RESUMEN
The epigenetic dysregulation of the brain genome associated with the clinical manifestations of schizophrenia (SZ) includes altered DNA promoter methylation of several candidate genes. We and others have reported that two enzymes that belong to the DNA-methylation/demethylation network pathways-DNMT1 (DNA-methyltransferase) and ten-eleven translocator-1(TET1) methylcytosine deoxygenase are abnormally increased in corticolimbic structures of SZ postmortem brain. The objective of this study was to investigate whether the expression of these components of the DNA-methylation-demethylation pathways known to be altered in the brain of SZ patients are also altered in peripheral blood lymphocytes (PBL). The data show that increases in DNMT1 and TET1 and in glucocorticoid receptor (GCortR) and brain derived neurotrophic factor (BDNF) mRNAs in PBL of SZ patients are comparable to those reported in the brain of SZ patients. The finding that the expressions of DNMT1 and TET1 are increased and SZ candidate genes such as BDNF and GCortR are altered in the same direction in both the brain and PBL together with recent studies showing highly correlated patterns of DNA methylation across the brain and blood, support the hypothesis that a common epigenetic dysregulation may be operative in the brain and peripheral tissues of SZ patients.
Asunto(s)
Metilación de ADN/genética , Redes Reguladoras de Genes , Linfocitos/metabolismo , Esquizofrenia/genética , Esquizofrenia/patología , Adulto , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , ADN (Citosina-5-)-Metiltransferasa 1 , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oxigenasas de Función Mixta , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , ARN Mensajero/metabolismo , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Estadística como Asunto , Adulto JovenRESUMEN
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.
Asunto(s)
Etanol/farmacología , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Recompensa , Factores de Edad , Alcoholismo/complicaciones , Alcoholismo/metabolismo , Alcoholismo/psicología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Interacciones Farmacológicas , Etanol/efectos adversos , Femenino , Humanos , Masculino , Neurotransmisores/metabolismo , Nicotina/efectos adversos , Agonistas Nicotínicos/efectos adversos , Receptores de Neurotransmisores/metabolismo , Receptores Nicotínicos/metabolismo , Factores Sexuales , Síndrome de Abstinencia a Sustancias/metabolismo , Síndrome de Abstinencia a Sustancias/psicología , Tabaquismo/complicaciones , Tabaquismo/metabolismo , Tabaquismo/psicologíaRESUMEN
The present study examined the effect of repeated nicotine and cocaine administration on the expression of neurofilament proteins (NF-L, -M, and -H), actin, and on alpha-7 nicotinic, dopamine D1 and NMDA NR1 receptors in brain. Whole tissue homogenate and synaptoneurosomal preparations from hippocampus, striatum and cortex were assayed. C57BL/6By mice were treated for 2 weeks with a daily injection of nicotine (0.4 mg/kg) or cocaine (25mg/kg). The mice were killed 60 min after the last injection and tissue prepared for Western blot analysis of expression of NFs and receptor expression. Actin protein was affected by cocaine and nicotine treatment, decreasing in homogenate fraction (striatum and cortex) and showing an increase in the synaptoneurosome preparation (hippocampus and cortex). NF expression was affected; with regional and response differences dependent on tissue preparation. NF-M increased in all three brain regions; NF-L increased in the cortex and NF-H increased in the striatum in the synaptoneurosomal preparations. Change in nicotinic and dopamine receptor expression was dependent on region and tissue preparation. NMDA NR1 expression increased in the three brain regions in the synaptoneurosomal preparation. The results suggest that specific brain protein levels are affected by repeated drug administration. Drug effects on cytoskeletal elements are selective, regionally heterogeneous, and change with time after drug administration. Changes in cytoskeletal proteins maybe part of the mechanism in drug-induced neurotransmitter changes. We have found previously that drug-induced changes in neurotransmitters are regionally heterogeneous and are drug specific. We now found similar regional heterogeneity and drug specificity in drug-induced changes in cytoskeletal and receptor proteins.
Asunto(s)
Encéfalo , Cocaína/farmacología , Proteínas de Filamentos Intermediarios/metabolismo , Nicotina/farmacología , Sinaptosomas/efectos de los fármacos , Animales , Encéfalo/citología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Citoesqueleto/efectos de los fármacos , Citoesqueleto/metabolismo , Inhibidores de Captación de Dopamina/farmacología , Estimulantes Ganglionares/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Nicotínicos/metabolismo , Sinaptosomas/metabolismo , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
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.
Asunto(s)
Encéfalo/fisiología , Recompensa , Acetaldehído/farmacología , Consumo de Bebidas Alcohólicas/fisiopatología , Consumo de Bebidas Alcohólicas/psicología , Animales , Encéfalo/crecimiento & desarrollo , Condicionamiento Psicológico/fisiología , Alimentos , Humanos , Aprendizaje/fisiología , Factores Sexuales , Trastornos Relacionados con Sustancias/genética , Trastornos Relacionados con Sustancias/fisiopatología , Trastornos Relacionados con Sustancias/psicologíaRESUMEN
In previous studies, we found differences between nicotine and cocaine-induced changes in the levels of neurotransmitters in various brain areas, which suggested differences in their reward - preference mechanisms. The present study was based on the idea that drug preference is modulated by a number of different factors, among them several neurotransmitters and their receptors, and antagonists of specific receptors will influence preference. We also assumed that the factors (components of reward mechanisms) involved are different in the case of different drugs. We compared the inhibition of nicotine preference with cocaine preference. We assayed preference as conditioned place preference (CPP) and measured CPP inhibition by receptor subtype antagonists using mice. In general, induced CPP of cocaine was stronger than of nicotine as shown by more time spent in the nonpreferred area after conditioning with cocaine. We measured inhibition by four antagonists: mecamylamine, atropine, SCH23390, and phentolamine: antagonists respectively of nicotinic, and muscarinic acetylcholine, dopamine D1, and alpha noradrenergic receptors. The inhibition by the antagonists of cocaine CPP was lower in most instances than that of nicotine CPP. Atropine and SCH23390 inhibited nicotine and cocaine CPP approximately to the same degree, while the inhibition by mecamylamine and phentolamine of nicotine CPP was 100%; that of cocaine was 20% and 0, respectively. We conclude that several receptor systems and transmitters play a role in drug preference, some represent essential elements or circuits, some may be only required partially or their role can be partially substituted. The composition of such systems is different for different drugs - in the present study, some of the components influencing CPP are different for nicotine as opposed to cocaine.
Asunto(s)
Cocaína/farmacología , Condicionamiento Clásico/efectos de los fármacos , Inhibidores de Captación de Dopamina/farmacología , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Percepción Espacial/efectos de los fármacos , Antagonistas Adrenérgicos alfa/farmacología , Animales , Atropina/farmacología , Benzazepinas/farmacología , Antagonistas de Dopamina/farmacología , Masculino , Mecamilamina/farmacología , Ratones , Ratones Endogámicos C57BL , Antagonistas Muscarínicos/farmacología , Antagonistas Nicotínicos/farmacología , Fentolamina/farmacologíaRESUMEN
Several lines of schizophrenia (SZ) research suggest that a functional downregulation of the prefrontal cortex GABAergic neuronal system is mediated by a promoter hypermethylation, presumably catalyzed by an increase in DNA-methyltransferase-1 (DNMT-1) expression. This promoter hypermethylation may be mediated not only by DNMT-1 but also by an entire family of de novo DNA-methyltransferases, such as DNA-methyltransferase-3a (DNMT-3a) and -3b (DNMT-3b). To verify the existence of an overexpression of DNMT-3a and DNMT-3b in the brain of schizophrenia patients (SZP), we compared their mRNA expression in Brodmann's area 10 (BA10) and in the caudate nucleus and putamen obtained from the Harvard Brain Tissue Resource Center (Belmont, MA) from both nonpsychiatric subjects (NPS) and SZP. Our results demonstrate that DNMT-3a and DNMT-1 are expressed and co-localize in distinct GABAergic neuron populations whereas DNMT-3b mRNA is virtually undetectable. We also found that unlike DNMT-1, which is frequently overexpressed in telencephalic GABAergic neurons of SZP, DNMT-3a mRNA is overexpressed only in layer I and II GABAergic interneurons of BA10. To ascertain whether these DNMT expression differences observed in brain tissue could also be detected in peripheral tissues, we studied whether DNMT-1 and DNMT-3a mRNAs were overexpressed in peripheral blood lymphocytes (PBL) of SZP. Both DNMT-1 and DNMT-3a mRNAs are expressed in the PBL and although DNMT-3a mRNA levels in the PBL are approximately 1/10 of those of DNMT-1, the comparison of the PBL content in NPS and SZP showed a highly significant 2-fold increase of both DNMT-1 and DNMT-3a mRNA in SZP. These changes were unaffected by the dose, the duration, or the type of antipsychotic treatment. The upregulation of DNMT-1 and to a lesser extent that of DNMT-3a mRNA in PBL of SZP supports the concept that this readily available peripheral cell type can express an epigenetic variation of specific biomarkers relevant to SZ morbidity. Hence, PBL studies may become useful to investigate a diagnostic epigenetic marker of SZ morbidity.
Asunto(s)
ADN (Citosina-5-)-Metiltransferasas/metabolismo , Linfocitos/patología , Neuronas/fisiología , Esquizofrenia , Telencéfalo/citología , Regulación hacia Arriba , Ácido gamma-Aminobutírico/metabolismo , Adulto , Anciano , Estudios de Cohortes , ADN (Citosina-5-)-Metiltransferasa 1 , ADN (Citosina-5-)-Metiltransferasas/genética , ADN Metiltransferasa 3A , Femenino , Glutamato Descarboxilasa/metabolismo , Humanos , Masculino , Microscopía Confocal , Persona de Mediana Edad , Cambios Post Mortem , ARN Mensajero/metabolismo , Esquizofrenia/sangre , Esquizofrenia/patología , Esquizofrenia/fisiopatologíaRESUMEN
The aim of the present study was to examine the effect of acetaldehyde administration on neurotransmitters in the presence of nicotine in brain areas associated with cognition and reward. We assayed these effects via microdialysis in conscious freely moving male Sprague-Dawley rats. It was reported that low doses of acetaldehyde enhance nicotine self-administration in young, but not in adult rats. Since nicotine enhances reward and learning, while acetaldehyde is reported to enhance reward but inhibit learning, acetaldehyde thus would be likely to stimulate reward without stimulating learning. We hoped that examining the effects of acetaldehyde (on nicotine-mediated neurotransmitter changes) would help to distinguish reward mechanisms less influenced by learning mechanisms. To avoid the aversive effect of acetaldehyde, we used a low dose of acetaldehyde (0.16 mg/kg) administered after nicotine (0.3mg/kg). We analyzed six brain regions: nucleus accumbens shell (NAccS), ventral tegmental area (VTA), ventral and dorsal hippocampus (VH and DH), and prefrontal and medial temporal cortex (PFC, MTC), assaying dopamine (DA), norepinephrine (NE) and serotonin (5-HT) and their metabolites in young and adult rats. The effect of acetaldehyde on nicotine-induced transmitter changes was different in young as compared to adult rat brain regions. In the NAccS of the young, DA was not affected while NE and 5-HT were increased. In the adult in this area DA and NE were decreased, while 5-HT was not altered. In other areas also in many cases, the effect of acetaldehyde in the young and in the adult was different. As an example, acetaldehyde administration increased NE in young and decreased NE in adult DH. We found stimulation of nicotine-induced changes by acetaldehyde in seven instances - six of these were observed in areas in young brain, NE in four areas (NAccS, DH, VH, and PFC), and 5-HT in two (NAccS and DH). Only one increase was noted in adult brain (DA in VTA). Inhibition of nicotine-induced changes by acetaldehyde was noticed in four young brain areas (DA in PFC and MTC, 5-HT in VTA, and VH) and in 13 adult brain areas (DA in NAccS, DH, VH, PFC, MTC, NE in NAccS, DH, PFC, MTC, and 5-HT in DH, VH, MTC, and PFC). Thus acetaldehyde was more stimulatory in young and more inhibitory in the adult brain areas tested, which could explain its stimulating nicotine reward only in young animals. That increases in NE were noted only in young, decreases in NE only in adult brain areas further suggest the role of NE in the age-dependent response. In general, six areas showed some increase and four showed decrease in the young versus one showing increase and thirteen showing decrease in the adult. Clearly the effects of acetaldehyde in young animals are different from those in adult animals. Because acetaldehyde did not induce elevated DA levels in the NAccS of the young, we believe that the higher reward in the young caused by acetaldehyde is not likely due to DA changes in the accumbens. The increase of NE and 5-HT in the brain areas of the young only raises the possibility that they may play an important role in reward in some cases when DA in the accumbens does not. Areas involved in cognitive mechanisms and a number of transmitters seem to play a role in reward stimulation.
Asunto(s)
Acetaldehído/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Fármacos del Sistema Nervioso Central/farmacología , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Envejecimiento , Animales , Cateterismo , Dopamina/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/crecimiento & desarrollo , Masculino , Microdiálisis , Norepinefrina/metabolismo , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/crecimiento & desarrollo , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismo , Lóbulo Temporal/efectos de los fármacos , Lóbulo Temporal/crecimiento & desarrollo , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/crecimiento & desarrolloRESUMEN
A number of studies in various species including man indicated a greater risk of drug preference and addictive behavior in young as compared to adults. Such age dependent preference was also found with nicotine. To examine possible mechanisms for this difference in our continuing study of reward mechanisms, we compared nicotine-induced neurotransmitter changes in the brain regions of adult and young Sprague-Dawley rats, assaying the transmitters via microdialysis in conscious freely moving animals. In general, nicotine-induced changes were significantly less in the regions measured in the young. Nicotine-induced effects on dopamine in the dorsal and ventral hippocampus (VH), prefrontal and medial temporal cortex, and superior cerebral peduncle were lower in the young than in adult, the same in the ventral tegmental area (VTA) and lateral septal nucleus (LS), and somewhat higher in the nucleus accumbens shell (NAccS). Norepinephrine levels in the young were lower in all areas except in the VH where they were the same, and serotonin levels were lower except in the VTA and LS where they remained the same, and higher in the NAccS. Age-dependent differences in the metabolites measured were more mixed. We conclude that the greater nicotine preference in young is not paralleled by a greater effect of nicotine on the release of monoamines at least in most of the brain areas assayed. Thus, increases of nicotine reward are not likely due to increases of monoamines in reward and cognitive areas. The small increase of dopamine (DA) and more significant increase of serotonin (5-HT) only in the NAccS are of significance, and would indicate a more significant role of 5-HT than of DA at least in the age difference in nicotine preference. Developmental changes in receptor composition and distribution involving several transmitter systems and other components such as neuropeptides are also likely to play a role.
Asunto(s)
Monoaminas Biogénicas/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Neurotransmisores/metabolismo , Nicotina/farmacología , Factores de Edad , Animales , Cromatografía Líquida de Alta Presión , Dopamina/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Microdiálisis , Nicotina/administración & dosificación , Agonistas Nicotínicos/administración & dosificación , Agonistas Nicotínicos/farmacología , Norepinefrina/metabolismo , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas , Ratas Sprague-Dawley , Recompensa , Núcleos Septales/efectos de los fármacos , Núcleos Septales/metabolismo , Serotonina/metabolismo , Tegmento Mesencefálico/efectos de los fármacos , Tegmento Mesencefálico/metabolismo , Lóbulo Temporal/efectos de los fármacos , Lóbulo Temporal/metabolismo , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/metabolismoRESUMEN
In the present study, we tested the effects of glutamate and GABA receptor antagonists on nicotine-induced neurotransmitter changes in the hippocampal (dorsal and ventral) and cortical (medial temporal and prefrontal) brain areas of conscious freely moving rats via microdialysis. Both the antagonists and nicotine were administered intracerebrally. The antagonists tested were NMDA, AMPA-kainate, and metabotropic glutamate receptor subtype antagonists (MK801, CNQX, and LY 341495, respectively) and GABA(A) and GABA(B) receptor subtype antagonists (bicuculline and hydroxysaclofen, respectively). We assayed nicotine-induced changes in dopamine (DA), norepinephrine (NE), serotonin (5-HT), and their metabolites. We found with the antagonists, both decreases and increases in nicotine-induced neurotransmitter responses. In the presence of nicotine all the antagonists (except LY 341495) caused a decrease in DA levels in the regions tested. NE levels were decreased in the cortex by all antagonists. In the hippocampus, GABA antagonists decreased NE levels, as did the metabotropic glutamate antagonist, LY 341495, while the other glutamate antagonists increased NE levels. The results of the 5-HT assay were more variable and dependent on the region and antagonist examined; increases were found slightly more often than decreases. The changes in metabolites were not often parallel with changes in their associated neurotransmitters, indicating that the antagonists also affect the metabolism of the neurotransmitters. The effect of the antagonists in the absence of nicotine was mostly to decrease the level of neurotransmitters, although increases were seen in a few cases. The results suggest that the excitatory glutamatergic- and inhibitory GABAergic-amino acid receptors are both involved in mediating nicotine-induced neurotransmitter responses, and their inhibitory or stimulatory effects are receptor subtype and brain region dependent.
Asunto(s)
Química Encefálica/efectos de los fármacos , Química Encefálica/fisiología , Cognición/fisiología , Antagonistas del GABA/farmacología , Ácido Glutámico/farmacología , Neurotransmisores/metabolismo , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Receptores de GABA/efectos de los fármacos , Animales , Cromatografía Líquida de Alta Presión , Antagonistas de Receptores de GABA-A , Antagonistas de Receptores de GABA-B , Masculino , Microdiálisis , Ratas , Ratas Sprague-DawleyRESUMEN
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.
Asunto(s)
Corteza Cerebral/efectos de los fármacos , Indanos/farmacología , Memantina/farmacología , Neurotransmisores/metabolismo , Piperidinas/farmacología , Terminales Presinápticos/efectos de los fármacos , Acetilcolina/metabolismo , Animales , Corteza Cerebral/metabolismo , Inhibidores de la Colinesterasa/farmacología , Donepezilo , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/farmacología , Líquido Extracelular/efectos de los fármacos , Líquido Extracelular/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Microdiálisis , Norepinefrina/metabolismo , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Terminales Presinápticos/metabolismo , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismo , Lóbulo Temporal/efectos de los fármacos , Lóbulo Temporal/metabolismo , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/metabolismoRESUMEN
The present study examined the effect of a low-dose of nicotine; below that one expects to be achieved from a single cigarette, on brain regional heterogeneity and sensitivity of catecholaminergic responses. 1 microM nicotine was infused into six brain areas via a microdialysis probe: the dorsal and ventral hippocampus, the medial temporal and prefrontal cortex, the basolateral amygdala, and the ventral tegmental area (VTA). The nicotine concentration in the brain tissue near the probe site was approximately 0.1 microM. Nicotine-induced increases and decreases could be noted in dopamine (DA), norepinephrine (NE), and serotonin (5HT) levels. In particular, DA and 5HT decreased in both hippocampal areas, while NE increased in the dorsal and decreased in the ventral hippocampus. In the cortical areas, DA and NE increased and 5HT was not significantly altered. In the amygdala all three neurotransmitters increased and in the VTA, all three decreased. Many of the nicotine-induced changes in neurotransmitter concentrations were reversed in the presence of atropine. Where nicotine induced decreases in DA and 5HT in the VTA, increases were observed in the presence of atropine. A similar reversal was seen with NE in the VTA and ventral hippocampus. In contrast, the increases in DA observed in the cortex and amygdala and the increases in NE observed in the cortex, amygdala and dorsal hippocampus were inhibited by the presence of atropine. 5HT was also significantly decreased in the amygdala and both cortical areas in the presence of atropine, where nicotine alone had no significant effect. We conclude, that at low doses, nicotine significantly alters the release of DA, NE, and 5HT--in some areas increasing, in others decreasing endogenous neurotransmitter levels. This data, in conjunction with previous experiments, indicates that the effects of nicotine are regionally heterogeneous and arise from both direct and indirect actions on various receptors and neurotransmitter systems and nicotine's effects at low doses differ from that at higher doses. The changes in effects in the presence of atropine suggest that muscarinic acetylcholine receptors play a major role in nicotine's actions on neurotransmitter systems.
Asunto(s)
Encéfalo/efectos de los fármacos , Cognición , Neurotransmisores/metabolismo , Nicotina/farmacología , Animales , Atropina/farmacología , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Masculino , Microdiálisis , Nicotina/administración & dosificación , Nicotina/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
In a continuing study of nicotine-induced mechanisms in brain areas associated with cognitive processes, the effects of cholinergic and dopaminergic antagonists on nicotine-induced changes in dopamine, norepinephrine, and serotonin were examined. These effects were measured via in vivo microdialysis in the dorsal and ventral hippocampus and in the prefrontal and medial temporal cortex of conscious, freely moving, adult male rats. Nicotine (0.3 mg/kg, free base) was administered subcutaneously and the antagonists were infused locally via the microdialysis probe. Nicotine alone induced an increase of dopamine and its metabolites in all areas, an increase of norepinephrine in the cortex, and an increase of the norepinephrine metabolite 4-hydroxy-3-methoxy-phenylglycol in all areas. Serotonin was decreased in the hippocampus and increased in the cortex. Nicotine-induced dopamine increases were inhibited by nicotinic (mecamylamine 100 microM, methyllycaconitine 500 microM), muscarinic (atropine 100 microM), and dopaminergic D1 (SCH23390 100 microM) and D2 (eticlopride 100 microM) antagonists, in the hippocampal and cortical areas. In the hippocampal areas, these antagonists had less significant effect on norepinephrine and serotonin. However, in the cortical areas, all antagonists inhibited the nicotine-induced increase of serotonin to varying degrees; and some, primarily nicotinic and dopamine D1 antagonists, inhibited the induced increase of norepinephrine. In the hippocampal and cortical areas, the mechanisms of nicotine-induced dopamine increase seem to be similar, but the mechanisms seem to be different for noradrenergic and serotonergic systems, as shown by the fact that nicotine induces no change in norepinephrine and a decrease in serotonin in the hippocampus, while it induces an increase in both in the cortex. Nicotine-induced dopamine release seems to be mediated, in part locally, by nicotinic and muscarinic receptors on dopaminergic cells. In contrast, nicotine's effect on norepinephrine and serotonin is at least partially mediated by initial changes at other than local sites, and through different receptors. Thus, the effects of nicotine and the mechanisms involved differ for different neurotransmitters and in different brain areas.
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Química Encefálica/efectos de los fármacos , Antagonistas de Dopamina/farmacología , Neurotransmisores/metabolismo , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Parasimpatolíticos/farmacología , Aconitina/análogos & derivados , Aconitina/farmacología , Animales , Atropina/farmacología , Benzazepinas/farmacología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Dopamina/metabolismo , Hipocampo/metabolismo , Masculino , Microdiálisis , Antagonistas Nicotínicos/farmacología , Norepinefrina/metabolismo , Ratas , Ratas Sprague-Dawley , Salicilamidas/farmacología , Serotonina/metabolismoRESUMEN
In our recent studies on nicotine-induced changes in neurotransmitters in brain areas associated with cognitive function using a nicotine dose of 0.5 mg/kg administered subcutaneously to conscious freely moving rats, we found changes in dopamine, norepinephrine, and serotonin, and their metabolites, in the areas examined. For the present report we examined changes in these neurotransmitters following administration of lower nicotine doses, to test regional differences in nicotine response and possible threshold levels for some effects of nicotine. The doses used were 0.15 mg/kg and 0.03 mg/kg nicotine administered subcutaneously. Nicotine levels in the brain reached peak values in less than 10 min and decreased with a half-life of about 60 min (0.15 mg/kg) or 30 min (0.03 mg/kg) to values below detection limits (1 ng/g), by the later time points of the 0.03 mg/kg experiments. Nicotine-induced dopamine (DA) increase (and increase in DA metabolites) and decrease in 5-HT levels at 0.15 mg/kg were significant in the cortex, less so in the hippocampus. Norepinephrine (NE) increase at 0.15 mg/ kg was much less significant than found previously at 0.5 mg/kg. At a low nicotine dose (0.03 mg/kg), the significant changes observed were a decrease in 5-HT in the hippocampus and small increases of DA and NE in the prefrontal cortex and of NE in the medial temporal cortex. In the nucleus accumbens DA, NE, and 5-HT and their metabolites in the ventral tegmental area, mostly DA and metabolites were increased. We conclude that in areas of cognitive function nicotine-induced DA changes are more concentration dependent than changes in NE or 5-HT, and that there are regional differences in neurotransmitter changes induced by nicotine, with NE changes detectable only in the cortex and 5-HT changes only in the hippocampus at a low nicotine dose, indicating significant regional variation in sensitivity to nicotine-induced neurotransmitter changes in brain areas associated with cognitive function. The decrease in 5-HT shows that nicotine also has indirect effects caused by neurotransmitters released by nicotine. The effects of a low nicotine dose are more significant in areas of reward function, indicating differences in sensitivity between cognitive and reward functions.
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Monoaminas Biogénicas/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Nicotina/administración & dosificación , Animales , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Nicotine, one of the most widespread drugs of abuse, has long been shown to impact areas of the brain involved in addiction and reward. Recent research, however, has begun to explore the positive effects that nicotine may have on learning and memory. The mechanisms by which nicotine interacts with areas of cognitive function are relatively unknown. Therefore, this paper is part of an ongoing study to evaluate regional effects of nicotine enhancement of cognitive function. Nicotine-induced changes in the levels of three neurotransmitters, dopamine (DA), serotonin (5-HT), norepinepherine (NE), their metabolites, homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA), and their precursor, L-DOPA, were evaluated in the ventral and dorsal hippocampus (VH and DH), prefrontal and medial temporal cortex (PFC and MTC), and the ventral tegmental area (VTA) using in vivo microdialysis in awake, freely moving, male Sprague-Dawley rats. The animals were treated with acute nicotine (0.5 mg/kg, s.c.) halfway through the 300-min experimental period. The reuptake blockers, desipramine (100 microM) and fluoxetine (30 microM), were given to increase the levels of NE and 5-HT so that they could be detected. Overall, a nicotine-induced DA increase was found in some areas, and this increase was potentiated by desipramine and fluoxetine. The two DA metabolites, HVA and DOPAC, increased in all the areas throughout the experiments, both with and without the inhibitors, indicating a rapid metabolism of the released DA. The increase in these metabolites was greater than the increase in DA. 5-HT was increased in the DH, MTC, and VTA in the presence of fluoxetine; its metabolite, 5-HIAA, was increased in the presence and absence of fluoxetine. Except in the VTA, NE levels increased to a similar extent with desipramine and fluoxetine. Overall, nicotine appeared to increase the release and turnover of these three neurotransmitters, which was indicated by significant increases in their metabolites. Furthermore, DA, and especially HVA and DOPAC, increased for the 150 min following nicotine administration; 5-HT and NE changes were shorter in duration. As gas chromatography experiments showed that nicotine levels in the brain decreased by 75% after 150 min, this may indicate that DA is more susceptible to lower levels of nicotine than 5-HT or NE. In conclusion, acute nicotine administration caused alterations in the levels of DA, 5-HT, and NE, and in the metabolism of DA and 5-HT, in brain areas that are involved in cognitive processes.
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Encéfalo/metabolismo , Cognición/fisiología , Neurotransmisores/metabolismo , Nicotina/farmacología , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Encéfalo/efectos de los fármacos , Cognición/efectos de los fármacos , Dopamina/metabolismo , Ácido Hidroxiindolacético/metabolismo , Levodopa/metabolismo , Masculino , Norepinefrina/metabolismo , Especificidad de Órganos , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismoRESUMEN
In a study of the possible mechanism of action of metaphit and phencyclidine in the brain, the uptake of glutamate at the luminal side of the blood-brain barrier (BBB) was studied by means of an in situ brain perfusion technique in normal guinea pigs and in those pretreated with metaphit. Metaphit, an isothiocyanate analog of phencyclidine (PCP), induces time-dependent epileptogenic changes in the electroencephalogram in guinea pig, reaching a maximum 18-24 h after metaphit administration (50 mg/kg IP). In metaphit-pretreated animals a significant reduction of glutamate BBB uptake was found, in comparison with that of controls. Reduction of glutamate transport from blood to brain ranged from 77% to 79% in all brain structures studied. This inhibition was probably due to changes in the properties of saturable components responsible for transport of glutamate across the BBB. Kinetic measurements revealed a saturable amino acid influx into the parietal cortex, caudate nucleus, and hippocampus, with a Km between 3.1 and 5.1 microM, and the V(max) ranging from 14.3 to 27.8 pmol(-1) g(-1). The nonsaturable component, K(id), was statistically different from zero, ranging from 1.47 to 2.00 microM min(-1) g(-1). Influx of glutamate into the brain was not altered in the presence of 1 mM D-aspartate, but it was significantly inhibited in the presence of 1 mM L-aspartate. We conclude that the cerebrovascular permeability of circulating glutamate is due to the presence of a higher-capacity saturable receptor and/or a carrier-mediated transport system (75%) and also a low-capacity diffusion transport system (25%) for the glutamate located at the luminal side of the BBB. The glutamate transport system is probably fully saturated at physiological plasma glutamate concentrations.
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Barrera Hematoencefálica/fisiología , Ácido Glutámico/metabolismo , Fenciclidina/análogos & derivados , Fenciclidina/farmacología , Convulsiones/inducido químicamente , Animales , Transporte Biológico/efectos de los fármacos , Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Núcleo Caudado/efectos de los fármacos , Núcleo Caudado/metabolismo , Dextranos/farmacocinética , Femenino , Cobayas , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Cinética , Masculino , Lóbulo Parietal/efectos de los fármacos , Lóbulo Parietal/metabolismo , Convulsiones/fisiopatologíaRESUMEN
Phencyclidine (PCP) administration in rodents has been used to model aspects of schizophrenia. One aspect of such treatment has been the enhancement of amphetamine-induced increase of dopamine in the prefrontal cortex and striatum. To further characterize this mechanism rats were treated for 2 weeks with continuous PCP (15 mg/kg per day via Alzet minipump). Rats were implanted with a microdialysis probe into the prefrontal cortex (PFC) or striatum. Amphetamine was administered locally via the dialysis probe during one collection period and changes in extracellular dopamine were monitored. The effect of local administration of the dopamine uptake blocker nomifensine was also measured. Amphetamine (10 microM) and nomifensine (10 microM) increased the level of dopamine in both the PFC and striatum. PCP administration did not alter the response to amphetamine or nomifensine in the PFC, but reduced this response about 2-fold in striatum. To examine effects of continuous PCP administration on dopamine autoreceptor function, release of [3H]dopamine in response to electrical stimulation and in the presence of a dopamine agonist or antagonist was tested in striatal and prefrontal cortical tissue. Autoreceptor responses were similar in control and PCP-treated tissues. We conclude that the brain region-specific enhancement of dopamine release by peripheral amphetamine administration in rats after PCP is not likely mediated by alterations in the dopamine autoreceptors or changes in the dopamine transporter. The selective local responses of amphetamine indicates heterogeneous regional effects of continuous PCP on NMDA receptor function; effects that influence both regional excitatory responses and the overall dynamics of tonic excitatory/inhibitory inputs to the PFC and striatum.
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Anfetaminas/farmacología , Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Fenciclidina/farmacología , Corteza Prefrontal/efectos de los fármacos , Animales , Cuerpo Estriado/metabolismo , Técnicas In Vitro , Masculino , Microdiálisis , Corteza Prefrontal/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Studies have shown a greater preference for the self-administration of drugs such as nicotine and cocaine in the Lewis rat strain than in the Fischer 344 strain. We examined some factors that could contribute to such a difference. The baseline level of extracellular dopamine in nucleus accumbens shell was about 3-times higher in Fischer rats than in Lewis rats (3.18 +/- 0.26 vs. 1.09 +/- 0.14 pg/ sample). Nicotine (50-100 microg/kg)-induced release of dopamine, expressed in absolute terms, was similar in the two strains. Dopamine release expressed in relative terms (as percent of baseline), however, was significantly greater in Lewis rats than in Fischer rats at 30 min after the first nicotine injection. We suggest that the relative increase is of more influence than the absolute level for determining preference; a lower physiological extracellular dopamine level thus represent a risk factor for increased preference. Amphetamine-induced dopamine release expressed in relative terms was not greater in the Lewis strain. In the initial time period of the microdialysis experiments, a sharper peak in nicotine-induced accumbal dopamine release in Lewis and a less but more sustained release in Fischer rats was observed. This release pattern paralleled the faster clearance of nicotine from blood of Lewis compared to Fischer rats. In tissue slices the electrically induced dopamine release was highest in the nucleus accumbens and lowest in the ventral tegmentum. A significant effect of nicotine was lowering the electrically induced release of dopamine in frontal cortex slices from Fischer brain and increasing this dopamine release in the ventral tegmentum of Lewis brain slices indicating that the ventral tegmentum, an area controlling dopamine release in the accumbens, is more responsive to nicotine in the Lewis rat. Nicotine levels tended to be more sustained in Fischer rats in different brain regions, although the difference in nicotine levels between the strains was not significant at any time period. Several factors contribute to nicotine preference, including the endogenous dopamine level, and the sensitivity of ventral tegmentum neurons to nicotine-induced dopamine release. Strain differences in pharmacokinetics of nicotine may also play a role.
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Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Dopamina/metabolismo , Nicotina/farmacología , Nicotina/farmacocinética , Ratas Endogámicas F344/metabolismo , Ratas Endogámicas Lew/metabolismo , Animales , Técnicas In Vitro , Microdiálisis , Ratas , Especificidad de la Especie , Factores de Tiempo , Distribución TisularRESUMEN
Modulation of striatal dopamine (DA) release by serotonin (5HT) and its antagonists was studied utilizing in vitro perfusion techniques. In isolated striatal tissue, 5HT (10 microM) increased the fractional basal release of labeled DA. The 5HT(2/1c) antagonist ketanserin (5 microM) also stimulated the basal release. These two effects were mediated by different mechanisms as cocaine (10 microM) greatly inhibited the 5HT-mediated response, but slightly increased the ketanserin-mediated response. 6-Nitroquipazine maleate (10 microM, 5HT uptake inhibitor) partially inhibited both responses. Inhibition by GBR 12909 (DA uptake inhibitor) at 1 microM of the 5HT-mediated DA release was similar to that of cocaine, but at 10 microM it increased release before addition of 5HT, and maintained elevated DA release while present in the incubation medium. At 1 microM GBR 12909, ketanserin-mediated DA release was stimulated and a much greater release was seen at 10 microM, but the prolonged release was not observed as after 5HT-mediated release. Among other antagonists methiothepin (5HT(1,2,6) antagonist) also enhanced DA release, whereas oxymetazoline (5HT(1A,1B,1D) agonist) had no effect. RS2359-190 (5HT(4) antagonist) had a small effect (slight stimulation) on 5HT-mediated DA release, and no effect on ketanserin-mediated DA release. CGS 12066A (5HT(1B) agonist) inhibited 5HT-mediated DA release. The glutamate antagonist MK-801 and the GABA(A) antagonist bicuculline had no affect on either response. These results indicate that 5HT-mediated DA release occurs via reversal of the DA transporter and that inhibitory presynaptic 5HT heteroreceptors and both inhibitory and stimulatory somato-dendritic 5HT receptors regulate release. In addition to the reversal of the transporter, an inhibitory 5HT(2) component was identified.
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Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Quipazina/análogos & derivados , Receptores de Serotonina/fisiología , Serotonina/farmacología , Animales , Bicuculina/farmacología , Cocaína/farmacología , Cuerpo Estriado/metabolismo , Maleato de Dizocilpina/farmacología , Inhibidores de Captación de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/farmacología , Antagonistas del GABA/farmacología , Ketanserina/farmacología , Masculino , Metiotepina/farmacología , Ratones , Ratones Endogámicos C57BL , Oximetazolina/farmacología , Piperazinas/farmacología , Quinoxalinas/farmacología , Quipazina/farmacología , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacologíaRESUMEN
Phencyclidine (PCP) and other N-methyl-D-aspartate (NMDA) antagonists induce schizophrenia-like symptoms in humans. In rodents, PCP induces a syndrome of stereotypies and hyperactivity that is accompanied by stimulation of striatal dopamine release. Glycine and other NMDA agonists reverse PCP-induced behaviors in rodents and ameliorate PCP psychosis-like symptoms of schizophrenia in clinical trials. Glycine levels in vivo are regulated by the actions of glycine (GLYT1) transporters. The present study investigates effects of glycine and the prototypic glycine transport inhibitor glycyldodecylamide (GDA) on striatal dopamine release in vitro using a mouse striatal assay. Glycine and GDA significantly inhibit NMDA-induced striatal dopamine release, consistent with their ability to enhance local striatal inhibitory neurotransmission in vitro and to reverse PCP-induced hyperactivity in vivo.