RESUMEN
In previous studies we described that perinatal protein deprivation facilitates the development and expression of behavioral sensitization to cocaine. In this research, we explored whether the increased reactivity observed in deprived (D) versus control (C) rats is also evident during drug-free withdrawal periods. Considering that activation of the extracellular signal-regulated protein kinase (ERK) is suggested to be involved in cocaine-induced behavioral sensitization, we study the effects of perinatal protein deprivation on phosphorylated ERK2 (pERK2) protein levels in the NAc (core and shell) during different drug-free withdrawal periods. To induce behavioral sensitization, C- and D-rats received a daily injection of cocaine (5-10 mg/kg, i.p.) for 7 days and locomotor activity was performed on days 1 and 7. Cocaine-sensitized animals were left drug-free and pERK2 was assessed on withdrawal days (WD) 1, 4, 7 and 21. In the NAc core, cocaine induced ERK signaling pathway activation in a dose-dependent manner, and only D-rats showed a significant increase in pERK2 protein levels with the lowest dose of cocaine (5 mg/kg). Moreover, sensitized C-rats with 10 mg/kg showed an increase in pERK2 levels from WD7 while D-rats showed this activation on WD4, which remained increased on WD7 and 21. In contrast, in the NAc shell, only sensitized D-rats with cocaine 10 mg/kg showed ERK2 activation on WD21. These results suggest that perinatal protein deprivation facilitates the molecular processes involved in neuronal plasticity occurring during withdrawal.
Asunto(s)
Cocaína/farmacología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Desnutrición/metabolismo , Núcleo Accumbens/metabolismo , Síndrome de Abstinencia a Sustancias/metabolismo , Animales , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Núcleo Accumbens/efectos de los fármacos , Fosforilación/efectos de los fármacos , Fosforilación/fisiología , Ratas , Ratas WistarRESUMEN
The development of sensitization to the locomotor effects of morphine and cross-sensitization between morphine and cocaine were evaluated in adult rats submitted to a protein malnutrition schedule from the 14th day of gestation up to 30 days of age (D-rats), and compared with well-nourished animals (C-rats). Dose-response curves to morphine-induced locomotor activity (5, 7.5, 10 or 15 mg/kg, i.p., every other day for 5 days) revealed a shift to the left in D-rats compared to C-rats. This implies that D-rats showed behavioral sensitization to the lower dose of morphine used (5 mg/kg), which was ineffective in C-rats. Furthermore, when a cocaine challenge (10 mg/kg, i.p) was given 48 h after the last morphine administration, only D-rats exhibited cross-sensitization in morphine-pretreated animals (7.5 and 10 mg/kg). In order to correlate the differential response observed with the functioning of the mesocorticolimbic dopaminergic system, extracellular dopamine (DA) levels were measured in the nucleus accumbens (core and shell) and the dorsal caudate-putamen. A challenge with cocaine in morphine pre-exposed animals produced an increase in DA release, but only in the nucleus accumbens "core" of D-rats. Similar DA levels were found in the nucleus accumbens "shell" and in the dorsal caudate-putamen of both groups. Finally, these results demonstrate that D-rats had a lower threshold for developing both a progressive behavioral sensitization to morphine and a cross-sensitization to cocaine. In accordance with these behavioral findings, a higher responsiveness of the nucleus accumbens core, expressed by increased DA levels, both basal and after cocaine challenge, was observed in D-rats.
Asunto(s)
Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Locomoción/efectos de los fármacos , Desnutrición/fisiopatología , Morfina/farmacología , Narcóticos/farmacología , Envejecimiento , Animales , Núcleo Caudado/efectos de los fármacos , Núcleo Caudado/fisiopatología , Cocaína/administración & dosificación , Cocaína/sangre , Dopamina/metabolismo , Inhibidores de Captación de Dopamina/administración & dosificación , Inhibidores de Captación de Dopamina/sangre , Relación Dosis-Respuesta a Droga , Femenino , Locomoción/fisiología , Masculino , Morfina/administración & dosificación , Morfina/sangre , Narcóticos/administración & dosificación , Narcóticos/sangre , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/fisiopatología , Embarazo , Efectos Tardíos de la Exposición Prenatal , Putamen/efectos de los fármacos , Putamen/fisiopatología , Ratas , Ratas WistarAsunto(s)
Factores de Coagulación Sanguínea/efectos adversos , Trombosis , Animales , Argentina , Factores de Coagulación Sanguínea/administración & dosificación , Factores de Coagulación Sanguínea/química , Modelos Animales de Enfermedad , Combinación de Medicamentos , Diseño de Fármacos , Femenino , Humanos , Ratas , Trombosis/inducido químicamente , Trombosis/prevención & controlRESUMEN
In the current research, we assessed the influence of a protein malnutrition schedule from the 14th day of gestation up to 40 days of age (D-rats) on the rewarding properties of morphine in adult rats by means of the conditioned place preference paradigm. Well-nourished animals (C-rats) administered with different doses of morphine (0.75, 1.5, 3, 6, 12 or 24 mg/kg i.p.) exhibited a conditioning place preference with doses of 3 and 6 mg/kg, whereas in D-rats such a conditioning effect was observed with doses of 1.5 and 3 mg/kg. No adverse effects were observed in either C- or D-rats for the higher doses of morphine. In addition, when animals of both groups were pretreated twice a day for 3 days with increasing doses of morphine (5, 10 and 20 mg/kg s.c.), only D-rats elicited sensitization to the conditioning effect with the lowest dose of morphine (0.75 mg/kg i.p.). Furthermore, sensitized D-rats showed a selective and significant increase in FosB expression in the nucleus accumbens (core and shell), basolateral amygdala and medial prefrontal cortex, brain areas that are functionally related to the rewarding neural circuit. These results demonstrate that a deficient nutritional status during the perinatal period results in adult subjects having neural alterations, leading to an increased responsiveness to morphine and/or enhanced reinforcement effects, which correlates with an overexpression of FosB in selective brain areas related to the rewarding network.
Asunto(s)
Encéfalo/efectos de los fármacos , Trastornos Nutricionales en el Feto/fisiopatología , Dependencia de Morfina/fisiopatología , Morfina/farmacología , Deficiencia de Proteína/fisiopatología , Recompensa , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Amígdala del Cerebelo/fisiopatología , Animales , Encéfalo/metabolismo , Encéfalo/fisiopatología , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Sistema Límbico/efectos de los fármacos , Sistema Límbico/metabolismo , Sistema Límbico/fisiopatología , Dependencia de Morfina/metabolismo , Narcóticos/farmacología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiopatología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiopatología , Embarazo , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Wistar , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiologíaRESUMEN
The rewarding properties of cocaine were assessed in adult rats submitted to a protein malnutrition schedule from the 14th day of gestation up to 40 days of age (deprived rats), as compared with well-nourished animals (control rats) using the conditioned place preference paradigm. Dose-response curves to cocaine (3, 5, 10, 15, 30, 45 or 60 mg/kg i.p.) revealed in deprived rats a conditioning effect with doses of 5 and 10mg/kg; doses of 15 and 30 mg/kg did not show any conditioning place preference and doses of 45 and 60 mg/kg revealed a significant aversive effect. In control rats, cocaine elicited place preference with doses of 10, 15 and 30 mg/kg, whereas 45 and 60 mg/kg did not show either conditioning or aversive effects. Furthermore, sensitization to the conditioning effect of cocaine was obtained in deprived animals with a low dosage of cocaine, that was ineffective in controls (5 mg/kg/day for 10 days). Related to the higher rewarding effects, sensitized deprived rats showed a selective and significant increase in FosB expression in nucleus accumbens (core and shell) and basolateral amygdala, brain areas related to the rewarding neuronal circuits. These results suggest that a deficient nutritional status during early life may induce in adult subjects an increased responsiveness to behavioral effects of cocaine and/or enhanced its reinforcement properties.
Asunto(s)
Cocaína/farmacología , Condicionamiento Operante/efectos de los fármacos , Inhibidores de Captación de Dopamina/farmacología , Desnutrición Proteico-Calórica/fisiopatología , Recompensa , Animales , Animales Recién Nacidos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Inmunohistoquímica , Masculino , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , RatasRESUMEN
Bisphosphonates are now in the vanguard of osteoporosis treatment. Frequently, gastro-oesophageal symptoms are associated with these drugs. The objective of this study was to compare side effects and bone turnover markers in postmenopausal women who had received alendronate daily or weekly in tablets with or without enteric coating. We conducted a randomised, double-blind, 3-month trial. The trial involved 75 volunteers, aged 45-58 with moderate to severe osteopenia (T-score lower than -2 SD) assessed by quantitative ultrasound. Women were assigned randomly to receive: (a) alendronate 10mg/day: (b) alendronate 70 mg once a week: or (c) enteric alendronate 70 mg per week. We recorded side effects, C-telopeptide, osteocalcin and urine hydroxyproline at the start of the study and at 3 months. After 3 months, pyrosis (heartburn) was noted by seven women in group A (28%), three in group B (12%) and two in group C (8%); nausea: by one woman in group B; and headache by one patient in each group. C-telopeptide (A: 40.7%; B: 34.1% and C: 38.5%); hydroxyproline (A: 31.1%;B: 25.3% and C: 31.5%) and osteocalcin (A: 27.0%; B: 25.4% and C: 25.1%) decreased similarly in the three groups. Weekly intake of alendronate, whether conventional or enteric-coated; is associated with less heartburn and nausea. Enteric alendronate has a similar action to the conventional tablets on biochemical markers.
Asunto(s)
Alendronato/administración & dosificación , Densidad Ósea/efectos de los fármacos , Osteoporosis Posmenopáusica/prevención & control , Administración Oral , Adulto , Alendronato/efectos adversos , Colágeno Tipo I , Esquema de Medicación , Femenino , Pirosis , Humanos , Hidroxiprolina/orina , Incidencia , Persona de Mediana Edad , Náusea , Osteocalcina/orina , Osteoporosis Posmenopáusica/patología , Fragmentos de Péptidos/sangre , Péptidos , Procolágeno/sangre , Índice de Severidad de la Enfermedad , Comprimidos Recubiertos , Resultado del TratamientoRESUMEN
The spontaneous activity of locus coeruleus (LC) noradrenergic neurons was assessed by single unit recording in adult recovered rats undernourished at perinatal age as compared with wellnourished animals. Locus coeruleus activity, measured by the firing rate of noradrenergic neurons and the number of spontaneously active cells/track was significantly higher in deprived rats than in controls. In addition, dose-response curves for the inhibitory LC activity of clonidine showed a shift to the right in deprived animals indicating a subsensitivity of alpha2-adrenergic autoreceptors. This fact suggests an alteration in the negative feedback mechanism mediated by somatodentritic alpha2 autoreceptors that modulate the activity of LC neurons, and may account for the behavioral alterations attributed to early undernutrition. Repeated desipramine (DMI) administration to deprived rats reduced LC activity to values comparable to controls, which were not affected after a similar treatment. These data extend to previous reports on long-lasting or permanent plastic changes in the CNS induced by early undernutrition, which may be reverted by pharmacological manipulations. In addition, these results support the hypothesis that alterations induced by early undernutrition are in the same direction as and resemble those described for patients with panic disorders. Furthermore, together with behavioral alterations and selective anxiolytic effect of DMI and other drugs with antipanic effects described in early malnourished rats, the present data support the proposal that perinatally deprived rats may be a useful model for screening drugs with potential antipanic activity.
Asunto(s)
Desipramina/farmacología , Locus Coeruleus/fisiopatología , Neuronas/fisiología , Trastornos Nutricionales/fisiopatología , Animales , Clonidina/farmacología , Femenino , Locus Coeruleus/efectos de los fármacos , Modelos Animales , Neuronas/efectos de los fármacos , Embarazo , Ratas , Ratas WistarRESUMEN
The aim of this study was to evaluate the influence of an early chronic variable stress procedure (CVS) associated or not with repeated administration of various antidepressants on cortical restraint-induced dopamine (DA) release in vivo. Animals were subjected to the CVS schedule and one day after submitted to persistent administration with vehicle, desipramine (DMI, 10 mg/kg, i.p.), fluoxetine (FLU, 10 mg/kg, i.p.) or phenelzine (PHE; 10 mg/kg, i.p.) and later on exposed to a 60-min restraint period. In addition, we also explored the effect of acute administration of these antidepressants on cortical DA overflow in response to restraint in CVS treated rats. A higher increase in cortical DA release in response to restraint was observed in CVS animals as compared with those without previous CVS. Persistent, but not acute, administration with DMI, FLU and PHE blocked the sensitized output induced by restraint following CVS exposure.
Asunto(s)
Antidepresivos/farmacología , Dopamina/metabolismo , Corteza Prefrontal/metabolismo , Restricción Física , Estrés Psicológico/metabolismo , Animales , Antidepresivos Tricíclicos/farmacología , Monoaminas Biogénicas/análisis , Monoaminas Biogénicas/metabolismo , Masculino , Microdiálisis , Inhibidores de la Monoaminooxidasa/farmacología , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Wistar , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
The present research studied the influence of an early chronic variable stress (CVS) paradigm - an animal model of depression - on behavioral responses to subsequent environmental challenges suggested to model anhedonia and emotional reactions such as anxiety and fear. In order to explore a potential involvement of an endogenous opiate mechanism - presumably activated during CVS exposure - in the development of such behavioral reactions, in all experiments rats were administered naltrexone (NAL, 2 mg/kg, i.p.) or vehicle (VH) prior to each daily stressor of the CVS procedure. Animals were exposed to CVS and 1 week later tested for sucrose preference (1%) in a free choice paradigm after the presentation or not of a 90-min restraint period. Only CVS treated animals that were later exposed to restraint showed a reduction of sucrose preference, this reduction was absent when CVS rats were pretreated previously with NAL. Moreover, CVS rats were one week later tested on the elevated plus maze (EPM) and in their conditioned and unconditioned freezing response to a single shock session. Early chronic stress resulted in an anxiogenic behavior in the EPM and in an enhanced conditioned and unconditioned freezing which were all abolished by NAL pretreatment. These behavioral findings suggest that the potential activation of an endogenous opiate mechanism during CVS participates in the development of anhedonia and exaggerated emotional reactions in response to subsequent stressful experiences.
Asunto(s)
Depresión/prevención & control , Depresión/psicología , Miedo , Aprendizaje por Laberinto/efectos de los fármacos , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Péptidos Opioides/metabolismo , Estrés Psicológico/complicaciones , Animales , Reacción de Prevención , Conducta Animal/efectos de los fármacos , Enfermedad Crónica , Condicionamiento Psicológico , Modelos Animales de Enfermedad , Conducta Alimentaria , Masculino , Péptidos Opioides/antagonistas & inhibidores , Péptidos Opioides/efectos de los fármacos , Distribución Aleatoria , Ratas , Ratas Wistar , Método Simple Ciego , Estrés Psicológico/tratamiento farmacológicoRESUMEN
One widely used animal model of anxiety is the electrical stimulation of a given structure supposed to be involved in the neural circuitry underlying emotional behavior. Indeed, electrical stimulation of midbrain structures with substrates for the processing of fear-like responses, such as the dorsal periaqueductal gray matter (DPAG) or the inferior colliculus (IC), produces behavioral, sensorial and autonomic responses very similar to the defense reactions observed in environmental threatening situations. It has also been proposed that the required level of integration of all these components of the defense reaction needs an integrative process situated at higher brain level, as the prefrontal cortex. As a matter of fact, substantial cortical inputs to the midbrain tectum have already been found. In view of this evidence, it seems important to know whether animals stimulated in the midbrain tectum would present neurochemical changes in the prefrontal cortex. To this end, we examined the temporal course of the effects of the electrical stimulation of the DPAG and IC on the dopamine (DA) release in the prefrontal cortex. Electrical stimulation of these structures was performed at the alertness (control) and escape thresholds. Electrical stimulation of the inferior colliculus at the escape threshold produced a long-lasting increase in the levels of corticofrontal dopamine in relation to these measurements in the control group. No significant changes in extracellular DA release in this cortical area could be observed following DPAG electrical stimulation. These findings bring evidence for the involvement of dopamine of the frontal cortex in the setting up of adaptive responses to stressful situations generated at the inferior colliculus level.
Asunto(s)
Dopamina/metabolismo , Lóbulo Frontal/metabolismo , Techo del Mesencéfalo/fisiología , Ácido 3,4-Dihidroxifenilacético/metabolismo , Análisis de Varianza , Animales , Nivel de Alerta/fisiología , Estimulación Eléctrica , Electrodos Implantados , Reacción de Fuga/fisiología , Espacio Extracelular/metabolismo , Colículos Inferiores/fisiología , Masculino , Microdiálisis , Sustancia Gris Periacueductal/fisiología , Ratas , Ratas WistarRESUMEN
In the present work, we investigated the effects of chronic risperidone administration on the activity of locus coeruleus noradrenergic neurons. In addition, the effect of chronic risperidone administration on the basal level of norepinephrine in the prefrontal cortex was evaluated. Results of this research showed that chronic risperidone administration increased the activity of locus coeruleus noradrenergic neurons. The sensitivity of alpha(2)-adrenoceptors in the somatodendritic region of the locus coeruleus was assessed by using the ID(50) of clonidine. Results indicated that the firing rate of locus coeruleus noradrenergic neurons was the same in risperidone-treated rats and controls. Similarly, the ID(50) for (+/-)-2,5-dimetoxy-4-iodoamphetamine (DOI), an agonist of 5-HT(2) receptors which inhibits the activity of locus coeruleus neurons by acting on these receptors, did not show any differences between the firing rate of these neurons in risperidone treated rats and controls. Unlike controls, chronically treated rats showed a significant decrease in norepinephrine levels in the prefrontal cortex. The decreased release of norepinephrine following continuous risperidone administration could be explained by the sustained increase in locus coeruleus neuronal activity after chronic risperidone administration. This low norepinephrine level in the prefrontal cortex may contribute to the relief of certain negative schizophrenic symptoms and to the improvement of cognitive function.
Asunto(s)
Antipsicóticos/farmacología , Locus Coeruleus/efectos de los fármacos , Norepinefrina/metabolismo , Risperidona/farmacología , Transmisión Sináptica/efectos de los fármacos , Anfetaminas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Locus Coeruleus/metabolismo , Masculino , Microdiálisis , Ratas , Ratas WistarRESUMEN
The present study examined the influence of an early chronic variable stress procedure with or without concurrent naloxone administration at different doses (1, 2 or 3 mg/kg, i.p.) on stress (restraint)-induced dopamine release in the frontal cortex in vivo. A higher increase in cortical dopamine release in response to a subsequent restraint event was observed in chronically stressed rats as compared with those without chronic stress exposure. Naloxone pretreatment normalized this sensitized response only at the higher dose (3 mg/kg, i.p.). The present results indicate that cortical dopamine response to a novel and uncontrollable stressor sensitizes after exposure to a chronic variable stress procedure and that an endogenous opiate mechanism, presumably activated during chronic stress, may be involved in the development of such a sensitization process.
Asunto(s)
Dopamina/metabolismo , Lóbulo Frontal/metabolismo , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Estrés Fisiológico/fisiopatología , Animales , Enfermedad Crónica , Lóbulo Frontal/efectos de los fármacos , Masculino , Microdiálisis , Péptidos Opioides/metabolismo , Ratas , Ratas Wistar , Restricción FísicaRESUMEN
The influence of early chronic variable stress (CVS) associated with persistent desipramine (DMI) administration was examined on escape performance. Animals were exposed to CVS and 1 day later administered DMI (5 mg/kg, i.p. twice a day) or vehicle (VH) during six consecutive days. Escape performance was assessed over 24 h following inescapable shock (IS) exposure. Higher escape failures were observed in CVS shocked rats compared with unstressed shocked animals. DMI normalized escape failures in both groups. In order to investigate the role of an endogenous opiate mechanism presumably activated by CVS exposure in this behavioral deficit, rats were administered naltrexone (NAL, 2 mg/kg i.p.) or VH prior to each daily stressor of the CVS regime. NAL pretreatment blocked escape failures performed only by CVS shocked rats. In addition, animals were daily administered morphine (MOR, 10 mg/kg, i.p.) or VH during seven consecutive days and subsequently administered DMI. A significant increase in escape deficit in shocked rats was observed after chronic MOR but not following the associated treatment with MOR and DMI. These behavioral data suggest that early experience with a CVS facilitated the onset of escape deficit induced by a brief IS event, an effect that can be prevented by chronic DMI. Furthermore, this sensitized escape deficit response seems to be partially modulated by the previous activation of an opiate mechanism.
Asunto(s)
Inhibidores de Captación Adrenérgica/farmacología , Nivel de Alerta/efectos de los fármacos , Desipramina/farmacología , Reacción de Fuga/efectos de los fármacos , Receptores Opioides/efectos de los fármacos , Animales , Nivel de Alerta/fisiología , Encéfalo/efectos de los fármacos , Electrochoque , Reacción de Fuga/fisiología , Desamparo Adquirido , Masculino , Naltrexona/farmacología , Ratas , Ratas Wistar , Receptores Opioides/fisiologíaRESUMEN
Amphetamine-induced psychosis is frequently associated with a chronic, high-dose, daily pattern of amphetamine exposure. In the present study we investigate the effects of prenatal exposure to amphetamine during the development of the central noradrenergic (NA) system in adult rats. Pregnant Wistar rats were given 4 mg/kg/day of d-amphetamine (AMPH), subcutaneously, from gestational day 8 to 21. No additional drug treatment was given to the animals until the beginning of the experiments, in adult, control and prenatally amphetamine treated rats. Since we study the electrophysiology and neurochemistry of the central NA system, we investigated the electric activity of locus coeruleus (LC) norepinephrine (NE) neurons and the levels of NE on prefrontal cortex. What we found, was a decreased number of spontaneously active cells in the LC nucleus with a lower pattern of discharge whereas, the basal levels of NE in the prefrontal cortex, was greatly increased. The increased cortical NE levels, observed in the present study may account for the proposed hyperactive NA system being responsible for some psychotic symptoms observed in paranoid schizophrenia. Besides, our results concerning the permanent alteration observed in the central NA system, in rats prenatally exposed to amphetamine, raise the possibility that this animal model may be useful to further study the neurobiologic alterations underlying certain clinical features involved in some psychosis such as schizophrenia.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Estimulantes del Sistema Nervioso Central/administración & dosificación , Dextroanfetamina/administración & dosificación , Norepinefrina/fisiología , Efectos Tardíos de la Exposición Prenatal , Animales , Encéfalo/crecimiento & desarrollo , Estimulantes del Sistema Nervioso Central/farmacología , Dextroanfetamina/farmacología , Electrofisiología , Femenino , Locus Coeruleus/citología , Locus Coeruleus/efectos de los fármacos , Locus Coeruleus/fisiología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Embarazo , Ratas , Ratas WistarRESUMEN
MF-268 bitartrate [(3a S, 8a R)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol- 5-ol[8-(cis2,-6-dimethyl-morpholin-4-yl)octyl]-carbamate L-bitartrate hydrate; Mediolanum Farmaceutici, Milan, Italy] is a pseudo-reversible carbamate-type cholinesterase inhibitor (ChEI) which interacts with the catalytic and regulatory anionic site of the enzyme. Its effects on extracellular levels of acetylcholine (ACh), norepinephrine (NE), dopamine (DA), and serotonin (5-HT, 5-hydroxytryptamine) were studied in rat cortex by using a microdialysis technique coupled with high-performance liquid chromatography-electrochemical detection (HPLC-ECD). Conscious, freely moving rats were systemically [per os (p.o.) and subcutaneously (s.c.)] administered MF-268 with no ChEI in the probe. Cholinesterase inhibition in brain was assayed in parallel experiments. Oral administration of MF-268 (0.5, 2.0, and 5.0 mg/kg) produced a significant increase of extracellular ACh in cortex; the maximal increase was 300% [not significant (n.s.)], 460% and 1,200%, respectively. Maximal cholinesterase (ChE) inhibition was 2.3% (n.s.) at 9 hr and 9.7% (P < .05) at 12 hr after the 2.0 and 5.0 mg/kg doses, respectively. Norepinephrine and DA levels were increased 180% and 100% after the 5.0 mg/kg dose, respectively; 100% and 60% after the 2.0 mg/kg dose, respectively; and 70% for both amines after the 0.5 mg/kg dose, respectively. The elevation lasted at least 5 hr with the 2.0 and 5.0 mg/kg doses. There were no major changes in 5-HT levels at these three doses. Subcutaneous administration (0.5 and 2.0 mg/kg) produced a maximal 360% (5.5 hr) and 2,500% (5 hr) increase in extracellular ACh, respectively. Maximal ChE inhibition was 13% (0.5 mg/kg) and 41% (2.0 mg/kg). Neither 0.5 nor 2.0 mg/kg produced a consistent modification of NE. Only a transient increase in DA was seen with the 0.5 mg/kg dose. There were no changes in 5-HT levels at these two doses. MF-268-treated animals showed slight cholinergic side effects (chewing, tremor) at both doses. MF-268 administered intracortically through the microdialysis probe at a concentration of 50 microM induced a 5,900% increase in ACh levels at 6 hr. This effect started 30 min after injection and continued throughout the period of administration. MF-268 produced a significant decrease in NE levels (-44%) starting at 30 min, and a slight but significant increase in DA levels of 45% at 2.5 hr. A significant increase of 5-HT (58%) was also observed starting at 4 hr. Slight symptoms of cholinergic toxicity were observed during intracortical administration.
Asunto(s)
Acetilcolina/biosíntesis , Aminas Biogénicas/biosíntesis , Corteza Cerebral/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Morfolinas/farmacología , Administración Oral , Animales , Corteza Cerebral/metabolismo , Inhibidores de la Colinesterasa/administración & dosificación , Inhibidores de la Colinesterasa/toxicidad , Dopamina/biosíntesis , Relación Dosis-Respuesta a Droga , Espacio Extracelular/química , Inyecciones , Inyecciones Subcutáneas , Masculino , Microdiálisis , Morfolinas/administración & dosificación , Morfolinas/toxicidad , Norepinefrina/biosíntesis , Ratas , Ratas Sprague-Dawley , Serotonina/biosíntesisRESUMEN
In previous investigations, we have demonstrated that cholinesterase inhibitors such as physostigmine (PHY) and heptylphysostigmine (HEP) elicit a significant and simultaneous increase in acetylcholine (ACh) and norepinephrine (NE) levels in the rat cortex. This effect is enhanced by idazoxan, a selective alpha-2 antagonist. These data suggest that a combination of cholinergic and adrenergic drug may improve the pharmacological effect of the cholinesterase inhibitor on cortical neurotransmitters such as ACh-NE. In order to obtain additional information on cortical cortical neurotransmitter interaction, we tested, in the cerebral cortex of the rat, the effect of PHY and HEP in animals pretreated with clonidine (CLO), a selective alpha-2 agonist, on ACh, NE, dopamine and 5-hydroxytryptamine) extracellular levels. We detected no effect of systemic or intracortical CLO administration of ACh levels, but NE, dopamine and 5-hydroxytryptamine levels were all decreased. Systemic coadministration of CLO and PHY significantly elevated ACh levels and decreased NE, dopamine and 5-hydroxytryptamine levels. Systemic coadministration of CLO and HEP produced a significant elevation in ACh levels. Comparison between the two treatment combinations shows that, although CLO coadministration reduces the effect of PHY on ACh levels, HEP administered to animals pretreated with CLO produces a stronger effect than HEP alone. A possible explanation for this difference is the variation in duration of the two drugs on ACh elevation and muscarinic receptor desensitization. As a result of the alpha-2 agonist cholinesterase inhibitor coadministration, our data suggest that such a combination does not represent an advantage as a therapeutical alternative for treatment of cognitive impairment in Alzheimer disease patients.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Corteza Cerebral/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Clonidina/farmacología , Neurotransmisores/metabolismo , Fisostigmina/análogos & derivados , Fisostigmina/farmacología , Acetilcolina/metabolismo , Agonistas de Receptores Adrenérgicos alfa 2 , Animales , Corteza Cerebral/química , Diálisis , Dopamina/metabolismo , Interacciones Farmacológicas , Masculino , Norepinefrina/metabolismo , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismoRESUMEN
The effect of systemic and local administration of metrifonate (MTF), a long-acting cholinesterase inhibitor (ChEl) on extracellular levels of acetylcholine (ACh), norepinephrine (NE), dopamine (DA) and serotonin (5-HT) was investigated in the rat cortex by using transcortical microdialysis. Metrifonate (20, 40, and 80 mg/kg, s.c.) increased ACh levels in a dose-dependent manner above the baseline. Two consecutive administrations (80 mg/kg) enhanced ACh levels producing two similar patterns of elevation. A significant increase in NE was also seen at 80 mg/kg. Systemic administration (20 mg/kg) of MTF produced a significant increase of DA levels. Local cortical perfusion of MTF through the probe caused a significant but slow increase of ACh as well as an increase of NE levels. Compared to NE, the elevation of DA was more rapid and more long-lasting. The cortical levels of 5-HT were not modified by MTF given by either route. These results support the concept of MTF being a potential drug for treatment of Alzheimer disease (AD).
Asunto(s)
Acetilcolina/metabolismo , Corteza Cerebral/efectos de los fármacos , Dopamina/metabolismo , Norepinefrina/metabolismo , Serotonina/metabolismo , Triclorfón/farmacología , Animales , Corteza Cerebral/metabolismo , Masculino , Microdiálisis , Ratas , Ratas Sprague-DawleyRESUMEN
Based on previous results indicating that cholinesterase inhibitors (ChEI) elicit a significant and simultaneous increase in acetylcholine (ACh) and norepinephrine (NE) levels, we studied whether the NE elevation could down-regulate ACh levels and possibly decrease the therapeutical effect of these drugs. A modified microdialysis technique without ChEI in the probe was used to study the putative interaction of these neurotransmitters in cerebral cortex of freely moving rats. We administered physostigmine (PHY) (0.03 mg/kg) and heptylphysostigmine (HEP) (2 mg/kg) subcutaneously to animals pretreated with idazoxan (IDA) (i.p. or in the probe), a selective alpha-2 antagonist. IDA (20 mg/kg i.p. and 10(-4) M in the probe) did not modify the basal release of ACh. On the other hand, NE and dopamine (DA) were increased after both types of administration. PHY administered to rats pretreated with IDA (systemically or locally) induced a similar increase in the ACh levels as demonstrated for PHY alone. Conversely, coadministration of HEP with IDA i.p. produced a more sustained effect on ACh cortical levels than did HEP alone. These data suggest that a combination of cholinergic-adrenergic drugs may improve the pharmacological effect of ChEI.
Asunto(s)
Antagonistas Adrenérgicos alfa/farmacología , Corteza Cerebral/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Dioxanos/farmacología , Neurotransmisores/metabolismo , Acetilcolina/metabolismo , Animales , Corteza Cerebral/metabolismo , Dopamina/metabolismo , Sinergismo Farmacológico , Idazoxan , Masculino , Microdiálisis , Norepinefrina/metabolismo , Fisostigmina/análogos & derivados , Fisostigmina/farmacología , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismoRESUMEN
A microdialysis technique was used to investigate the effect of physostigmine (PHY) and heptylphysostigmine (HEP), administered systemically or locally, on the extracellular levels of acetyl-choline (ACh), norepinephrine, dopamine and 5-hydroxytryptamine in the cerebral cortex of the rat. Levels of these neurotransmitters in dialysates were assayed simultaneously with two different high pressure liquid chromatography systems. No cholinesterase inhibitor was added into the probe to increase detection of ACh after systemic administration. Cholinesterase inhibition and its relation to ACh levels were also studied. Systemic administration of two doses of cholinesterase inhibitor [PHY (30 and 300 micrograms/kg) and HEP (2 and 5 mg/kg)] produced a dose-dependent increase in ACh levels. Local perfusion of these drugs through the probe elicited a strong increase in extracellular ACh. HEP produced a longer lasting inhibition of cholinesterase and a more prolonged elevation of ACh in cerebral cortex than PHY. After systemic administration of PHY (both doses), we observed a significant increase of norepinephrine levels. This effect was weaker after HEP. Local administration through the probe did not modify norepinephrine concentration. Dopamine levels were also increased after systemic administration. ONly HEP perfused into the probe elicited a significant increase in extracellular dopamine. Systemic or local administration did not modify 5-hydroxytryptamine levels. These observations suggest a more favorable pharmacological profile for HEP as a potential drug for Alzheimer disease, as compared to PHY.
Asunto(s)
Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Inhibidores de la Colinesterasa/farmacología , Neurotransmisores/metabolismo , Fisostigmina/análogos & derivados , Fisostigmina/farmacología , Acetilcolina/metabolismo , Animales , Corteza Cerebral/enzimología , Diálisis , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Espacio Extracelular/metabolismo , Inyecciones Subcutáneas , Masculino , Norepinefrina/metabolismo , Perfusión , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismo , Cloruro de Sodio/farmacologíaRESUMEN
Un sistema de salud integral requiere atender las necesidades de salud mental de la población. Para ello se necesita formación e interés por parte de los profesionales y planificación de las atenciones con el fin de destinar a la consulta el tiempo necesario para abarcar estos problemas. En este artículo se revisan algunas sugerencias de manejo en la comunicación médico-paciente, luego se enfatiza la promoción y prevención en salud mental y finalmente se realiza una descripción breve de los principales problemas de salud mental que pueden abarcarse en la atención primaria. Es importante también la forma en que se deriva a un paciente a un servicio de psiquiatría y reconocer las patologías que deben ser derivadas a especialista