences of NF proteins in psychiatric as well as neurological states.
Assuntos
Encéfalo/fisiologia , Atividade Motora/fisiologia , Proteínas de Neurofilamentos/metabolismo , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Animais , Axônios/efeitos dos fármacos , Axônios/fisiologia , Encéfalo/efeitos dos fármacos , Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Potenciação de Longa Duração/fisiologia , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Proteínas de Neurofilamentos/genética , Receptores de Dopamina D1/metabolismo , Sinapses/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacosRESUMO
The finding that many drugs that have abuse potential and other natural stimuli such as food or sexual activity cause similar chemical changes in the brain, an increase in extracellular dopamine (DA) in the shell of the nucleus accumbens (NAccS), indicated some time ago that the reward mechanism is at least very similar for all stimuli and that the mechanism is relatively simple. The presently available information shows that the mechanisms involved are more complex and have multiple elements. Multiple brain regions, multiple receptors, multiple distinct neurons, multiple transmitters, multiple transporters, circuits, peptides, proteins, metabolism of transmitters, and phosphorylation, all participate in reward mechanisms. The system is variable, is changed during development, is sex-dependent, and is influenced by genetic differences. Not all of the elements participate in the reward of all stimuli. Different set of mechanisms are involved in the reward of different drugs of abuse, yet different mechanisms in the reward of natural stimuli such as food or sexual activity; thus there are different systems that distinguish different stimuli. Separate functions of the reward system such as anticipation, evaluation, consummation and identification; all contain function-specific elements. The level of the stimulus also influences the participation of the elements of the reward system, there are possible reactions to even below threshold stimuli, and excessive stimuli can change reward to aversion involving parts of the system. Learning and memory of past reward is an important integral element of reward and addictive behavior. Many of the reward elements are altered by repeated or chronic stimuli, and chronic exposure to one drug is likely to alter the response to another stimulus. To evaluate and identify the reward stimulus thus requires heterogeneity of the reward components in the brain.
Assuntos
Encéfalo/fisiologia , Recompensa , Acetaldeído/farmacologia , Consumo de Bebidas Alcoólicas/fisiopatologia , Consumo de Bebidas Alcoólicas/psicologia , Animais , Encéfalo/crescimento & desenvolvimento , Condicionamento Psicológico/fisiologia , Alimentos , Humanos , Aprendizagem/fisiologia , Fatores Sexuais , Transtornos Relacionados ao Uso de Substâncias/genética , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/psicologiaRESUMO
It is well established that the continued intake of drugs of abuse is reinforcing-that is repeated consumption increases preference. This has been shown in some studies to extend to other drugs of abuse; use of one increases preference for another. In particular, the present review deals with the interaction of nicotine and alcohol as it has been shown that smoking is a risk factor for alcoholism and alcohol use is a risk factor to become a smoker. The review discusses changes in the brain caused by chronic nicotine and chronic alcohol intake to approach the possible mechanisms by which one drug increases the preference for another. Chronic nicotine administration was shown to affect nicotine receptors in the brain, affecting not only receptor levels and distribution, but also receptor subunit composition, thus affecting affinity to nicotine. Other receptor systems are also affected among others catecholamine, glutamate, GABA levels and opiate and cannabinoid receptors. In addition to receptor systems and transmitters, there are endocrine, metabolic and neuropeptide changes as well induced by nicotine. Similarly chronic alcohol intake results in changes in the brain, in multiple receptors, transmitters and peptides as discussed in this overview and also illustrated in the tables. The changes are sex and age-dependent-some changes in males are different from those in females and in general adolescents are more sensitive to drug effects than adults. Although nicotine and alcohol interact-not all the changes induced by the combined intake of both are additive-some are opposing. These opposing effects include those on locomotion, acetylcholine metabolism, nicotine binding, opiate peptides, glutamate transporters and endocannabinoid content among others. The two compounds lower the negative withdrawal symptoms of each other which may contribute to the increase in preference, but the mechanism by which preference increases-most likely consists of multiple components that are not clear at the present time. As the details of induced changes of nicotine and alcohol differ, it is likely that the mechanisms of increasing nicotine preference may not be identical to that of increasing alcohol preference. Stimulation of preference of yet other drugs may again be different -representing one aspect of drug specificity of reward mechanisms.
Assuntos
Etanol/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Recompensa , Fatores Etários , Alcoolismo/complicações , Alcoolismo/metabolismo , Alcoolismo/psicologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Interações Medicamentosas , Etanol/efeitos adversos , Feminino , Humanos , Masculino , Neurotransmissores/metabolismo , Nicotina/efeitos adversos , Agonistas Nicotínicos/efeitos adversos , Receptores de Neurotransmissores/metabolismo , Receptores Nicotínicos/metabolismo , Fatores Sexuais , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/psicologia , Tabagismo/complicações , Tabagismo/metabolismo , Tabagismo/psicologiaRESUMO
Cholinesterase inhibitors including donepezil, rivastigmine, and galantamine and the N-methyl-D-aspartate (NMDA) antagonist, memantine are the medications currently approved for the treatment of Alzheimer's disease (AD). In addition to their beneficial effects on cognitive and functional domains typically disrupted in AD, these agents have also been shown to slow down the emergence of behavioral and psychotic symptoms associated with this disease. However, the underlying mechanisms for these therapeutic effects remain poorly understood and could involve effects of these medications on non-cholinergic or non-glutamatergic neurotransmitter systems respectively. These considerations prompted us to initiate a series of investigations to examine the acute and chronic effects of donepezil (Aricept (+/-)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-1 hydrochloride and memantine (1-amino-3,5-dimethyladamantane hydrochloride C12H21N.HCl)). The present study focuses on the acute effects of donepezil and memantine on brain extracellular levels of acetylcholine, dopamine, serotonin, norepinephrine and their metabolites. We assayed changes in the ventral and dorsal hippocampus and the prefrontal and medial temporal cortex by microdialysis. Memantine resulted in significant increases in extracellular dopamine (DA), norepinephrine (NE), and their metabolites, in the cortical regions, and in a reduction of DA in the hippocampus. Donepezil produced an increase in extracellular DA in the cortex and in the dorsal hippocampus. Norepinephrine increased in the cortex; with donepezil it increased in the dorsal hippocampus and the medial temporal cortex, and decreased in the ventral hippocampus. Interestingly both compounds decreased extracellular serotonin (5HT) levels. The metabolites of the neurotransmitters were increased in most areas. We also found an increase in extracellular acetylcholine (ACh) by memantine in the nucleus accumbens and the ventral tegmental area. Our results suggest both region and drug specific neurotransmitter effects of these agents as well as some similarities. We conclude that drugs influencing cognitive mechanisms induce changes in a number of neurotransmitters with the changes being both region and drug specific. Release and metabolism are altered and extracellular neurotransmitter levels can be increased or decreased by the drugs. Other studies are in progress to determine the pharmacological effects associated with chronic treatment with these compounds, which may be more pertinent to the clinical situation in which patients take these medications for months or years.
Assuntos
Córtex Cerebral/efeitos dos fármacos , Indanos/farmacologia , Memantina/farmacologia , Neurotransmissores/metabolismo , Piperidinas/farmacologia , Terminações Pré-Sinápticas/efeitos dos fármacos , Acetilcolina/metabolismo , Animais , Córtex Cerebral/metabolismo , Inibidores da Colinesterase/farmacologia , Donepezila , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/farmacologia , Líquido Extracelular/efeitos dos fármacos , Líquido Extracelular/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Microdiálise , Norepinefrina/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Terminações Pré-Sinápticas/metabolismo , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Lobo Temporal/efeitos dos fármacos , Lobo Temporal/metabolismo , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismoRESUMO
The B6.C quasi-congenic Recombinant QTL Introgression (RQI) strains of the b4i5 series have similar genetic background, but differ in about 5% of their genome from the C57BL/6ByJ (B6) background strain because they carry short chromosome segments introgressed from the BALB/cJ (C) donor strain. These RQI strains were derived from mouse lines selectively bred for high activity of mesencephalic tyrosine hydroxylase (TH/MES), therefore genetic variation in dopamine system-related behaviours, such as ethanol-induced motor activity, can be expected. Males and females of 17 RQI and two progenitor strains were tested for initial motor activity for 15 min after a habituating injection of saline, which was followed by an i.p. injection of saline or ethanol (2 g/kg) and an additional test of motor activity for 30 min. This procedure was repeated during 4 subsequent days. In all strains, the first-day ethanol treatment showed an inhibitory effect. With repetition of the treatment the inhibitory effect decreased, and a stimulatory effect could be observed with significant strain- and sex-dependent variation. Females exhibited higher activity in the saline group than males, and reached an equilibrium of inhibition and stimulation sooner than males with repetition of the ethanol treatment. The highest (> 25-fold) difference in activity after repeated ethanol treatment was detected between females of the two strains B6.Cb4i5-Alpha4/Vad and B6.Cb4i5-Beta13/Vad. These results firstly suggest that females are more sensitive to repeated ethanol exposure than males, secondly they support the observations that ethanol has both inhibitory and stimulatory effects on motor activity, which are affected by sex, genotype, and repetition of treatment, and thirdly offer new quasi-congenic animal models with highly different responses to ethanol allowing one to more quickly move to gene detection.
Assuntos
Nível de Alerta/genética , Etanol/farmacologia , Camundongos Congênicos/genética , Atividade Motora/efeitos dos fármacos , Animais , Nível de Alerta/efeitos dos fármacos , Depressão Química , Relação Dose-Resposta a Droga , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/fisiologia , Masculino , Mesencéfalo/fisiologia , Camundongos , Atividade Motora/fisiologia , Locos de Características Quantitativas/genética , Seleção Genética , Fatores Sexuais , Especificidade da Espécie , Estimulação Química , Tirosina 3-Mono-Oxigenase/genéticaRESUMO
BACKGROUND: Phencycline (PCP, "angel dust") and other noncompetitive antagonists of N-methyl-D-aspartate (NMDA)-type glutamatergic neurotransmission induce psychotic effects in humans that closely resemble positive, negative, and cognitive symptoms of schizophrenia. Behavioral effects of PCP in rodents are reversed by glycine (GLY) and other NMDA augmenting agents. In rodents, behavioral effects of PCP are mediated, in part, by secondary dysregulation of subcortical dopaminergic neurotransmission. This study evaluates effects of GLY and GLY transport antagonists on behavioral and neurochemical consequences of PCP administration in rodents. METHODS: Two separate experiments were performed. In the first, effects of GLY on PCP-induced stimulation of dopaminergic neurotransmission in nucleus accumbens were evaluated using in vivo microdialysis in awake animals. In the second, effects of a series of GLY transport antagonists were evaluated for potency in inhibiting PCP-induced hyperactivity. RESULTS: In microdialysis studies, GLY significantly inhibited PCP-induced stimulation of subcortical DA release in a dose-dependent fashion. In behavioral studies, the potency of a series of GLY transport antagonists for inhibiting PCP-induced hyperactivity in vivo correlated significantly with their potency in antagonizing GLY transport in vitro. CONCLUSIONS: These findings suggest, first, that GLY reverses not only the behavioral, but also the neurochemical, effects of PCP in rodents. Second, the findings suggest that GLY transport antagonists may induce similar effects to GLY, and may therefore represent an appropriate site for targeted drug development.
Assuntos
Dopamina/metabolismo , Glicinérgicos/metabolismo , Glicinérgicos/farmacocinética , Alucinógenos/metabolismo , Alucinógenos/farmacocinética , N-Metilaspartato/metabolismo , Inibidores da Captação de Neurotransmissores/farmacologia , Fenciclidina/metabolismo , Fenciclidina/farmacocinética , Esquizofrenia/metabolismo , Animais , Distinções e Prêmios , Encéfalo/metabolismo , Masculino , Microdiálise , Psiquiatria , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
Functional dopaminergic hyperactivity is a key feature of schizophrenia. Recent in vivo imaging studies have demonstrated greater striatal dopamine release in response to amphetamine challenge in schizophrenia subjects than in normal controls. N-methyl-D-aspartate (NMDA) receptors are known to play a prominent role in regulation of striatal dopamine release. In humans, NMDA antagonists induce a psychotic state that closely resembles schizophrenia. The present study investigates the degree to which chronic continuous administration of the NMDA antagonist phencyclidine (PCP) induces schizophrenia-like hyperreactivity of striatal dopamine release to amphetamine in rodents. Rats were treated with 10 or 15 mg/kg/d PCP for two weeks by osmotic minipump, and striatal dopamine release to amphetamine challenge (1 mg/kg) was monitored by microdialysis. PCP-treated rats showed significant enhancement in amphetamine-induced dopamine release, along with significantly enhanced locomotor activity. These findings support the concept that NMDA receptor dysfunction may contribute to dopaminergic dysfunction in schizophrenia.
Assuntos
Corpo Estriado/efeitos dos fármacos , Dopamina/biossíntese , Antagonistas de Aminoácidos Excitatórios/farmacologia , Fenciclidina/administração & dosagem , Fenciclidina/farmacologia , Agitação Psicomotora/metabolismo , Esquizofrenia/metabolismo , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Anfetamina/farmacologia , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Corpo Estriado/metabolismo , Ácido Homovanílico/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Ratos , Ratos Sprague-Dawley , Esquizofrenia/induzido quimicamenteRESUMO
Phencyclidine (PCP) induces a psychotic state that closely resembles schizophrenia. In preclinical studies, PCP has been shown to induce its unique behavioral effects by blocking excitatory neurotransmission mediated at the N-methyl-D-aspartate (NMDA) receptors, suggesting that agents which potentiate NMDA receptor-mediated neurotransmission might have clinically beneficial effects. The present study demonstrates that the NMDA co-agonist glycine inhibits rodent hyperactivity induced by PCP, but not amphetamine. Glycyldodecylamide, a compound that blocks neuronal glycine uptake and which may therefore increase intrasynaptic glycine levels, inhibits PCP-induced hyperactivity more potently than glycine. These results complement recent clinical studies with glycine and suggest that glycine-uptake inhibitors, as well as glycine, may be beneficial in the treatment of PCP-induced psychosis and schizophrenia.
Assuntos
Anfetamina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Glicina/análogos & derivados , Glicina/farmacologia , Atividade Motora/efeitos dos fármacos , Fenciclidina/farmacologia , Animais , Inibidores da Captação de Dopamina/farmacologia , Camundongos , Fenciclidina/antagonistas & inibidoresRESUMO
Cocaine and its analogs bound saturably to membranes of brain and liver of mice. The binding sites on membranes of liver had a lower affinity for cocaine than those of brain. In addition, there were striking differences between the two tissues in regard to the relative potencies of cocaine analogs in competing with [3H]cocaine for binding. In comparison with the binding sites in brain, those in liver had only moderate stereospecificity, and they discriminated less between the centrally active compounds and the centrally inert analogs.
Assuntos
Encéfalo/metabolismo , Cocaína/metabolismo , Fígado/metabolismo , Receptores Opioides/metabolismo , Animais , Ligação Competitiva , Cocaína/análogos & derivados , Masculino , Camundongos , Camundongos Endogâmicos BALB C/metabolismoRESUMO
The effect of nicotine on MPTP-induced changes in striatal dopamine receptors binding activity was investigated. Dopamine D1 and D2 receptors were labeled with [3H]SCH-23390 and [3H]spiperone respectively in BALB/cBy mice. With administration of only MPTP, which caused more than an 80% decrease in striatal dopamine level, binding of 0.15 nM [3H]spiperone was increased by 37%; whereas 0.3 nM [3H]SCH-23390 binding was unchanged. With chronic nicotine treatment (0.4 mg/kg twice daily for 7-9 days), [3H]SCH-23390 binding activity was increased by 27% and [3H]spiperone binding activity was unchanged. When nicotine was administered after MPTP, their separate effects could be seen in that both the D1 and D2 dopamine receptor ligand binding activities were increased and that nicotine elevated the ratio of D1/D2 receptor binding activities in MPTP-treated mice.
Assuntos
Nicotina/farmacologia , Piridinas/farmacologia , Receptores Dopaminérgicos/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Benzazepinas/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Receptores Dopaminérgicos/efeitos dos fármacos , Espiperona/metabolismoRESUMO
Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 2 X 8 mg/kg retro-orbital) to BALB/cBy mice reduced [3H]mazindol binding to striatal membranes by 50%. Reactive oxygen derivatives have been suggested to be involved in MPTP neurotoxicity; therefore we examined the effects of ascorbic acid (an antioxidant). Ascorbic acid (100 mg/kg) given 20 min prior to MPTP administration appreciably prevented the reduction of [3H]mazindol binding. The involvement of oxidative processes in the mechanism of MPTP neurotoxicity may suggest a relationship to the etiology of Parkinson's disease, and the possible benefit of treatment with ascorbic acid.
Assuntos
Ácido Ascórbico/farmacologia , Sistema Nervoso/efeitos dos fármacos , Piridinas/toxicidade , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Corpo Estriado/metabolismo , Mazindol/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Piridinas/antagonistas & inibidores , Sinaptossomos/metabolismoRESUMO
Metaphit, an isothiocyanate analog of phencyclidine and a proposed phencyclidine receptor acylator, inactivated the carrier involved in the neuronal uptake of dopamine in in vitro experiments with preparations of the striatum in the mouse. In ex vivo experiments 2 and 24 hr after the intravenous administration of metaphit, no changes were observed either in the binding of [3H]cocaine to striatal membranes or in the uptake of [3H]dopamine into synaptosomes or slices. In in vivo experiments 24 hr after pretreatment with metaphit, selective labelling of uptake sites for dopamine in the striatum of the mouse with [3H]GBR 12935 was unaffected. In these in vivo experiments, however, metaphit antagonized the locomotor stimulation induced by blockers of the uptake of dopamine (methylphenidate, mazindol, cocaine, GBR 12909) but not that induced by drugs that affect locomotion by other mechanisms (amphetamine, phencyclidine). Twenty-four hours after treatment with metaphit there was an increase in homovanillic acid in all regions of the brain studied (striatum, olfactory tubercle, cerebral cortex). There was no effect of metaphit on the disappearance rate of 3,4-dihydroxyphenylacetic acid and homovanillic acid from the striatum during the inhibition of monoamine oxidase with pargyline. If the increase in homovanillic acid reflected a greater rate of dopamine catabolism in metaphit-treated mice, it could explain the lack of locomotor stimulation of blockers uptake of the dopamine in these animals, resulting from a rapid breakdown of extracellularly accumulated dopamine.
Assuntos
Anfetamina/antagonistas & inibidores , Cocaína/antagonistas & inibidores , Dopamina/fisiologia , Atividade Motora/efeitos dos fármacos , Fenciclidina/análogos & derivados , Animais , Aminas Biogênicas/metabolismo , Química Encefálica/efeitos dos fármacos , Cocaína/metabolismo , Dopamina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fenciclidina/farmacologia , Receptores Dopaminérgicos/efeitos dos fármacosRESUMO
In the present study we investigated the effect of different nicotinic agonists (dimethylphenyl-piperazinium-iodide (DMPP), (-)nicotine, cytisine, (-)-lobeline, and (-)epibatidine) and antagonists (mecamylamine and dihydro-beta-erythroidine) on the release of [3H]5-HT from hippocampal slices. The nicotinic agonists DMPP and lobeline and electrical field stimulation, released [3H]5-HT from the hippocampus; other nicotinic agonists, such as (-)-nicotine, cytisine, and (-)-epibatidine had no effect. Unlike lobeline-induced release of [3H]5-HT, the effect of DMPP (10 and 40 microM) was antagonized by mecamylamine (20 and 10 microM). The effect of DMPP was [Ca2+]o-independent. In experiments carried out at 7 degrees C, i.e. the membrane carrier proteins are inhibited and the release by lobeline was abolished while the DMPP-induced release of 5-HT was rather potentiated. It is proposed that the effect of DMPP and lobeline, to enhance the release of [3H]5-HT from the hippocampus, was mediated by two different mechanisms. While DMPP-induced 5-HT release can be linked to a non-classical nAChR activation ([Ca2+]o-independence), the effect of lobeline was likely mediated by uptake carriers.
Assuntos
Iodeto de Dimetilfenilpiperazina/farmacologia , Hipocampo/fisiologia , Lobelina/farmacologia , Agonistas Nicotínicos/farmacologia , Serotonina/metabolismo , Alcaloides/farmacologia , Animais , Azocinas , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Cálcio/metabolismo , Estimulação Elétrica , Hipocampo/efeitos dos fármacos , Técnicas In Vitro , Cinética , Masculino , Mecamilamina/farmacologia , Nicotina/farmacologia , Piridinas/farmacologia , Quinolizinas , Ratos , Ratos Sprague-Dawley , Receptores Nicotínicos/fisiologia , Trítio , Tubocurarina/farmacologiaRESUMO
The present results show the potentiating effect of amphetamine on the ability of MPTP to destroy dopaminergic neurons in striatum of the mouse. A single injection of MPTP (8 mg/kg, retro-orbital) reduced the binding of [3H]mazindol, a marker for dopamine terminals, by 24%. When D-amphetamine (10 mg/kg, s.c.) was given 20 min prior to MPTP, the binding of [3H]mazindol, measured 3-5 days later, was reduced by 58%. It is proposed that the mechanism of this potentiation primarily involves an increased release of dopamine by D-amphetamine, and free radical-mediated processes. Although nicotine also releases dopamine from the striatum, no effect was observed when it was administered prior to MPTP. The lack of effect is probably related to short duration of action of nicotine and the modest effect on release of dopamine as compared to that of amphetamine.
Assuntos
Corpo Estriado/efeitos dos fármacos , Dextroanfetamina/administração & dosagem , Dopamina/metabolismo , Nicotina/administração & dosagem , Piridinas/administração & dosagem , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Membrana Celular/metabolismo , Corpo Estriado/metabolismo , Sinergismo Farmacológico , Feminino , Mazindol/metabolismo , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Amphetamine has been shown to either potentiate or protect against MPTP neurotoxicity. The time course of changes in dopamine and its metabolites was examined after MPTP, amphetamine, or MPTP plus amphetamine administration. Results suggest that under conditions of granular depletion and release of dopamine by 10 mg/kg amphetamine, increased MPTP neurotoxicity occurs. Amphetamine injections at 2-5 mg/kg prevents the decline in dopamine possibly by blockade of the uptake of MPP+, rather than by an inhibition of monoamine oxidase.
Assuntos
Corpo Estriado/metabolismo , Dextroanfetamina/administração & dosagem , Dopamina/metabolismo , Piridinas/administração & dosagem , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Ácido 3,4-Di-Hidroxifenilacético/análise , Animais , Dopamina/análogos & derivados , Dopamina/análise , Interações Medicamentosas , Ácido Homovanílico/análise , Camundongos , Camundongos Endogâmicos BALB CRESUMO
The release of endogenous ATP, measured by the luciferin-luciferase assay, and of [3H]noradrenaline from the in vitro superfused rat hypothalamic slices were studied. ATP and [3H]noradrenaline were released simultaneously during resting conditions and in response to low and high frequency field electrical stimulation; the release of both substances were frequency dependent between 2 Hz and 16 Hz. The stimulation-induced release of ATP and [3H]noradrenaline was diminished by more than 80% under Ca2+-free conditions. Tetrodotoxin inhibited the majority of the evoked release of both ATP and [3H]noradrenaline, however, it was less effective in reducing the release of [3H]noradrenaline, than that of ATP. Bilateral stereotaxic injection of 6-hydroxydopamine (4 microg/side) to the ventral part of the ventral noradrenergic bundle, originating from the A1 cell group in the brainstem, resulted in a 55% reduction of endogenous noradrenaline content of the hypothalamic slices, and the tritium uptake and the stimulation-evoked release of [3H]noradrenaline was also markedly reduced. While the basal release of ATP was not affected, the evoked release was diminished by 72% by this treatment. Perfusion of the slices with noradrenaline (100 microM) initiated rapid and continuous tritium release; on the other hand, it did not release any ATP. In contrast, 6 min perfusion of (-)nicotine and 1,1-dimethyl-4-phenyl-piperazinium iodide evoked parallel release of ATP and [3H]noradrenaline which was inhibited by the nicotinic receptor antagonist mecamylamine; 6-hydroxydopamine lesion of the ventral part of the ventral noradrenergic bundle did not affect the nicotine-evoked ATP and [3H]noradrenaline release. While CH 38083, a non subtype-selective alpha2-antagonist and BRL44408, the subtype-selective alpha2AD antagonist augmented the evoked release of [3H]noradrenaline, ARC239, a selective alpha2BC antagonist was without effect. In contrast, neither of the alpha2-antagonists significantly affected the evoked-release of ATP. In summary, we report here that endogenous ATP and [3H]noradrenaline are co-released stimulation-dependently from superfused rat hypothalamic slices. A significant part of the release of both compounds is derived from the nerve terminals, originating from the A1 catecholaminergic cell group of brainstem nuclei. Unlike that from the peripheral sympathetic transmission, noradrenaline and alpha1-adrenoceptor agonists were unable to promote the release of ATP. Conversely, parallel ATP and noradrenaline release could be induced by nicotine receptor activation, but this release does not originate from the same nerve endings. The evoked-release of [3H]noradrenaline is inhibited by endogenous noradrenaline via alpha2AD subtype of adrenoreceptors, while the release of ATP is not subject to this autoinhibitory modulation. In conclusion, our results support the view that ATP is involved in the neurotransmission in the hypothalamus, but the sources of the released ATP and noradrenaline seem to be not identical under different stimulatory and modulatory conditions.
Assuntos
Trifosfato de Adenosina/metabolismo , Hipotálamo/metabolismo , Norepinefrina/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Difosfato de Adenosina/metabolismo , Agonistas alfa-Adrenérgicos/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Hipotálamo/efeitos dos fármacos , Técnicas In Vitro , Masculino , Oxidopamina/farmacologia , Ratos , Ratos Sprague-Dawley , Fibras Simpáticas Pós-Ganglionares/efeitos dos fármacos , Fibras Simpáticas Pós-Ganglionares/metabolismo , Simpatolíticos/farmacologiaRESUMO
The pharmacological features of putative nicotinic acetylcholine receptor sites involved in the release of [3H]noradrenaline were assessed in rat hippocampus. The effect of nicotinic agonists to induce [3H]noradrenaline release was examined in superfused slices. The nicotinic agonists (-)-epibatidine, (+)-anatoxin-a, dimethylphenylpiperazinium, (-)-nicotine and (-)-lobeline released [3H]noradrenaline. The dose-response curves to nicotinic agonists were bell shaped, and indicated that their functional efficacies and potency vary across agonists. Maximal efficacy was seen with dimethyl-phenylpiperazinium and lobeline (Emax values two to three times higher than other agonists). The rank order of potency for the agonists to release [3H]noradrenaline was (-)-epibatidine > (+)- anatoxin-a > dimethylphenylpiperazinium > cytisine > nicotine > (-)-lobeline. The nicotinic acetylcholine receptor antagonists (n-bungarotoxin > mecamylamine > (+)-tubocurarine > hexamethonium > alpha-bungarotoxin = dihydro-beta-erythroidine) and tetrodotoxin antagonized the effect of dimethylphenylpiperazinium to release [3H]noradrenaline. The results, based on these pharmacological profiles, suggest the possible involvement of alpha 3 and beta 2 nicotinic acetylcholine receptor subunits in the control of [3H]noradrenaline release from hippocampal slices. The absence of effect of alpha-bungarotoxin and alpha-conotoxin-IMI excludes the possible involvement of nicotinic acetylcholine receptors containing the alpha 7 subunit. The release of [3H]noradrenaline by dimethylphenylpiperazinium was Ca2+ dependent. Nifedipine failed to prevent the dimethylphenylpiperazinium-induced release of [3H]noradrenaline, but Cd2+, omega-conotoxin and Ca(2+)-free conditions significantly reduced the dimethylphenylpiperazinium-induced release, suggesting that N-type voltage-sensitive Ca2+ channels are involved in the nicotinic acetylcholine receptor response. These voltage-sensitive Ca2+ channels are activated by the local depolarization produced by sodium influx through the nicotinic channels activated by dimethylphenylpiperazinium. Thus, the observed tetrodotoxin sensitivity of dimethylphenylpiperazinium-induced release of [3H]noradrenaline can be explained either by local depolarization and subsequent generation of action potentials at the preterminal area or that these nicotinic acetylcholine receptors are located on interneurons rather than directly on noradrenergic terminals.
Assuntos
Giro Denteado/química , Norepinefrina/farmacocinética , Receptores Nicotínicos/metabolismo , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/química , Canais de Cálcio/metabolismo , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Iodeto de Dimetilfenilpiperazina/farmacologia , Relação Dose-Resposta a Droga , Agonistas Nicotínicos/farmacologia , Antagonistas Nicotínicos/farmacologia , Norepinefrina/metabolismo , Técnicas de Cultura de Órgãos , Terminações Pré-Sinápticas/química , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Nicotínicos/química , Tetrodotoxina/farmacologia , TrítioRESUMO
We report here saturation analysis of [3H]cocaine binding in various mouse brain regions, and the necessary structure-activity relationships for cocaine congeners to inhibit Na+-dependent [3H]cocaine binding and [3H]dopamine uptake in the mouse striatum, and to inhibit [3H]cocaine binding that cannot be stimulated by Na+ and [3H]serotonin uptake in the mouse cerebral cortex. Generally similar structure-activity relationships were noted for all these processes. The ester linkage between the tropane and phenyl rings was not required for activity, in contrast to the configuration of the groups on C2, and to a lesser extent C3, in the tropane ring. Stereospecificity was evident from the differences between cocaine and (+)-pseudococaine, and between WIN 35,065-2 and WIN 35,065-3. There were remarkable differences between the above structure-activity relationships and those for local anesthetic activity of cocaine congeners, indicating that sodium channels were not labeled to a measurable extent with [3H]cocaine under the present conditions. Preliminary data indicated a significant correlation between the potencies of cocaine congeners in inhibiting the Na+-dependent binding of [3H]cocaine and their potencies in inducing stereotyped sniffing upon intraventricular administration.
Assuntos
Encéfalo/metabolismo , Cocaína/farmacologia , Dopamina/metabolismo , Serotonina/metabolismo , Comportamento Estereotipado/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neurônios/metabolismo , Potássio/metabolismo , Sódio/metabolismo , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
Presynaptic nerve terminals when depolarized are sensitive to morphological and functional alteration by horseradish peroxidase. Mouse brain slices, 0.1 mm, depolarized by a K(+)-HEPES buffer and exposed to horseradish peroxidase exhibited alterations in both synaptic vesicle membrane structure and in high-affinity [(14)C]?-aminobutyric acid uptake. The post stimulatory retrieval of synaptic vesicles from the nerve terminal plasma membrane in the presence of horseradish peroxidase resulted in a decrease in the synaptic vesicle population with a concurrent increase in non-synaptic vesicle membrane structures. High-affinity [(14)C]?-aminobutyric acid uptake into 0.1-mm slices of mouse cerebral cortex and ponsmedulla-spinal cord was inhibited by 31% and 24%, respectively, after incubation for 60 min in K(+)-HEPES buffer containing horseradish peroxidase. Superoxide dismutase protected both the synaptic vesicle membrane and the high-affinity uptake system from the deleterious effects of horseradish peroxidase, pointing to the possible involvement of superoxide anion radicals in the horseradish peroxidase-related effects. These horseradish peroxidase induced alterations appear to be directed towards the exposed synaptic vesicle membrane, since non-stimulated brain slices exposed to horseradish peroxidase do not exhibit a reduction in either high- or low-affinity [(14)C]?-aminobutyric acid uptake. Low-affinity uptake of [(14)C]?-aminobutyric acid and [(14)C]?-aminoisobutyric acid into cortical slices was not affected after incubation in K(+)-HEPES with horseradish peroxidase. Low-affinity uptake, however, is reduced by the high-K(+)/Na(+)-free stimulatory incubation prior to uptake. It appears, thus, that high- and low-affinity uptake are distinct and different systems, with the high-affinity transport system structurally associated with synaptic vesicle membrane.