RESUMEN
Depression and substance use disorder (SUD) often co-exist and are typically associated with an inaccurate diagnosis, worsened clinical course and poor medication adherence compared to either disorder alone. To date, the biological mechanisms contributing to their strong association remain largely unknown. In this review, we critically analyze preclinical literature on psychostimulant drugs and reconsider the common view that depression is a risk factor for drug use and the development of SUD. Unexpectedly, this investigation led us to conclude that depressive-like states in rodents are associated with a low predisposition to drug intake, at least when considering initial, voluntary and regulated psychostimulant intake. We identified several conceptual gaps and methodological challenges potentially misleading when modeling depression and SUD comorbidity. On the basis of these observations, we propose new innovative perspectives to guide future experiments and advance our knowledge in this field, including the use of newly refined rodent models that better capture hallmarks of depression and SUD.
Asunto(s)
Depresión , Trastornos Relacionados con Sustancias , Comorbilidad , Trastorno Depresivo , Humanos , Factores de RiesgoRESUMEN
Evidence accumulates suggesting a complex interplay between neurodegenerative processes and serotonergic neurotransmission. We have previously reported an overexpression of serotonin 5-HT1A receptors (5-HT(1A)R) after intrahippocampal injections of amyloid-beta 1-40 (Aß40) fibrils in rats. This serotonergic reactivity paralleled results from clinical positron emission tomography studies with [(18)F]MPPF revealing an overexpression of 5-HT(1A)R in the hippocampus of patients with mild cognitive impairment. Because Aß40 and Aß42 isoforms are found in amyloid plaques, we tested in this study the hypothesis of a peptide- and region-specific 5-HT(1A)R reactivity by injecting them, separately, into the hippocampus or striatum of rats. [(18)F]MPPF in vitro autoradiography revealed that Aß40 fibrils, but not Aß42, were triggering an overexpression of 5-HT(1A)R in the hippocampus and striatum of rat brains after 7 days. Immunohistochemical approaches targeting neuronal precursor cells, mature neurons, and astrocytes showed that Aß42 fibrils caused more pathophysiological damages than Aß40 fibrils. The mechanisms of Aß40 fibrils-induced 5-HT(1A)R expression remains unknown, but hypotheses including neurogenesis, glial expression, and axonal sprouting are discussed.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/administración & dosificación , Cuerpo Estriado/metabolismo , Hipocampo/metabolismo , Fragmentos de Péptidos/administración & dosificación , Receptores de Serotonina 5-HT1/metabolismo , Animales , Disfunción Cognitiva/metabolismo , Cuerpo Estriado/diagnóstico por imagen , Modelos Animales de Enfermedad , Hipocampo/diagnóstico por imagen , Inmunohistoquímica , Inyecciones , Masculino , Placa Amiloide/metabolismo , Tomografía de Emisión de Positrones , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Major depression has multiple comorbidities, in particular drug use disorders, which often lead to more severe and difficult-to-treat illnesses. However, the mechanisms linking these comorbidities remain largely unknown. METHODS: We investigated how a depressive-like phenotype modulates cocaine-related behaviors using a genetic model of depression: the Helpless H/Rouen (H) mouse. We selected the H mouse line for its long immobility duration in the tail suspension test when compared to non-helpless (NH) and intermediate (I) mice. Since numerous studies revealed important sex differences in drug addiction and depression, we conducted behavioral experiments in both sexes. RESULTS: All mice, regardless of phenotype or sex, developed a similar behavioral sensitization after 5 daily cocaine injections (10 mg/kg). Male H and NH mice exhibited similar cocaine-induced conditioned place preference scores that were only slightly higher than in I mice, whereas female H mice strikingly accrued much higher preferences for the cocaine-associated context than those of I and NH mice. Moreover, female H mice acquired cocaine-associated context learning much faster than I and NH mice, a facilitating effect that was associated to a rapid increase in striatal and accumbal brain-derived neurotrophic factor levels (BDNF; up to 35% 24 h after cocaine conditioning). Finally, when re-exposed to the previously cocaine-associated context, female H mice displayed greater Fos activation in the cingulate cortex, nucleus accumbens, and basolateral amygdala. CONCLUSIONS: Our data indicate that neurobiological mechanisms such as alterations in associative learning, striato-accumbal BDNF expression, and limbic-cortico-striatal circuit reactivity could mediate enhanced cocaine vulnerability in female depressive-like mice.
Asunto(s)
Encéfalo/fisiopatología , Trastornos Relacionados con Cocaína/fisiopatología , Condicionamiento Psicológico/fisiología , Trastorno Depresivo/fisiopatología , Caracteres Sexuales , Acatisia Inducida por Medicamentos/fisiopatología , Animales , Encéfalo/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cocaína/farmacología , Condicionamiento Psicológico/efectos de los fármacos , Modelos Animales de Enfermedad , Inhibidores de Captación de Dopamina/farmacología , Femenino , Masculino , Memoria/efectos de los fármacos , Memoria/fisiología , Ratones , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Conducta Espacial/efectos de los fármacos , Conducta Espacial/fisiología , Factores de TiempoRESUMEN
Discontinuation of drug intake in cocaine abusers commonly produces a variety of adverse withdrawal symptoms among which anxiety and depression-related behavior are prevailing during the initial period of abstinence. The aim of this study was to provide further insight into the neurobiological dysregulations that might contribute to these pathological states. Rats were treated with cocaine or saline for 14 days (20 mg/kg; i.p) and anxiety-related behavior was assessed in different paradigms (elevated plus-maze (EPM), confinement to an open arm of the EPM and shock-probe burying tests) for up to 4 weeks after withdrawal. Depression-like behavior was assessed by the forced swim test and sucrose preference test. Altogether our results demonstrated that cocaine withdrawal induced persistent heightened levels of anxiety that last for at least 28 days but did not affect depression-like behavior. We then used Fos immunohistochemistry to map neuronal activation patterns in withdrawn rats confined to one open arm of an EPM, and a double labeling procedure using Fos immunohistochemistry and in situ hybridization of glutamic acid decarboxylase or vesicular glutamate transporter mRNAs to identify the phenotype of the activated neurons. Our data showed that the exacerbated anxiety observed in cocaine withdrawn rats exposed to an elevated open arm was accompanied by an altered reactivity of the dorsal part of the medial prefrontal cortex (anterior cingulate and dorsal prelimbic cortices), the paraventricular thalamic nucleus and the lateral and anterior areas of the hypothalamus. In the medial prefrontal cortex, we evidenced a negative correlation between Fos expression in its dorsal part and open arm-induced freezing in NaCl-treated rats but not in cocaine withdrawn rats. We also found that more than 65% of activated neurons were glutamatergic projection neurons. The present study provides new insights into the neuroanatomical regions and neuronal cell types that may underlie pathological anxiety during cocaine withdrawal.
Asunto(s)
Ansiedad/metabolismo , Ansiedad/fisiopatología , Cocaína/efectos adversos , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiopatología , Síndrome de Abstinencia a Sustancias/metabolismo , Síndrome de Abstinencia a Sustancias/fisiopatología , Animales , Ansiedad/etiología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
STUDY OBJECTIVES: To determine whether sublaterodorsal tegmental nucleus (SLD) neurons triggering paradoxical (REM) sleep (PS) are glutamatergic. DESIGN: Three groups of rats were used: controls, rats deprived of PS for 72 h, and rats allowed to recover for 3 h after deprivation. Brain sections were processed for double labeling combining Fos immunohistochemistry and vesicular glutamate transporter 2 (vGLUT2) in situ hybridization. MEASUREMENTS AND RESULTS: The number of single Fos+ and Fos/vGLUT2+ double-labeled neurons was counted for each experimental condition. A very large number of Fos+ neurons expressing vGLUT2 mRNA specifically after PS hypersomnia was counted in the SLD. These double-labeled cells accounted for 84% of the total number of Fos+ cells. CONCLUSIONS: This finding adds further evidence to the concept that PS-on neurons of the SLD generating PS are of small size and glutamatergic in nature. By means of their descending projections to medullary and/or spinal glycinergic/GABAergic premotoneurons, they may be especially important for the induction of muscle atonia during PS, a disturbed phenomenon in narcolepsy and REM sleep behavior disorder.
Asunto(s)
Tronco Encefálico/fisiología , Sueño REM/fisiología , Sistema de Transporte de Aminoácidos X-AG/fisiología , Animales , Tronco Encefálico/anatomía & histología , Electroencefalografía , Electromiografía , Transportador de Glucosa de Tipo 2/fisiología , Hibridación in Situ , Neuronas/fisiología , Ratas , Receptores de Glutamato/fisiologíaRESUMEN
Current antidepressants still display unsatisfactory efficacy and a delayed onset of therapeutic action. Here we show that the pharmacological blockade of serotonin 7 (5-HT(7)) receptors produced a faster antidepressant-like response than the commonly prescribed antidepressant fluoxetine. In the rat, the selective 5-HT(7) receptor antagonist SB-269970 counteracted the anxiogenic-like effect of fluoxetine in the open field and exerted an antidepressant-like effect in the forced swim test. In vivo, 5-HT(7) receptors negatively regulate the firing activity of dorsal raphe 5-HT neurons and become desensitized after long-term administration of fluoxetine. In contrast with fluoxetine, a 1-week treatment with SB-269970 did not alter 5-HT firing activity but desensitized cell body 5-HT autoreceptors, enhanced the hippocampal cell proliferation, and counteracted the depressive-like behavior in olfactory bulbectomized rats. Finally, unlike fluoxetine, early-life administration of SB-269970, did not induce anxious/depressive-like behaviors in adulthood. Together, these findings indicate that the 5-HT(7) receptor antagonists may represent a new class of antidepressants with faster therapeutic action.
Asunto(s)
Antidepresivos/farmacología , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/metabolismo , Fenoles/farmacología , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Sulfonamidas/farmacología , Animales , Antidepresivos/uso terapéutico , Trastorno Depresivo/inducido químicamente , Modelos Animales de Enfermedad , Masculino , Fenoles/uso terapéutico , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Receptores de Serotonina/fisiología , Antagonistas de la Serotonina/uso terapéutico , Sulfonamidas/uso terapéuticoRESUMEN
A recent [(18)F]MPPF-positron emission tomography study has highlighted an overexpression of 5-HT(1A) receptors in the hippocampus of patients with mild cognitive impairment compared to a decrease in those with Alzheimer's disease (AD) [Truchot, L., Costes, S.N., Zimmer, L., Laurent, B., Le Bars, D., Thomas-Antérion, C., Croisile, B., Mercier, B., Hermier, M., Vighetto, A., Krolak-Salmon, P., 2007. Up-regulation of hippocampal serotonin metabolism in mild cognitive impairment. Neurology 69 (10), 1012-1017]. We used in vivo and in vitro neuroimaging to evaluate the longitudinal effects of injecting amyloid-ß (Aß) peptides (1-40) into the dorsal hippocampus of rats. In vivo microPET imaging showed no significant change in [(18)F]MPPF binding in the dorsal hippocampus over time, perhaps due to spatial resolution. However, in vitro autoradiography with [(18)F]MPPF (which is antagonist) displayed a transient increase in 5-HT(1A) receptor density 7 days after Aß injection, whereas [(18)F]F15599 (a radiolabelled 5-HT(1A) agonist) binding was unchanged suggesting that the overexpressed 5-HT(1A) receptors were in a non-functional state. Complementary histology revealed a loss of glutamatergic neurons and an intense astroglial reaction at the injection site. Although a neurogenesis process cannot be excluded, we propose that Aß injection leads to a transient astroglial overexpression of 5-HT(1A) receptors in compensation for the local neuronal loss. Exploration of the functional consequences of these serotoninergic modifications during the neurodegenerative process may have an impact on therapeutics targeting 5-HT(1A) receptors in AD.
Asunto(s)
Péptidos beta-Amiloides/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Fragmentos de Péptidos/farmacología , Receptor de Serotonina 5-HT1A/metabolismo , Alanina/análogos & derivados , Alanina/farmacocinética , Animales , Autorradiografía/métodos , Radioisótopos de Flúor/farmacocinética , Proteína Ácida Fibrilar de la Glía/metabolismo , Hipocampo/diagnóstico por imagen , Tomografía de Emisión de Positrones , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismo , Proteína 1 de Transporte Vesicular de Glutamato/metabolismoRESUMEN
We recently discovered, using Fos immunostaining, that the tuberal and mammillary hypothalamus contain a massive population of neurons specifically activated during paradoxical sleep (PS) hypersomnia. We further showed that some of the activated neurons of the tuberal hypothalamus express the melanin concentrating hormone (MCH) neuropeptide and that icv injection of MCH induces a strong increase in PS quantity. However, the chemical nature of the majority of the neurons activated during PS had not been characterized. To determine whether these neurons are GABAergic, we combined in situ hybridization of GAD(67) mRNA with immunohistochemical detection of Fos in control, PS deprived and PS hypersomniac rats. We found that 74% of the very large population of Fos-labeled neurons located in the tuberal hypothalamus after PS hypersomnia were GAD-positive. We further demonstrated combining MCH immunohistochemistry and GAD(67)in situ hybridization that 85% of the MCH neurons were also GAD-positive. Finally, based on the number of Fos-ir/GAD(+), Fos-ir/MCH(+), and GAD(+)/MCH(+) double-labeled neurons counted from three sets of double-staining, we uncovered that around 80% of the large number of the Fos-ir/GAD(+) neurons located in the tuberal hypothalamus after PS hypersomnia do not contain MCH. Based on these and previous results, we propose that the non-MCH Fos/GABAergic neuronal population could be involved in PS induction and maintenance while the Fos/MCH/GABAergic neurons could be involved in the homeostatic regulation of PS. Further investigations will be needed to corroborate this original hypothesis.
Asunto(s)
Trastornos de Somnolencia Excesiva/fisiopatología , Hipotálamo/fisiología , Neuronas/metabolismo , Sueño REM/fisiología , Ácido gamma-Aminobutírico/metabolismo , Animales , Trastornos de Somnolencia Excesiva/genética , Trastornos de Somnolencia Excesiva/metabolismo , Electroencefalografía , Electromiografía , Hormonas Hipotalámicas/genética , Hormonas Hipotalámicas/metabolismo , Hipotálamo/metabolismo , Inmunohistoquímica , Hibridación in Situ , Técnicas In Vitro , Masculino , Melaninas/genética , Melaninas/metabolismo , Neuronas/citología , Hormonas Hipofisarias/genética , Hormonas Hipofisarias/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Ácido gamma-Aminobutírico/genéticaRESUMEN
Paradoxical sleep (PS) is a state characterized by cortical activation, rapid eye movements and muscle atonia. Fifty years after its discovery, the neuronal network responsible for the genesis of PS has been only partially identified. We recently proposed that GABAergic neurons would have a pivotal role in that network. To localize these GABAergic neurons, we combined immunohistochemical detection of Fos with non-radioactive in situ hybridization of GAD67 mRNA (GABA synthesis enzyme) in control rats, rats deprived of PS for 72 h and rats allowed to recover after such deprivation. Here we show that GABAergic neurons gating PS (PS-off neurons) are principally located in the ventrolateral periaqueductal gray (vlPAG) and the dorsal part of the deep mesencephalic reticular nucleus immediately ventral to it (dDpMe). Furthermore, iontophoretic application of muscimol for 20 min in this area in head-restrained rats induced a strong and significant increase in PS quantities compared to saline. In addition, we found a large number of GABAergic PS-on neurons in the vlPAG/dDPMe region and the medullary reticular nuclei known to generate muscle atonia during PS. Finally, we showed that PS-on neurons triggering PS localized in the SLD are not GABAergic. Altogether, our results indicate that multiple populations of PS-on GABAergic neurons are distributed in the brainstem while only one population of PS-off GABAergic neurons localized in the vlPAG/dDpMe region exist. From these results, we propose a revised model for PS control in which GABAergic PS-on and PS-off neurons localized in the vlPAG/dDPMe region play leading roles.
Asunto(s)
Proteínas Transportadoras de GABA en la Membrana Plasmática/metabolismo , Glutamato Descarboxilasa/biosíntesis , Neuronas/metabolismo , Sueño REM/fisiología , Ácido gamma-Aminobutírico/metabolismo , Animales , Tronco Encefálico , Trastornos de Somnolencia Excesiva/metabolismo , Masculino , Muscimol/farmacología , Perfusión , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Privación de SueñoRESUMEN
This study examined the long-term effects of the antidepressant escitalopram on rat serotonin (5-HT) neuronal activity and hippocampal neuroplasticity. In the dorsal raphe nucleus, a 2-week treatment with escitalopram (10 mg/kg/day, subcutaneous) did not modify the firing activity of 5-HT neurons, whereas a cotreatment with R-citalopram (20 mg/kg/day, subcutaneous) decreased it. In the dentate gyrus of dorsal hippocampus, escitalopram increased significantly (57%) the number of de novo cells and this was prevented by a cotreatment with R-citalopram. The present results support the role of the allosteric modulation of the 5-HT transporter in the regulation of the recovery of 5-HT neuronal activity and long-lasting hippocampal cellular plasticity induced by escitalopram, two adaptive changes presumably associated with the antidepressant response.
Asunto(s)
Adaptación Fisiológica/efectos de los fármacos , Antidepresivos/farmacología , Citalopram/farmacología , Neuronas/fisiología , Animales , Antidepresivos/química , Proliferación Celular/efectos de los fármacos , Citalopram/química , Espacio Extracelular/efectos de los fármacos , Espacio Extracelular/metabolismo , Hipocampo/citología , Hipocampo/efectos de los fármacos , Masculino , Plasticidad Neuronal/efectos de los fármacos , Neuronas/efectos de los fármacos , Núcleos del Rafe/citología , Núcleos del Rafe/efectos de los fármacos , Núcleos del Rafe/metabolismo , Ratas , Ratas Sprague-Dawley , Serotonina/fisiología , Estereoisomerismo , Relación Estructura-Actividad , Transmisión Sináptica/efectos de los fármacosRESUMEN
The ventral tegmental area (VTA), primary source of the mesocorticolimbic dopaminergic system, is regarded as a critical site for initiation of behavioural sensitization to psychostimulants. The present study was undertaken to identify the neural pathways converging on the VTA that are potentially implicated in this process. Rats were sensitized by a single exposure to amphetamine (5 mg/kg, s.c.). The distribution of VTA-projecting neurons activated by amphetamine was examined by combining retrograde transport of the cholera toxin beta subunit (CTb), injected into the VTA, with immunodetection of Fos. The quantitative analysis of CTb-Fos double labelling demonstrates that amphetamine induced a rapid activation of Fos in a large number of brain areas projecting to the VTA. More than half of the CTb-Fos double-labelled neurons were located in the prefrontal cortex, lateral preoptic area-lateral hypothalamus, pontomesencephalic tegmentum, dorsal raphe nucleus, ventral pallidum and nucleus accumbens. In addition, scattered CTb-Fos double-labelled cells were observed in many other VTA afferent structures, such as claustrum, lateral septum, diagonal band-magnocellular preoptic nucleus, deep mesencephalic nucleus, oral part of pontine reticular nucleus and dorsomedial tegmental area. This suggests that systemic amphetamine activates a wide population of neurons projecting to the VTA that may be important for the modulation of neurobehavioural plasticity produced by this psychostimulant.
Asunto(s)
Vías Aferentes/efectos de los fármacos , Anfetamina/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Área Tegmental Ventral/efectos de los fármacos , Vías Aferentes/citología , Animales , Recuento de Células , Toxina del Cólera/farmacología , Genes fos/genética , Inmunohistoquímica , Masculino , Microinyecciones , Plasticidad Neuronal/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Estimulación Química , Área Tegmental Ventral/citologíaRESUMEN
Neurons expressing VIP/PHI precursor mRNA have been localized in the interstitial nucleus of Cajal. Unilateral surgical cut through the medial forebrain bundle failed to influence VIP/PHI mRNA expression in the Cajal nucleus while brainstem hemisection or unilateral transection of the medial longitudinal fascicle reduced it markedly, ipsilateral to the knife cuts. Thus, in contrast to forebrain projecting VIP neurons in the rostral periaqueductal gray, VIP/PHI neurons in the Cajal nucleus project downwards, to the lower brainstem.
Asunto(s)
Cuerpos Enrollados , Neuronas , Péptido PHI/análisis , Péptido Intestinal Vasoactivo/análisis , Animales , Cuerpos Enrollados/química , Femenino , Masculino , Neuronas/química , ARN Mensajero/análisis , Ratas , Ratas Sprague-DawleyRESUMEN
Chronic use of psychostimulants induces enduringly increased responsiveness to a subsequent psychostimulant injection and sensitivity to drug-associated cues, contributing to drug craving and relapse. Neurotensin (NT), a neuropeptide functionally linked to dopaminergic neurons, was suggested to participate in these phenomena. We and others have reported that SR 48692, an NT receptor antagonist, given in pre- or co-treatments with cocaine or amphetamine, alters some behavioral effects of these drugs in rats. However, its efficacy when applied following repeated cocaine administration remains unknown. We, therefore, evaluated the ability of SR 48692, administered after a cocaine regimen, to interfere with the expression of locomotor sensitization and conditioned place preference (CPP) in rats. We demonstrated that the expression of locomotor sensitization, induced by four cocaine injections (15 mg/kg, i.p.) every other day and a cocaine challenge 1 week later, was attenuated by a subsequent 2-week daily administration of SR 48692 (1 mg/kg, i.p.). Furthermore, the expression of cocaine-induced CPP was suppressed by a 10-day SR 48692 treatment started after the conditioning period (four 15 mg/kg cocaine injections every other day). Taken together, our data show that a chronic SR 48692 treatment given after a cocaine regimen partly reverses the expression of locomotor sensitization and CPP in the rat, suggesting that NT participates in the maintenance of these behaviors. Our results support the hypothesis that targeting neuromodulatory systems, such as the NT systems may offer new strategies in the treatment of drug addiction.
Asunto(s)
Cocaína/efectos adversos , Condicionamiento Operante/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Pirazoles/administración & dosificación , Quinolinas/administración & dosificación , Receptores de Neurotensina/antagonistas & inhibidores , Síndrome de Abstinencia a Sustancias/fisiopatología , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Esquema de Medicación , Masculino , Ratas , Ratas Sprague-Dawley , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Factores de TiempoRESUMEN
Neurotensin exerts complex effects on the mesolimbic dopamine system that alter motivation and contribute to neuroadaptations associated with psychostimulant drug administration. Activation of abundant neurotensin receptors in the ventral tegmental area (VTA) enhances dopamine neuron activity and associated release of dopamine in the nucleus accumbens (Acb) and cortex. In view of recent anatomical studies demonstrating that 70% of all neurotensin-containing neurons projecting to the VTA occupy the lateral preoptic area-rostral lateral hypothalamus (LPH) and lateral part of the medial preoptic area (MPOA), the present study examined functionality in the LPH-MPOA neurotensinergic pathway in the rat. Disinhibition (resulting ultimately in stimulation-like effects) of LPH-MPOA neurons with microinjected bicuculline (50 or 100 ng in 0.25 microL) produced locomotor activation that was considerably attenuated by systemic administration of the neurotensin antagonist SR 142948 A (0.03 and 0.1 mg/kg). In contrast, locomotion elicited in this manner was completely blocked by SR 142948 A infused directly into the VTA (5.0 and 15.0 ng in 0.25 microL). Baseline locomotion was unaffected by systemic or intra-VTA administration of SR 142948 A and LPH-MPOA-elicited locomotion was unaffected by infusion of SR 142948 A into the substantia nigra pars compacta and sites rostral and dorsal to the VTA. Locomotion was not elicited by infusions of bicuculline into the lateral hypothalamus at sites caudal to the LPH-MPOA, where neurotensin neurons projecting to the VTA are fewer. The results demonstrate the capacity of a neurotensin-containing pathway from LPH-MPOA to VTA to modulate locomotion. This pathway may be important in linking hippocampal and mesolimbic mechanisms in normal behaviour and drug addiction.
Asunto(s)
Locomoción/efectos de los fármacos , Neurotensina/antagonistas & inhibidores , Prosencéfalo/efectos de los fármacos , Receptores de Neurotensina/antagonistas & inhibidores , Animales , Bicuculina/farmacología , Área Hipotalámica Lateral/efectos de los fármacos , Área Hipotalámica Lateral/fisiología , Masculino , Microinyecciones , Vías Nerviosas , Neurotensina/fisiología , Área Preóptica/efectos de los fármacos , Área Preóptica/fisiología , Prosencéfalo/anatomía & histología , Prosencéfalo/fisiología , Pirazoles/farmacología , Quinolinas/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Neurotensin (NT) is a peptide that is widely distributed throughout the brain. NT is involved in locomotion, reward, stress and pain modulation, and in the pathophysiology of drug addiction and depression. In its first part this review brings together relevant literature about the neuroanatomy of NT and its receptors. The second part focuses on functional-anatomical interactions between NT, the mesotelencephalic dopamine system and structures targeted by dopaminergic projections. Finally, recent data about the actions of NT in processes underlying behavioral sensitization to psychostimulant drugs and the involvement of NT in the regulation of the hypothalamo-pituitary-adrenal gland axis are considered.
Asunto(s)
Encéfalo/metabolismo , Neurotensina/metabolismo , Animales , Encéfalo/anatomía & histología , Encéfalo/efectos de los fármacos , Dopamina/metabolismo , Dopamina/farmacología , Humanos , Sistema Hipotálamo-Hipofisario/metabolismo , Neurotensina/genética , Sistema Hipófiso-Suprarrenal/metabolismo , Psicotrópicos/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores de Neurotensina/metabolismo , Estrés Fisiológico/metabolismoRESUMEN
Although many studies have revealed alterations in neurotransmission during ischaemia, few works have been devoted to the neurochemical effects of mild hypoxia, a situation encountered during life in altitude or in several pathologies. In that context, the present work was undertaken to determine the in vivo mechanisms underlying the striatal dopamine efflux induced by mild hypoxaemic hypoxia. For that purpose, the extracellular concentrations of dopamine and its metabolite 3,4-dihydroxyphenyl acetic acid were simultaneously measured using brain microdialysis during acute hypoxic exposure (10% O(2), 1h) in awake rats. Hypoxia induced a +80% increase in dopamine. Application of the dopamine transporters inhibitor, nomifensine (10 microM), just before the hypoxia prevented the rise in dopamine during the early part of hypoxia; in contrast the application of nomifensine after the beginning of hypoxia, failed to alter the increase in dopamine. Application of the voltage-dependent Na(+) channel blocker tetrodotoxin abolished the increase in dopamine, whether administered just before or after the beginning of hypoxia. These data show that the neurochemical mechanisms of the dopamine efflux may change over the course of the hypoxic exposure, dopamine transporters being involved only at the beginning of hypoxia.
Asunto(s)
Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Hipoxia Encefálica/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Ácido 3,4-Dihidroxifenilacético/metabolismo , Adaptación Fisiológica/efectos de los fármacos , Adaptación Fisiológica/fisiología , Animales , Cuerpo Estriado/fisiopatología , Modelos Animales de Enfermedad , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Inhibidores de Captación de Dopamina/farmacología , Líquido Extracelular/metabolismo , Hipoxia Encefálica/fisiopatología , Masculino , Glicoproteínas de Membrana/antagonistas & inhibidores , Moduladores del Transporte de Membrana , Proteínas de Transporte de Membrana/antagonistas & inhibidores , Microdiálisis , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Nomifensina/farmacología , Ratas , Ratas Sprague-Dawley , Bloqueadores de los Canales de Sodio/farmacología , Regulación hacia Arriba/fisiologíaRESUMEN
Recent findings have given evidence a role for noradrenergic transmission in the mechanisms underlying behavioural sensitization to psychostimulants. This work was undertaken to investigate the possible role of beta-adrenergic receptors in amphetamine-induced behavioural sensitization in rats. Rats were sensitized by a single administration of amphetamine (1 mg/kg s.c.) and challenged with the same dose 7 d later. The beta(1) /beta(2) -adrenergic receptor antagonists timolol (10 mg/kg i.p.) and nadolol (10 mg/kg i.p.), which respectively cross or do not readily cross the blood-brain barrier, were injected prior to the first or second amphetamine administration. Timolol, but not nadolol, prevented the initiation of behavioural sensitization without interfering with the expression of the sensitized response or the acute locomotor response to amphetamine. Since we found amphetamine-induced fos-activated cells closely associated with dopamine beta-hydroxylase immunoreactive varicosities in the bed nucleus of the stria terminalis (BNST), we investigated the effect of a bilateral micro-injection of timolol into this nucleus. Similarly to systemic administration, intra-BNST timolol (2.5 microg/side) prevented the development of behavioural sensitization. These results suggest that central beta-adrenergic receptors could specifically modulate early neuronal changes leading to the development of behavioural sensitization to psychostimulants, and that the BNST could be an important part of the brain circuitry involved in these long-term neuroadaptations.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Anfetamina/antagonistas & inhibidores , Conducta Animal/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/antagonistas & inhibidores , Núcleos Septales/fisiología , Antagonistas Adrenérgicos beta/administración & dosificación , Anfetamina/farmacología , Animales , Estimulantes del Sistema Nervioso Central/farmacología , Dopamina beta-Hidroxilasa/metabolismo , Genes fos/genética , Inmunohistoquímica , Masculino , Microinyecciones , Actividad Motora/efectos de los fármacos , Nadolol/farmacología , Fibras Nerviosas/efectos de los fármacos , Fibras Nerviosas/enzimología , Ratas , Ratas Sprague-Dawley , Timolol/administración & dosificación , Timolol/farmacologíaRESUMEN
Studies showing psychostimulant-like effects of exogenous neurotensin (NT) infused into the ventral tegmental area (VTA) prompted us to examine the role in the VTA of the endogenous NT in behavioral sensitization to amphetamine. Rats were sensitized to amphetamine by means of a subcutaneous amphetamine (1 mg/kg) injection, and the same dose was injected 7 days later to evaluate the expression of sensitization. The highly selective NT-receptor antagonist SR 142948A was injected into the VTA prior to the first and/or second amphetamine administration. SR 142948A (5 pmol/side) given before the first amphetamine exposure prevented the induction of behavioral sensitization, but did not alter the acute response to amphetamine. SR 142948A given with the second amphetamine administration did not affect the expression of behavioral sensitization. In contrast to administration into the VTA, intraperitoneal administration of SR 142948A (0.03, 0.1, or 0.3 mg/kg) had no detectable effect on the induction of amphetamine sensitization. These results suggest that activation of VTA NT receptors by endogenous NT may contribute to the neuroadaptations underlying behavioral sensitization to amphetamine.
Asunto(s)
Adamantano/análogos & derivados , Anfetamina/farmacología , Conducta Animal/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Neurotensina/fisiología , Área Tegmental Ventral/fisiología , Adamantano/administración & dosificación , Adamantano/farmacología , Animales , Estimulantes del Sistema Nervioso Central/antagonistas & inhibidores , Imidazoles/administración & dosificación , Imidazoles/farmacología , Inyecciones Subcutáneas , Masculino , Microinyecciones , Actividad Motora/efectos de los fármacos , Neurotensina/antagonistas & inhibidores , Neurotensina/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Neurotensina/antagonistas & inhibidores , Área Tegmental Ventral/metabolismoRESUMEN
In order to determine the influence of long-term prenatal hypoxia on the maturation of the brain catecholaminergic structures involved in motor and cognitive functions, pregnant rats were subjected to hypoxia (10% O2) from the 5th to 20th day of gestation. The in vivo activity of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, was assessed, by accumulation of L-DOPA after i.p. administration of NSD-1015, in the motor cortex areas, the hippocampus, and the striatum at birth and at the 3rd, 7th, 14th, 21st, and 68th postnatal days. The motor reactivity to novelty and the circadian motor activity were measured at the 21st and 68th postnatal days. Exposure to prenatal hypoxia strongly altered the developmental pattern of in vivo TH activity in restricted noradrenergic terminals of the brain. In the 21-day-old prenatal hypoxic rats, the TH activity was reduced by 80% in the motor cortex areas and by 43% in the hippocampus, compared to control rats, while no differences could be detected in the striatum. Compared to control rats, the prenatal hypoxic pups exhibited a higher motor reactivity to novelty and a nocturnal motor hypoactivity at the 21st postnatal day. The neurochemical and behavioral alterations were no longer observed at the 68th postnatal day. The altered in vivo TH activity in the young rats might be part of the neural mechanisms contributing to the motor behavioral impairments induced by prenatal hypoxia. Long-term prenatal hypoxia could be linked to the development of psychopathologies that can be detected in infancy.
Asunto(s)
Encéfalo/metabolismo , Catecolaminas/metabolismo , Hipoxia , Actividad Motora/fisiología , Efectos Tardíos de la Exposición Prenatal , Tiempo , Factores de Edad , Análisis de Varianza , Animales , Conducta Animal , Peso Corporal , Encéfalo/anatomía & histología , Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Química Encefálica/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Conducta Exploratoria , Femenino , Hidrazinas/farmacología , Hipoxia/metabolismo , Hipoxia/fisiopatología , Levodopa/metabolismo , Masculino , Tamaño de los Órganos , Embarazo , Ratas , Factores de Tiempo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
The effects of nitric oxide synthase (NOS) inhibitors were examined simultaneously on the behavior and on the catecholaminergic metabolism in the locus coeruleus (LC) during morphine withdrawal using microdialysis in freely moving rats. Morphine withdrawal was precipitated by naltrexone administration to morphine-treated rats. Acute pretreatment of rats with NOmicron-nitro-L-arginine-p-nitroanilide (L-NAPNA) or 7-nitroindazole (7-NI) before naltrexone challenge attenuated the behavioral expression of morphine withdrawal and strongly reduced the withdrawal-induced increase in 3,4-dihydroxyphenylacetic acid (DOPAC) in the LC. The two NOS inhibitors also decreased DOPAC in absence of naltrexone challenge. These results suggest a role for NO in the expression of morphine withdrawal syndrome that may be mediated, at least in part, by LC noradrenergic neurons.