RESUMEN
Neurotensin (NT) is a neuropeptide that acts as a neurotransmitter and neuromodulator in the central nervous system. Several studies suggest a therapeutic role for NT analogs in nicotine and other psychostimulant addictions. We studied the effects of the nonselective NT receptor agonist NT69L, which has equal affinity for the two major NT receptors, NTS1 and NTS2, on the expression of cocaine-conditioned place preference (cocaine-CPP) and reinstatement after extinction. Robust cocaine-CPP was obtained after 5 days of conditioning. Extinction was induced using eight repeated daily injections of saline. Reinstatement was prompted by priming with one injection of cocaine (12 mg/kg intraperitoneally). On the test day, NT69L (1 mg/kg intraperitoneally) was administered 30 min before assessing cocaine-CPP. Extinction led to the loss of cocaine-CPP. One injection of cocaine (12 mg/kg intraperitoneally) for cocaine priming reinstated cocaine-CPP. NT69L blocked cocaine-CPP reinstatement in cocaine-primed animals. In addition, NT69L blocked cocaine-CPP reinstatement when administered before priming with cocaine. Thus, the NT agonist NT69L blocked both cocaine-CPP and reinstatement to cocaine preference. NT69L may exert this action by modulating the mesocorticolimbic dopamine and glutamatergic pathways involved in addiction and relapse processes. Therefore, NT agonists may represent a novel therapy for the treatment of addiction to cocaine and possibly to other psychostimulants.
Asunto(s)
Cocaína/farmacología , Condicionamiento Operante/efectos de los fármacos , Inhibidores de Captación de Dopamina/farmacología , Neurotensina/análogos & derivados , Fragmentos de Péptidos/farmacología , Refuerzo en Psicología , Animales , Interacciones Farmacológicas , Extinción Psicológica/efectos de los fármacos , Masculino , Ratones , Neurotensina/farmacologíaRESUMEN
Neurotensin (NT) is a tridecapeptide with naloxone-independent analgesic action. NT exerts its effects through three molecularly cloned receptor subtypes, NTS1, NTS2, and NTS3. The analgesic efficacy of NT agonists depends on their activation of NTS1 and/or NTS2. NT79 is an NTS2-selective agonist without hypothermic and hypotensive effects, produces analgesic effects in animal models of visceral (writhing), but not thermal (hot plate) pain. This study extends previous study with NT79 to test its efficacy in an animal model of persistent pain (formalin test) and to determine whether there is analgesic synergy between NT79 and morphine on visceral and persistent pain. NT79 enhanced the analgesic potency of morphine in the writhing test. In the persistent pain model, NT79 and morphine attenuated formalin-induced lifting and biting during the inflammatory phase. NT79 and morphine alone significantly blocked the lifting but not the biting response, which involves the activity of spinal nociceptive circuits. However, the combination of NT79 and morphine attenuated both lifting and biting responses, results indicating both spinal and supraspinal modulation of persistent nociception. Isobolographic analyses show analgesic synergism between NT79 and morphine in persistent pain, thus providing a promise of therapy for pain while minimizing adverse effects associated with morphine use.
Asunto(s)
Morfina/farmacología , Neurotensina/análogos & derivados , Dolor/tratamiento farmacológico , Fragmentos de Péptidos/farmacología , Receptores de Neurotensina/agonistas , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacología , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Morfina/administración & dosificación , Neurotensina/administración & dosificación , Neurotensina/farmacología , Fragmentos de Péptidos/administración & dosificación , Ratas , Ratas Sprague-DawleyRESUMEN
Much evidence suggests that targeting the neurotensin (NT) system may provide a novel and promising treatment for schizophrenia. Our recent work shows that: NTS1 knockout (NTS1(-/-)) mice may provide a potential animal model for studying schizophrenia by investigating the effect of deletion NTS1 receptor on amphetamine-induced hyperactivity and neurochemical changes. The data indicate a hyper-dopaminergic state similar to the excessive striatal DA activity reported in schizophrenia. The present study was done to determine if NTS1(-/-) mice also have similar changes in behavior, in prefrontal neurotransmitters, and in protein expression, as observed in wild type (WT) mice treated with the psychotomimetic phencylclidine (PCP), an animal model for schizophrenia. Our results showed many similarities between untreated NTS1(-/-) mice and WT mice chronically treated with PCP (as compared with untreated WT mice): 1) lower PCP-induced locomotor activity; 2) similar avolition-like behavior in forced-swim test and tail suspension test; 3) lower prefrontal glutamate levels; 4) less PCP-induced dopamine release in medial prefrontal cortex (mPFC); and 5) down-regulation of mRNA and protein for DA D(1), DA D(2), and NMDAR2A in mPFC. Therefore, these data strengthen the hypothesis that the NTS1(-/-) mouse is an animal model of schizophrenia, particularly for the dysfunction of the prefrontal cortex. In addition, after chronic PCP administration, the DA D(1) receptor was up-regulated in NTS1(-/-) mice, results which suggest a possible interaction of NTS1/DA D(1) in mPFC contributing to chronic PCP-induced schizophrenia-like signs.
Asunto(s)
Conducta Animal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Receptores de Neurotensina/deficiencia , Esquizofrenia/genética , Esquizofrenia/metabolismo , Psicología del Esquizofrénico , Animales , Cromatografía Líquida de Alta Presión , Modelos Animales de Enfermedad , Dopamina/genética , Dopamina/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Ácido Glutámico/genética , Ácido Glutámico/metabolismo , Pérdida de Tono Postural/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Actividad Motora/genética , Fenciclidina , Reacción en Cadena de la Polimerasa , Corteza Prefrontal/efectos de los fármacos , ARN Mensajero/efectos de los fármacos , ARN Mensajero/genética , Receptores de Neurotensina/genética , Receptores de Neurotensina/metabolismo , Esquizofrenia/inducido químicamente , Natación/psicología , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
Pre-pulse inhibition (PPI) of the acoustic startle reflex is deficient in patients with schizophrenia. This deficiency is mimicked in mice by the use of the psychotomimetic drugs d-amphetamine and dizolcipine. Antipsychotic drugs such as clozapine are used to treat schizophrenic patients and are also administered to mice to prevent PPI disruption. Neurotensin (NT) produces antipsychotic-like effects when injected into rodent brain through its effects at NT subtype 1 (NTS1) and 2 (NTS2) receptors. We hypothesized that the NT receptor agonist (NT69L) would prevent PPI disruption in mice challenged with d-amphetamine (10 mg kg(-1)) and dizocilpine (1 mg kg(-1)). We investigated the role of NTS1 and NTS2 in PPI using wild-type (WT), NTS1 (NTS1(-/-)) and NTS2 (NTS2(-/-)) knockout mice, via its disruption by psychotomimetic drugs, as well as the ability of clozapine and NT69L to block these PPI disruptions. There were no differences in baseline PPI across the three genotypes. d-Amphetamine and dizocilpine disrupted PPI in WT and NTS2(-/-) mice but not in NTS1(-/-) mice. In WT mice, clozapine (1 mg kg(-1)) and NT69L (1 mg kg(-1)) significantly blocked d-amphetamine-induced disruption of PPI. Similarly, in WT mice, clozapine significantly blocked dizocilpine-induced PPI disruption, but NT69L did not. In NTS2(-/-) mice clozapine blocked d-amphetamine-but not dizocilpine-induced PPI disruption, while NT69L blocked both d-amphetamine- and dizocilpine-induced PPI disruption. Our results indicate that NTS1 seems essential for d-amphetamine and dizocilpine disruption of PPI. Additionally, this report provides support to the hypothesis that NT analogs could be used as novel antipsychotic drugs.
Asunto(s)
Antipsicóticos/farmacología , Clozapina/farmacología , Dextroanfetamina/farmacología , Maleato de Dizocilpina/farmacología , Neurotensina/análogos & derivados , Fragmentos de Péptidos/farmacología , Receptores de Neurotensina/fisiología , Reflejo de Sobresalto/genética , Filtrado Sensorial/genética , Animales , Eliminación de Gen , Genotipo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos/fisiología , Neurotensina/farmacología , Receptores de Neurotensina/genética , Receptores de Neurotensina/metabolismo , Reflejo de Sobresalto/efectos de los fármacos , Filtrado Sensorial/efectos de los fármacosRESUMEN
Due to the putative involvement of dopaminergic circuits in depression, triple reuptake inhibitors are being developed as a new class of antidepressant, which is hypothesized to produce a more rapid onset and better efficacy than current antidepressants selective for serotonin or norepinephrine neurotransmission. (1S,2S)-3-(Methylamino)-2-(naphthalen-2-yl)-1-phenylpropan-1-ol (PRC200-SS), a new triple reuptake inhibitor, potently bound to the human serotonin, norepinephrine, and dopamine transporters with K(d) values of 2.3, 0.63, and 18 nM, respectively. Inhibition of serotonin, norepinephrine, and dopamine uptake by PRC200-SS was also shown in cells expressing the corresponding transporter (K(i) values of 2.1, 1.5, and 61 nM, respectively). In vivo, PRC200-SS dose-dependently decreased immobility in the forced-swim test in rats and in the tail-suspension test in mice, models predictive of antidepressant activity, with effects comparable with imipramine. These results in the behavioral models did not seem to result from the stimulation of locomotor activity. Consistent with the in vitro data and behavioral effects, peripheral administration of PRC200-SS (5 and 10 mg/kg i.p.) significantly increased extracellular levels of serotonin and norepinephrine in the medial prefrontal cortex, and of serotonin and dopamine in the core of nucleus accumbens, with reduction of levels of 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid compared with levels for saline control. Furthermore, PRC200-SS self-administration, which was used as a marker of abuse liability, was not observed with rats. Therefore, it seems that PRC200-SS may represent a novel triple reuptake inhibitor and possess antidepressant activity.
Asunto(s)
Inhibidores de Captación Adrenérgica/farmacología , Antidepresivos/farmacología , Inhibidores de Captación de Dopamina/farmacología , Naftalenos/farmacología , Propanolaminas/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Dopamina/metabolismo , Suspensión Trasera , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Norepinefrina/metabolismo , Ratas , Ratas Sprague-Dawley , Autoadministración , Serotonina/metabolismoRESUMEN
NT69L, is a novel neurotensin (8-13) analog that participates in the modulation of the dopaminergic pathways implicated in addiction to psychostimulants. NT69L blocks nicotine-induced hyperactivity as well as the initiation and expression of sensitization in rats. Recent evidence suggests that stimulation of mesocorticolimbic dopamine system, with influences from the other monoamine systems, e.g. norepinephrine and serotonin, is involved in nicotine's reinforcing properties. The aim of the present study was to investigate the effect of pretreatment with NT69L on nicotine-induced changes in monoamine levels in the rat brain using in vivo microdialysis. Acute or chronic (0.4 mg/kg, sc, once daily for 2 weeks) administration of nicotine elicited increases in extracellular levels of dopamine, dopamine metabolites, norepinephrine, or serotonin in medial prefrontal cortex, nucleus accumbens shell, and core of rats. Pretreatment with NT69L (1 mg/kg, intraperitoneally, ip) administered 40 min before nicotine injection significantly attenuated the acute nicotine-evoked increases in norepinephrine levels in medial prefrontal cortex, dopamine and serotonin in nucleus accumbens shell. After chronic nicotine administration, pretreatment of NT69L markedly reversed the increase in dopamine levels in the nucleus accumbens core. NT69L's attenuation of some of the biochemical effects of acute and chronic nicotine is consistent with this peptide's attenuation of nicotine-induced behavioral effects. These data further support a role for NT69L or other neurotensin receptor agonists to treat nicotine addiction.
Asunto(s)
Monoaminas Biogénicas/metabolismo , Encéfalo/efectos de los fármacos , Neurotensina/análogos & derivados , Neurotensina/agonistas , Nicotina/farmacología , Fragmentos de Péptidos/farmacología , Animales , Encéfalo/metabolismo , Encéfalo/fisiopatología , Química Encefálica/efectos de los fármacos , Química Encefálica/fisiología , Dopamina/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/fisiología , Esquema de Medicación , Interacciones Farmacológicas/fisiología , Sistema Límbico/efectos de los fármacos , Sistema Límbico/metabolismo , Sistema Límbico/fisiopatología , Masculino , Microdiálisis , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/metabolismo , Vías Nerviosas/fisiopatología , Neurotensina/farmacología , Neurotensina/uso terapéutico , Agonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/uso terapéutico , Norepinefrina/metabolismo , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiopatología , Fragmentos de Péptidos/uso terapéutico , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiopatología , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismo , Tabaquismo/tratamiento farmacológico , Tabaquismo/metabolismo , Tabaquismo/fisiopatologíaRESUMEN
A series of recent studies has demonstrated that the molecules involved in regulation of neuronal plasticity are also involved in the mode of action of antidepressants and mood stabilizer drugs. Intracellular calcium signaling, energy metabolism, and neuronal plasticity can be influenced by inducing axonal remodeling and increasing levels of certain synaptic proteins. Because antipsychotic drugs are used as mood stabilizers our studies focused on a newly-marketed antipsychotic drug, paliperidone. We determined changes in rat synaptoneurosomal proteins after chronic treatment with paliperidone, lithium salt, or valproic acid in order to find similarities or differences between the mode of action of paliperidone and these two classical mood stabilizers. We determined differential protein expression profiles in prefrontal cortex (PFC) of male Sprague-Dawley rats (n = 4/group). Synaptoneurosomal-enriched preparations were obtained from PFC after chronic treatment with these three drugs. Proteins were separated by 2D-DIGE and identified by nano-LC-MS/MS. We observed similar protein expression profiles at the synaptoneurosomal level, suggesting that the mode of action for paliperidone is similar to that of lithium and valproic acid. However, the expression profile for paliperidone was more similar to that of lithium. Pathways affected in common by these two drugs included oxidative phosphorylation, electron transport, carbohydrate metabolism, and post-synaptic cytokinesis implicating the effects of these drugs in signaling pathways, energy metabolism, and synaptic plasticity.
Asunto(s)
Antimaníacos/farmacología , Isoxazoles/farmacología , Compuestos de Litio/farmacología , Proteínas del Tejido Nervioso/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Pirimidinas/farmacología , Ácido Valproico/farmacología , Animales , Antimaníacos/administración & dosificación , Antipsicóticos/administración & dosificación , Antipsicóticos/farmacología , Esquema de Medicación , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Isoxazoles/administración & dosificación , Compuestos de Litio/administración & dosificación , Masculino , Neuronas/efectos de los fármacos , Palmitato de Paliperidona , Proteoma/efectos de los fármacos , Pirimidinas/administración & dosificación , Ratas , Ratas Sprague-Dawley , Sinaptosomas/efectos de los fármacos , Ácido Valproico/administración & dosificaciónRESUMEN
Neurotensin (NT) is a neuropeptide that, for decades, has been implicated in the biology of schizophrenia. It is closely associated with, and is thought to modulate, dopaminergic and other neurotransmitter systems involved in the pathophysiology of various neuropsychiatric diseases, including schizophrenia. This review outlines the neurochemistry and function of the NT system and the data implicating its role in schizophrenia. The data suggest that NT receptor agonists have the potential to be used as novel therapeutic agents for the treatment of schizophrenia, with the added benefits of (i) not causing weight gain, an adverse effect that is problematic with some of the currently used atypical antipsychotic drugs; and (ii) helping patients to stop smoking, a behaviour that is highly prevalent in those with schizophrenia.
Asunto(s)
Antipsicóticos/uso terapéutico , Neurotensina/agonistas , Neurotensina/fisiología , Esquizofrenia/tratamiento farmacológico , Animales , HumanosRESUMEN
NT69L is a neurotensin analog that can be administered peripherally. It blocks amphetamine- and cocaine-induced hyperactivity in rats. It also blocks nicotine-induced locomotor activity and has shown sustained efficacy in a rat model of nicotine-induced sensitization. The present study tested the effect of NT69L on responding for sucrose reinforcement on a continuous reinforcement schedule (CRF) and incrementing (FR1-FR5) discrimination schedule. Male Sprague-Dawley rats, on restricted food intake, were trained to press a lever for sucrose pellets on a CRF and incrementing discrimination schedule of reinforcement. On the following day, the testing session was followed by an extinction session, where lever pressing was not reinforced. Immediately after extinction, a reversal to CRF was implemented to test for relapse. Trained rats were injected with NT69L (1 mg/kg) or saline 30 min before each testing session. Dopamine, tyrosine 3-hydroxylase, and dopamine receptor mRNA levels were determined. NT69L significantly suppressed the lever pressing behavior for sucrose reinforcement on CRF which measures the "hedonic" value of the reward. NT69L also suppressed sucrose self-administration on the incrementing discrimination schedule of reinforcement (FR3-FR5) that is analogous to the motivational incentive. Reversal to CRF was significantly reduced by pretreatment with NT69L. The suppression of sucrose self-administration behavior by pretreatment with NT69L had a pattern similar to that for extinction. The effect of NT69L on dopamine, tyrosine 3-hydroxylase, and dopamine receptor mRNA levels is discussed relative to changes occurring during extinction.
Asunto(s)
Conducta Animal/fisiología , Encéfalo/metabolismo , Condicionamiento Operante/fisiología , Neurotensina/metabolismo , Receptores de Neurotensina/metabolismo , Refuerzo en Psicología , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Dopamina/metabolismo , Extinción Psicológica/efectos de los fármacos , Extinción Psicológica/fisiología , Privación de Alimentos/fisiología , Masculino , Neurotensina/análogos & derivados , Neurotensina/farmacología , Fragmentos de Péptidos/farmacología , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Dopaminérgicos/metabolismo , Receptores de Neurotensina/agonistas , Autoadministración , Sacarosa/farmacología , Tirosina 3-Monooxigenasa/genética , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Most currently prescribed antidepressants act by selectively increasing the synaptic availability of serotonin or norepinephrine, or through action on both serotonin and norepinephrine. However, most therapies require several weeks of treatment before improvement of symptoms is observed and not all patients respond to antidepressant treatment. One strategy that has emerged in new antidepressant development is the use of triple reuptake inhibitors, which inhibit reuptake of serotonin, norepinephrine, and dopamine. These compounds have been hypothesized to have a more rapid onset of activity and better efficacy over single or dual reuptake inhibitor antidepressants in part due to the addition of the dopamine component. We have developed novel compounds that are analogs of venlafaxine, of which two, racemic PRC025 ((2SR, 3RS)-N,N-dimethyl-3-cyclohexyl-3-hydroxy-2-(2'-naphthyl)propylamine) and PRC050 ((2RS,3RS)-N-methyl-3-hydroxy-2-(2'-naphthyl)-3-phenylpropylamine), are highly potent at human serotonin, norepinephrine, and dopamine transporters and inhibit the reuptake of serotonin, norepinephrine, and dopamine into rat brain synaptosomes. These compounds were tested in animal models used to evaluate potential antidepressants: the forced swim test in rats and the tail suspension test in mice. In the forced swim test, both PRC025 and PRC050 reduced the time spent immobile and increased the time spent swimming, comparable to the effects seen with imipramine, a tricyclic antidepressant. In addition, both PRC025 and PRC050 were effective in reducing the time spent immobile in the tail suspension test, again with effects comparable to imipramine. Therefore it appears that our compounds may possess antidepressant activity and represent a new class of triple reuptake inhibitors.
Asunto(s)
Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Naftalenos/farmacología , Inhibidores de la Captación de Neurotransmisores/farmacología , Propilaminas/farmacología , Animales , Dopamina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Norepinefrina/metabolismo , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismo , Sinaptosomas/metabolismoRESUMEN
Neurotensin (NT) is a 13-amino acid neuropeptide found in the central nervous system and in the gastrointestinal tract. It is closely associated anatomically with dopaminergic and other neurotransmitter systems, and evidence supports a role for NT agonists in the treatment of various neuropsychiatric disorders. However, NT is readily degraded by peptidases, so there is much interest in the development of stable NT agonists, that can be injected systemically, cross the blood-brain barrier (BBB), yet retains the pharmacological characteristics of native NT for therapeutic use in the treatment of diseases such as schizophrenia, Parkinson's disease and addiction.
Asunto(s)
Sistema Nervioso Central/efectos de los fármacos , Neurotensina/análogos & derivados , Animales , Antipsicóticos/farmacología , Conducta Animal/efectos de los fármacos , Sistema Nervioso Central/fisiología , Dopamina/metabolismo , Humanos , Drogas Ilícitas , Neurotensina/antagonistas & inhibidores , Neurotensina/farmacología , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/fisiopatología , Hormonas Adenohipofisarias/metabolismo , Psicotrópicos/farmacología , Receptores de Neurotensina/agonistas , Receptores de Neurotensina/efectos de los fármacos , Receptores de Neurotensina/fisiologíaRESUMEN
The effects of one or five daily intraperitoneal injections of a neurotensin (NT) receptor agonist NT69L (2 mg/kg, i.p.) on the expression of NT (NTS), dopamine 1 and 2 receptors, tyrosine hydroxylase, and DOPA decarboxylase using immunohistochemical and real-time PCR were investigated in rats. Except for the striatum, acute injection of NT69L did not affect neurotensin receptors as compared to saline control. However, 5 daily injections of NT69L resulted in down-regulation of both NTS-1 protein and mRNA levels in several brain regions with the striatum showing a dramatic decrease in NTS-1 expression (P<0.05). The down-regulation of NTS-1 in the striatum, hypothalamus, and substania nigra (SN) after 5 daily injections was confirmed by autoradiography. Acute injection of NT69L increased NTS-2 mRNA and protein level in prefrontal cortex (PFC). NTS-3 mRNA expression and protein levels were slightly down-regulated in hypothalamus, periaqueductal gray (PAG), and SN, though the difference was not significant. The results indicated a difference in the profile of NT receptors expression in response to NT69L. Tyrosine hydroxylase (TH) and DOPA decarboxylase (DDC) mRNA was significantly down-regulated in striatum but not in SN. Interestingly, Nurr 1, a transcriptional activator of TH, was dramatically up-regulated in striatum, but down-regulated in PFC, suggesting that different modulating mechanisms may participate in NT69L tolerance in different regions. The present results suggest that distinct NT receptors involved in the effects exerted by NT69L may contribute to the interactions of NT69L with both neural networks and cellular proteins.
Asunto(s)
Encéfalo/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Neurotensina/análogos & derivados , Fragmentos de Péptidos/administración & dosificación , Receptores de Neurotensina/metabolismo , Análisis de Varianza , Animales , Autorradiografía/métodos , Encéfalo/anatomía & histología , Encéfalo/metabolismo , Recuento de Células/métodos , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Dopa-Decarboxilasa/genética , Dopa-Decarboxilasa/metabolismo , Esquema de Medicación , Inmunohistoquímica/métodos , Masculino , Neurotensina/administración & dosificación , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares , ARN Mensajero/biosíntesis , Ratas , Ratas Sprague-Dawley , Receptores Dopaminérgicos/genética , Receptores Dopaminérgicos/metabolismo , Receptores de Neurotensina/clasificación , Receptores de Neurotensina/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Addiction to psychostimulant drugs such as nicotine, amphetamine, and cocaine is a serious public health problem for which there is a paucity of accepted forms of pharmacotherapy. Nicotine dependence has become more frequently associated with psychiatric illness in recent decades, and patients who have schizophrenia are at highest risk and have the poorest prognosis for stopping their addiction. Possible mechanisms for this association include self-medication, with nicotine attenuating attentional deficits and negative symptoms. Neurotensin has been postulated to be an endogenous neuroleptic, and the performance of neurotensin analogues in animal models of addiction makes such compounds intriguing candidates for treatment of addiction in high-risk psychiatric populations.
Asunto(s)
Encéfalo/fisiopatología , Estimulantes del Sistema Nervioso Central , Neurotensina/fisiología , Trastornos Relacionados con Sustancias/fisiopatología , Trastornos Relacionados con Sustancias/terapia , Tabaquismo/fisiopatología , Tabaquismo/terapia , Humanos , Cese del Hábito de Fumar/métodosRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disease associated with increased expression of amyloid precursor protein (APP) and the deposition of its proteolytic cleavage products, the amyloid-beta peptides, Abeta(1-40) and Abeta(1-42). Peptide nucleic acids (PNAs) have been shown to block the expression of proteins at transcriptional and translational levels. In this study we used a sense and an antisense PNA specifically targeted to APP to inhibit the transcription and translation of APP by complementary binding to DNA or mRNA, respectively. Using Western blotting, APP showed a drastic decrease (50% and 90% reduction, in two separate experiments, as compared with saline control) with the injection of sense APP. mRNA levels were higher at the same time point after injection of APP sense PNA, most probably because of a compensatory mechanism in response to the drop of APP that might have occurred at an earlier time point (0-1 h) and was reflected in a drop at the protein level at 1 h. The injection of antisense PNA showed about 70% decrease in APP as measured by Western blotting. Unmodified PNA can be used in vivo to reduce the levels of APP, which plays a critical role in the development of AD.
Asunto(s)
Precursor de Proteína beta-Amiloide/antagonistas & inhibidores , Encéfalo/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Ácidos Nucleicos de Péptidos/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/biosíntesis , Precursor de Proteína beta-Amiloide/genética , Animales , Elementos sin Sentido (Genética)/farmacología , Elementos sin Sentido (Genética)/uso terapéutico , Encéfalo/metabolismo , Encéfalo/fisiopatología , ADN/efectos de los fármacos , ADN/genética , Regulación hacia Abajo/fisiología , Masculino , Ácidos Nucleicos de Péptidos/uso terapéutico , Biosíntesis de Proteínas/efectos de los fármacos , Biosíntesis de Proteínas/genética , Inhibidores de la Síntesis de la Proteína/farmacología , Inhibidores de la Síntesis de la Proteína/uso terapéutico , ARN Mensajero/efectos de los fármacos , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/genética , Transcripción Genética/efectos de los fármacos , Transcripción Genética/genéticaRESUMEN
The effect of five daily intraperitoneal (i.p.) injections of NT69L on in vitro dopamine release, uptake, and [(3)H]NT binding in rat striatal tissue was investigated. NT69L perfusion increased K(+)-evoked and electrically evoked [(3)H]DA release. NT receptor-1 antagonist SR48692 inhibited the stimulatory effect of NT69L on K+-evoked [(3)H]DA release, but not on electrical depolarization. Pretreatment with NT69L, in vivo, daily for 5 days, did not cause significant change in K(+) evoked [(3)H]DA release, but reduced electrically evoked [(3)H]DA release induced by NT69L perfusion. Repeated perfusion with NT69L in vitro caused marked reduction on K(+)-evoked [(3)H]DA release and no change in electrically evoked [(3)H]DA release. [(3)H]NT binding was not significantly changed by one injection but was decreased after five injections of NT69L. Desensitization to the effects of NT69L in vitro was different depending upon whether tissue was preexposed to the compound in vivo or in vitro. These results provide further proof for the involvement of different NT receptor subtypes in mediating the effect of NT69L on dopamine release evoked by K(+) or electrical depolarization.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Neurotensina/análogos & derivados , Neurotensina/administración & dosificación , Fragmentos de Péptidos/administración & dosificación , Animales , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica/métodos , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Neurotensin is a tridecapeptide that participates in regulation of dopaminergic pathways implicated in nicotine addiction. Previously, we showed that one of our brain-penetrating neurotensin analogs, NT69L, blocks nicotine-induced locomotor sensitization. The present work demonstrates that NT69L blocks both the initiation and the expression of sensitization. In addition chronic NT69L administration blocked the acute effects of nicotine on norepinephrine and serotonin in prefrontal cortex.
Asunto(s)
Encéfalo/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Neurotensina/análogos & derivados , Neurotensina/farmacología , Fragmentos de Péptidos/farmacología , Animales , Encéfalo/metabolismo , Cromatografía Líquida de Alta Presión , Dopamina/análisis , Dopamina/metabolismo , Estimulantes Ganglionares/farmacología , Masculino , Actividad Motora/fisiología , Nicotina/farmacología , Norepinefrina/análisis , Norepinefrina/metabolismo , Ratas , Ratas Sprague-Dawley , Serotonina/análisis , Serotonina/metabolismo , Factores de TiempoRESUMEN
NT69L, a neurotensin analog that crosses the blood-brain barrier, reduces body temperature, reverses apomorphine-induced climbing, haloperidol-induced catalepsy, and D-amphetamine- and cocaine-induced locomotor activity in rats. In this study we tested the development of tolerance to these effects of NT69L in rats. The blockade of apomorphine-induced climbing behavior and D-amphetamine- and cocaine-induced hyperactivity seen after a single acute injection did not show significant change with repeated daily injections of NT69L. Thus, for example, NT69L after five daily injections at a fixed dosage was as effective at reversing cocaine-induced hyperactivity as after the first injection. On the other hand, repeated daily injections of NT69L resulted in a diminished hypothermic response and a diminished anticataleptic effect against haloperidol. The effect of NT69L on blood glucose, cortisol, and thyroxine (T(4)) were all back to control levels after five daily injections. Thus, tolerance developed to NT69L after the first injection, when it was tested for causing hypothermia, blockade of haloperidol-induced catalepsy, and change in blood glucose, cortisol and T(4) levels. Since tolerance did not develop to the effects of drugs acting as direct (apomorphine) or indirect (D-amphetamine and cocaine) agonists at dopamine receptors over the course of 5 days, these findings suggest a selective role of neurotensin in the modulation of dopamine neurotransmission. Furthermore, due to the lack of development of tolerance, NT69L or similar analogs might be useful in modulating certain behavioral effects of psychostimulants or have potential use as an antipsychotic drug in humans.
Asunto(s)
Conducta Animal/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Catalepsia/tratamiento farmacológico , Tolerancia a Medicamentos , Hipercinesia/tratamiento farmacológico , Neurotensina/análogos & derivados , Neurotensina/farmacología , Fragmentos de Péptidos/farmacología , Anfetamina , Animales , Glucemia/efectos de los fármacos , Barrera Hematoencefálica , Encéfalo/efectos de los fármacos , Catalepsia/inducido químicamente , Cocaína , Haloperidol , Hipercinesia/inducido químicamente , Hipotermia/inducido químicamente , Masculino , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Neurotensin is a tridecapeptide with anatomic and functional relationships to dopaminergic neurons. Previously we showed that one of our brain-penetrating neurotensin analogs, NT69L (N-met-L-Arg, L-Lys, L-Pro, L-neo-Trp, L-tert-Leu, L-Leu), blocks cocaine- and D-amphetamine-induced hyperactivity in rats. We have now performed a similar study in rats sensitized to nicotine over 15 days of administration. Male Sprague-Dawley rats were randomly assigned to receive daily injections for 15 days with one of the following combinations: saline/nicotine (0.35 mg/kg), NT69L (1 mg/kg)/nicotine, saline/saline, or NT69L/saline with a 30-min period between injections. On day 15 each group was given saline/nicotine or NT69L/nicotine and tested in an activity chamber. One-time administration of NT69L attenuated nicotine-induced activity with an ED(50) of 1.6 microg/kg. Rats injected with nicotine over the 15 days had a significant increase in locomotor activity, consistent with nicotine-induced locomotor sensitization. A single injection of NT69L on day 15 prior to nicotine markedly decreased nicotine-induced hyperactivity. Although daily injections of NT69L lessened its effect, statistically significant reductions in hyperactivity to nicotine persisted throughout the study. There was no significant difference in activity between rats injected with NT69L/saline and saline/saline. Thus, the activity reduction was not due to sedation. Acute and chronic nicotine injection caused an increase in cytisine binding in prefrontal cortex. NT69L significantly reduced the increase caused by acute but not chronic injection of nicotine. Nicotine injection resulted in an increase in dopamine levels in the striatum and dopamine and norepinephrine levels in the prefrontal cortex. NT69L lowered the norepinephrine and dopamine levels in the prefrontal cortex but did not affect striatal dopamine. The present study is the first report, to our knowledge, of a possible role for neurotensin in the development of nicotine dependence, and suggests that neurotensin analogs such as NT69L may be explored as treatment for nicotine and other psychostimulant abuse.
Asunto(s)
Actividad Motora/efectos de los fármacos , Neurotensina/análogos & derivados , Neurotensina/farmacología , Nicotina/administración & dosificación , Fragmentos de Péptidos/farmacología , Alcaloides/metabolismo , Animales , Azocinas , Conducta Animal/efectos de los fármacos , Unión Competitiva/efectos de los fármacos , Encéfalo/metabolismo , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Masculino , Norepinefrina/metabolismo , Quinolizinas , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D2/metabolismo , TritioRESUMEN
Neurotensin (NT) is a neuropeptide found in the central nervous system and gastrointestinal tract. It is closely associated with dopaminergic and other neurotransmitter systems, and evidence supports a role for NT in various neuropsychiatric disorders. Because NT is readily degraded by peptidases, our group has developed various NT agonists that can be injected systemically, cross the blood brain barrier (BBB), yet retain the characteristics of native NT. The most widely studied and successful of these compounds, called NT69L, holds promise as a therapeutic agent for Parkinson's disease, schizophrenia, psychostimulant abuse and nicotine dependence, and serves as a tool to study the cellular and molecular effects of NT.
Asunto(s)
Encéfalo/metabolismo , Proteínas del Tejido Nervioso , Neurotensina/análogos & derivados , Neurotensina/farmacocinética , Fragmentos de Péptidos/farmacocinética , Animales , Conducta Animal/efectos de los fármacos , Barrera Hematoencefálica , Agonistas de Dopamina/farmacología , Fosfoproteína 32 Regulada por Dopamina y AMPc , Humanos , Neurotensina/farmacología , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Fragmentos de Péptidos/farmacología , Fosfoproteínas/fisiología , RatasRESUMEN
Although many neuropeptides have been implicated in the pathophysiology of psychostimulant abuse, the tridecapeptide neurotensin holds a prominent position in this field due to the compelling literature on this peptide and psychostimulants. These data strongly support the hypothesis that a neurotensin agonist will be clinically useful to treat the abuse of psychostimulants, including nicotine. This paper reviews the evidence for a role for neurotensin in stimulant abuse and for a neurotensin agonist for its treatment.