RESUMEN
Our previous work has linked childhood violence exposure in Black youth to functional changes in the hippocampus, a brain region sensitive to stress. However, different contexts of violence exposure (e.g., community, home, school) may have differential effects on circuitry. We investigated the unique effect of community violence in predicting resting-state functional connectivity (rsFC) in the hippocampus. Fifty-two (26F) violence-exposed Black youth ages 8-15 performed resting-state functional neuroimaging scans while looking at a fixation cross for seven minutes with eyes open. Seed-based analyses were conducted to examine the association between total violence exposure and rsFC of the hippocampus to the whole brain. Follow-up hierarchical regression analysis were performed to specifically investigate community violence. Violence exposure was associated with higher hippocampus rsFC with a core node of the Default Mode Network (i.e., posterior cingulate cortex) and lower hippocampal rsFC with a core node of the Salience Network (i.e., insula). Community violence uniquely associated with lower hippocampus-insula rsFC, after controlling for home and school violence, sex and age. Age-related decreases in hippocampus-insula rsFC were also present in youth with lower violence exposure, but not in youth with higher violence exposure. This is one of the first studies to investigate the unique impact of community violence, above home and school violence, on threat circuitry. Our data suggest functional alterations in the hippocampus in violence-exposed youth, and that violence in the community may be a more salient form of threat exposure compared to other forms of violence experienced by youth.
Asunto(s)
Exposición a la Violencia , Adolescente , Encéfalo , Corteza Cerebral , Niño , Hipocampo/diagnóstico por imagen , Humanos , Imagen por Resonancia MagnéticaRESUMEN
Post-traumatic stress disorder (PTSD) develops in only some people following trauma exposure, but the mechanisms differentially explaining risk versus resilience remain largely unknown. PTSD is heritable but candidate gene studies and genome-wide association studies (GWAS) have identified only a modest number of genes that reliably contribute to PTSD. New gene-based methods may help identify additional genes that increase risk for PTSD development or severity. We applied gene-based testing to GWAS data from the Grady Trauma Project (GTP), a primarily African American cohort, and identified two genes (NLGN1 and ZNRD1-AS1) that associate with PTSD after multiple test correction. Although the top SNP from NLGN1 did not replicate, we observed gene-based replication of NLGN1 with PTSD in the Drakenstein Child Health Study (DCHS) cohort from Cape Town. NLGN1 has previously been associated with autism, and it encodes neuroligin 1, a protein involved in synaptogenesis, learning, and memory. Within the GTP dataset, a single nucleotide polymorphism (SNP), rs6779753, underlying the gene-based association, associated with the intermediate phenotypes of higher startle response and greater functional magnetic resonance imaging activation of the amygdala, orbitofrontal cortex, right thalamus and right fusiform gyrus in response to fearful faces. These findings support a contribution of the NLGN1 gene pathway to the neurobiological underpinnings of PTSD.
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Encéfalo/fisiopatología , Moléculas de Adhesión Celular Neuronal/genética , Trastornos por Estrés Postraumático/genética , Adulto , Negro o Afroamericano/genética , Amígdala del Cerebelo/diagnóstico por imagen , Amígdala del Cerebelo/fisiopatología , Encéfalo/diagnóstico por imagen , Expresión Facial , Reconocimiento Facial , Miedo , Femenino , Neuroimagen Funcional , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/fisiopatología , Reflejo de Sobresalto/fisiología , Trastornos por Estrés Postraumático/diagnóstico por imagen , Trastornos por Estrés Postraumático/fisiopatología , Trastornos por Estrés Postraumático/psicología , Lóbulo Temporal/diagnóstico por imagen , Lóbulo Temporal/fisiopatología , Tálamo/diagnóstico por imagen , Tálamo/fisiopatología , Población Blanca/genética , Adulto JovenRESUMEN
BACKGROUND: Crack cocaine dependence and addiction is typically associated with frequent and intense drug wanting or craving triggered by internal or environmental cues associated with past drug use. METHODS: Water O 15 positron emission tomography (PET) studies were used to localize alterations in synaptic activity related to cue-induced drug craving in 8 crack cocaine-dependent African American men. In a novel approach, script-guided imagery of autobiographical memories were used as individualized cues to internally generate a cocaine craving state and 2 control (ie, anger and neutral episodic memory recall) states during PET image acquisition. RESULTS: The mental imagery of personalized drug use and anger-related scripts was associated with self-ratings of robust drug craving or anger, and comparable alterations in heart rate. Compared with the neutral imagery control condition, imagery-induced drug craving was associated with bilateral (right hemisphere amygdala activation greater than left) activation of the amygdala, the left insula and anterior cingulate gyrus, and the right subcallosal gyrus and nucleus accumbens area. Compared with the anger control condition, internally generated drug craving was associated with bilateral activation of the insula and subcallosal cortex, left hippocampus, and anterior cingulate cortex and brainstem. A brain-wide pixel-by-pixel search indicated significant positive and negative correlations between imagery-induced cocaine craving and regional cerebral blood flow (rCBF) in distributed sites. CONCLUSIONS: The collected findings suggest the craving-related activation of a network of limbic, paralimbic, and striatal brain regions, including structures involved in stimulus-reward association (amygdala), incentive motivation (subcallosal gyrus/nucleus accumbens), and anticipation (anterior cingulate cortex).
Asunto(s)
Conducta Adictiva/psicología , Encéfalo/diagnóstico por imagen , Trastornos Relacionados con Cocaína/psicología , Tomografía Computarizada de Emisión/estadística & datos numéricos , Adulto , Ira/efectos de los fármacos , Ira/fisiología , Conducta Adictiva/diagnóstico por imagen , Conducta Adictiva/fisiopatología , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Trastornos Relacionados con Cocaína/diagnóstico por imagen , Trastornos Relacionados con Cocaína/fisiopatología , Cocaína Crack/administración & dosificación , Cocaína Crack/farmacología , Señales (Psicología) , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Humanos , Imaginación/fisiología , Masculino , Memoria/efectos de los fármacos , Memoria/fisiología , Radioisótopos de Oxígeno , Lectura , AguaRESUMEN
Fluorine-18 labeled 2beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(2-fluoroethyl)nort ropane (FECNT) was synthesized in the development of a dopamine transporter (DAT) imaging ligand for positron emission tomography (PET). The methods of radiolabeling and ligand synthesis of FECNT, and the results of the in vitro characterization and in vivo tissue distribution in rats and in vivo PET imaging in rhesus monkeys of [18F]FECNT are described. Fluorine-18 was introduced into 2beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(2-fluoroethyl)nort ropane (4) by preparation of 1-[18F]fluoro-2-tosyloxyethane (2) followed by alkylation of 2beta-carbomethoxy-3beta-(4-chlorophenyl)nortropane (3) in 21% radiochemical yield (decay corrected to end of bombardment [EOB]). Competition binding in cells stably expressing the transfected human DAT serotonin transporter (SERT) and norepinephrine transporter (NET) labeled by [3H]WIN 35428, [3H]citalopram, and [3H]nisoxetine, respectively, indicated the following order of DAT affinity: GBR 12909 > CIT >> 2beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(3-fluoropropyl) nortropane (FPCT) > FECNT. The affinity of FECNT for SERT and NET was 25- and 156-fold lower, respectively, than for DAT. Blocking studies were performed in rats with a series of transporter-specific agents and demonstrated that the brain uptake of [18F]FECNT was selective and specific for DAT-rich regions. PET brain imaging studies in monkeys demonstrated high [18F]FECNT uptake in the caudate and putamen that resulted in caudate-to-cerebellum and putamen-to-cerebellum ratios of 10.5 at 60 min. [18F]FECNT uptake in the caudate/putamen peaked in less than 75 min and exhibited higher caudate- and putamen-to-cerebellum ratios at transient equilibrium than reported for 11C-WIN 35,428, [11C]CIT/RTI-55, or [18F]beta-CIT-FP. Analysis of monkey arterial plasma samples using high performance liquid chromatography determined that there was no detectable formation of lipophilic radiolabeled metabolites capable of entering the brain. In equilibrium displacement experiments with CIT in rhesus monkeys, radioactivity in the putamen was displaced with an average half-time of 10.2 min. These results indicate that [18F]FECNT is a radioligand that is superior to 11C-WIN 35,428, [11C]CIT/RTI-55, [18F]beta-CIT-FP, and [18F]FPCT for mapping brain DAT in humans using PET.
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Encéfalo/diagnóstico por imagen , Proteínas Portadoras/metabolismo , Glicoproteínas de Membrana , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Nortropanos/metabolismo , Tomografía Computarizada de Emisión , Animales , Autorradiografía , Biotransformación , Encéfalo/metabolismo , Cromatografía Líquida de Alta Presión , Perros , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Radioisótopos de Flúor , Semivida , Humanos , Inyecciones Intravenosas , Ligandos , Macaca mulatta , Masculino , Ratones , Nortropanos/síntesis química , Ratas , Ratas Sprague-Dawley , Distribución TisularRESUMEN
This study examined the neural correlates of cue-induced anger in cocaine-dependent men in an initial investigation of possible neurobiological explanations for the putative association between cocaine addiction and violence. We used positron emission tomography (PET) to localize alterations in regional cerebral blood flow (rCBF) during mental imagery of a personal anger-associated scene and of an emotionally neutral scene in ten cocaine-dependent men. Compared to the emotionally neutral imagery control condition, anger was associated with marked decreases in rCBF in multiple areas of the frontal cortex (particularly the right inferior frontal gyrus), left posterior insula, left fusiform gyrus, and midbrain. Conversely, this same inferior frontal area was activated by anger imagery in nicotine-dependent men. Anger was also associated with increases in rCBF in the right fusiform gyrus, right and left middle occipital gyri, left post-central gyrus, left medial frontal gyrus, left cuneus, and in the left anterior cingulate gyrus. The study showed that cue-induced anger in cocaine-dependent men was associated with decreased activity in frontal cortical areas involved in response monitoring and inhibition. The lack of this association in nicotine-dependent men suggests a possible deficit in anger regulation associated with cocaine dependence and a possible link between cocaine dependence, violence, and relapse.
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Ira/fisiología , Trastornos Relacionados con Cocaína/fisiopatología , Lóbulo Frontal/fisiopatología , Imagen por Resonancia Magnética , Tomografía Computarizada de Emisión , Violencia/psicología , Adulto , Mapeo Encefálico , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/fisiopatología , Trastornos Relacionados con Cocaína/diagnóstico por imagen , Trastornos Relacionados con Cocaína/psicología , Dominancia Cerebral/fisiología , Lóbulo Frontal/diagnóstico por imagen , Humanos , Imaginación/fisiología , Masculino , Flujo Sanguíneo Regional/fisiología , Tabaquismo/diagnóstico por imagen , Tabaquismo/fisiopatología , Tabaquismo/psicologíaRESUMEN
Although the efficacy of lithium as a mood stabilizer is well documented, the mechanism of its therapeutic effect associated with prolonged treatment remains unknown. Identifying discrete brain regions and neural pathways that are functionally altered following long-term lithium treatment is central to elucidating a psychotherapeutic mechanism. We have used a sensitive and quantitative histochemical assay for the determination of cytochrome oxidase (CO) activity, a mitochondrial marker of neuronal activity, to determine the effect of repeated lithium treatment on regional neuronal activity in the rat brain. Oral lithium treatment (21 days) selectively decreased cytochrome oxidase activity in the cingulate cortex and regions of the nucleus accumbens. These decreases were not seen after 5 days of lithium administration, although serum lithium concentrations were similar after both 5 and 21 days of treatment. The analysis of interregional correlations further suggests a role for amygdala pathways in the effects of lithium following 21 days of treatment. The implications of these data for understanding the mechanisms of action of lithium are discussed.
Asunto(s)
Giro del Cíngulo/fisiología , Carbonato de Litio/farmacología , Neuronas/fisiología , Núcleo Accumbens/fisiología , Administración Oral , Animales , Biomarcadores , Esquema de Medicación , Complejo IV de Transporte de Electrones/análisis , Femenino , Giro del Cíngulo/efectos de los fármacos , Litio/sangre , Carbonato de Litio/administración & dosificación , Mitocondrias/enzimología , Neuronas/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Especificidad de Órganos , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Pleasant or aversive events are better remembered than neutral events. Emotional enhancement of episodic memory has been linked to the amygdala in animal and neuropsychological studies. Using positron emission tomography, we show that bilateral amygdala activity during memory encoding is correlated with enhanced episodic recognition memory for both pleasant and aversive visual stimuli relative to neutral stimuli, and that this relationship is specific to emotional stimuli. Furthermore, data suggest that the amygdala enhances episodic memory in part through modulation of hippocampal activity. The human amygdala seems to modulate the strength of conscious memory for events according to emotional importance, regardless of whether the emotion is pleasant or aversive.
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Amígdala del Cerebelo/fisiología , Emociones/fisiología , Memoria/fisiología , Adulto , Amígdala del Cerebelo/diagnóstico por imagen , Circulación Cerebrovascular/fisiología , Humanos , Masculino , Tomografía Computarizada de EmisiónRESUMEN
The endogenous tridecapeptide neurotensin exerts a wide range of behavioral, electrophysiological and neurochemical effects when administered directly into the brain. These effects are thought to result from the activation of distinct populations of neurotensin receptors distributed throughout the central nervous system. We have mapped the sites of functional change in the rat brain associated with the central administration of neurotensin using the induction of the nuclear protein products of the immediate early genes c-fos and zif268 as markers of cellular activation. The administration of neurotensin into the lateral ventricle of rats produced an increase in the number of nuclei positive for Fos and Zif268 immunoreactivity in the central and basolateral nuclei of the amygdala and the paraventricular and supraoptic nuclei of the hypothalamus. Neurotensin also produced an increase in serum corticosterone concentration and decrease in body temperature. The intraperitoneal administration of SR48692, a non-peptide neurotensin receptor antagonist, blocked the neurotensin-induced corticosterone secretion and significantly reduced the number of neurotensin-induced Fos-positive and Zif268-positive neurons in the amygdaloid complex. A significant positive correlation was found between the number of Fos-positive nuclei in the central or basolateral nucleus of the amygdala and the serum corticosterone concentration. A significant positive correlation was also found between the number of Zif-positive cells in the paraventricular nucleus of the hypothalamus and change in body temperature following treatment. Our findings indicate that the central role of neurotensin in increasing serum corticosterone involves the induction of Fos in the central and basolateral nuclei of the amygdala. In contrast, the neurotensin-induced hypothermia, which was unaffected by pretreatment with SR48692, involves Zif induction in the paraventricular nucleus of the hypothalamus. These data support further the existence of central neurotensin receptor subtypes which may regulate distinct immediate early genes.
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Ventrículos Cerebrales/fisiología , Proteínas de Unión al ADN/biosíntesis , Proteínas Inmediatas-Precoces , Sistema Límbico/metabolismo , Neurotensina/farmacología , Proteínas Proto-Oncogénicas c-fos/biosíntesis , Factores de Transcripción/biosíntesis , Amígdala del Cerebelo/metabolismo , Animales , Biomarcadores , Temperatura Corporal/efectos de los fármacos , Ventrículos Cerebrales/efectos de los fármacos , Corticosterona/sangre , Relación Dosis-Respuesta a Droga , Proteína 1 de la Respuesta de Crecimiento Precoz , Infusiones Parenterales , Sistema Límbico/efectos de los fármacos , Masculino , Neurotensina/administración & dosificación , Núcleo Hipotalámico Paraventricular/metabolismo , Ratas , Ratas Sprague-Dawley , Análisis de Regresión , Núcleo Supraóptico/metabolismo , Dedos de ZincRESUMEN
Populations of dopamine (DA) neurons in the rat brain are selectively activated by stress, and the response is attenuated by the administration of anxiolytics. Given the role of the component nuclei of the amygdaloid complex in conditioned associations, stress responses and the anxiolytic effects of benzodiazepines, we hypothesized that particular mesoamygdaloid DA projections might be especially sensitive to the effects of conditioned stress and to diazepam (DZ). We mapped the effect of a conditioned stressor on the concentration of the DA metabolite homovanillic acid (HVA) in distinct amygdaloid nuclei and other brain nuclei and areas and the effect of DZ (1 or 3 mg/kg) on the conditioned response in drug-experienced subjects. The conditioned stress paradigm resulted in significant elevations in classical indices of stress, including serum corticosterone and plasma epinephrine. Conditioned stress-induced increases in the estimated activity of DA neurons were specific for DA neurons projecting to the central, basolateral and lateral amygdaloid nuclei, and for DA projections to the dorsal septal nucleus. Conditioned stress-induced increases in the HVA concentration of responsive amygdaloid nuclei were antagonized by low, anxiolytic doses of DZ. These results indicate a role for a subset of mesoamygdaloid DA projections in transducing the impact of perceived stressors on the output of the amygdaloid complex. A role for particular amygdaloid DA projections in the formation of conditioned fear or anticipatory anxiety and its modulation by anxiolytics is also suggested.
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Amígdala del Cerebelo/efectos de los fármacos , Diazepam/farmacología , Dopamina/metabolismo , Neuronas/efectos de los fármacos , Estrés Fisiológico/fisiopatología , Amígdala del Cerebelo/química , Amígdala del Cerebelo/fisiopatología , Animales , Ansiedad/fisiopatología , Cromatografía Líquida de Alta Presión , Condicionamiento Clásico , Corticosterona/sangre , Ácido Homovanílico/análisis , Masculino , Prolactina/sangre , Ratas , Ratas Sprague-Dawley , Estrés Fisiológico/metabolismoRESUMEN
The findings of this study extend the observations of Deutch et al. who suggested that NT in the ventral mesencephalon may be involved in the environmentally elicited activation of selectively responsive populations of mesotelencephalic dopamine neurons. The unconditioned response of NT-LI to electric footshock was observed only at an intensity of 500 microA and only in the lateral subdivision of the VTA. The selective effect of footshock stress on the NT content of a specific cell body group of the ventral mesencephalon suggests that NT mechanisms in the lateral VTA may, in part, underlie the stress-induced activation of dopamine neurons that originate in the lateral VTA. However, it should be noted that populations of dopamine neurons are activated by footshock intensities less than 500 microA, while NT concentrations of mesencephalic dopamine cell body groups are not altered by these shock intensities. The disparity weakens the possibility of a role for NT in the stress-induced activation of brain dopamine neurons unless NT mechanisms may be involved in transducing the effects of higher intensity stressors versus low intensity stressors. However, it should be noted that changes in the concentration of NT-LI represent an endpoint of unknown sensitivity and functional significance and best serve as an initial approximation of the effects of a manipulation on NT-containing neurons. It is plausible that NT mechanisms in the ventral mesencephalon may act in concert with other neuropeptides such as substance P and Met-enkephalin to transduce the effects of stressors on alterations in the activity of mesotelencephalic dopamine neurons that originate in the ventral mesencephalon. An examination of the effects of footshock stress on the content of prepro-NT mRNA in the dopamine cell body groups of the ventral mesencephalon would be of interest in assessing whether stress enhances NT gene expression or alters the characteristics of release of this neuropeptide in the ventral mesencephalon. Lacking NT receptor antagonists, it would also be of interest to determine the effects of the passive immunoneutralization of NT in the ventral mesencephalon on footshock-induced increases in the biochemically estimated activity of mesotelencephalic dopamine neurons to better understand the involvement of NT as a transducer of the effects of stress on dopamine neuronal activity. The distinct topography of conditioned versus unconditioned stress on the concentration of NT-LI in the dopamine cell body groups of the ventral mesencephalon suggests that NT may be involved in the differential activation of distinct dopamine neuronal populations by these different stressors.(ABSTRACT TRUNCATED AT 400 WORDS)
Asunto(s)
Dopamina/metabolismo , Neurotensina/metabolismo , Estrés Fisiológico/metabolismo , Tegmento Mesencefálico/metabolismo , Animales , Encéfalo/metabolismo , Condicionamiento Psicológico , Diazepam/farmacología , Estimulación Eléctrica , Masculino , Neuronas/metabolismo , Neurotensina/farmacología , Ratas , Ratas Sprague-Dawley , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
The present study mapped the topographic distribution of, and the effect of neuropharmacologically distinct antipsychotic drugs on, the concentration of neurotensin (NT) in the rat brain at the level of discrete nuclei or areas. The chronic administration of either haloperidol or clozapine increased the concentration of NT-like immunoreactivity (NT-LI) in the nucleus accumbens and decreased it in the medial prefrontal and cingulate cortex and in the interstitial (bed) nucleus of the stria terminalis. In contrast, the prolonged administration of haloperidol, but not clozapine, increased the concentration of NT-LI in the anterior caudate nucleus and posterior caudate-putamen. The concentration of NT-LI in the great majority of the rat brain nuclei examined was unaffected by the chronic administration of either antipsychotic drug. This pattern of pharmacological response distinguishes NT from all other neuropeptides which have been shown to be influenced by prolonged antipsychotic drug administration. These findings suggest that the functional information imparted to NT-containing cells by neuronal dopamine (DA) release, as inferred from the consequences of receptor blockade, varies remarkably between different populations of DA neurons and further implicate NT as a neuroanatomically-selective neurochemical substrate of the adaptive responses mediating the therapeutic and motoric side effects of antipsychotic drugs.
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Química Encefálica/efectos de los fármacos , Clozapina/farmacología , Dibenzazepinas/farmacología , Haloperidol/farmacología , Neurotensina/metabolismo , Animales , Encéfalo/anatomía & histología , Masculino , Ratas , Ratas EndogámicasRESUMEN
Populations of DA neurons innervating the component nuclei of the amygdaloid complex differ in their inferred density of innervation, estimated rate of impulse activity, and adaptive response to the prolonged administration of antipsychotic drugs. Mesoamygdaloid DA neurons have in common the absence of tonically inhibitory, nerve terminal autoreceptors regulating DA synthesis, the nonassociation with a DA-stimulated adenylate cyclase, and the regulation of DA synthesis by receptor-mediated neuronal feedback mechanisms and end-product inhibition. The output of the amygdaloid complex appears to be organized into distinct functions subserved by component nuclei. The present findings suggest a differing role for DA afferents in modulating the functional output of discrete nuclei. The significance of this focal influence will be speculative pending a more complete understanding of the physiology of DA neurotransmission in the amygdaloid complex. Populations of DA neurons innervating discrete amygdaloid nuclei exhibit a composite of mechanisms of regulation and signal transduction and pharmacology that differ from that of other mesotelencephalic DA systems. These comparisons highlight the fact that the nucleus accumbens and olfactory tubercle do not represent or reflect DA neurotransmission in the limbic system. The study of the physiology, pharmacology, and pathology of mesolimbic DA neurons can and should extend beyond the nucleus accumbens and olfactory tubercle to the amygdala and other brain structures central to the organization of the limbic system. It is our opinion that the term "mesolimbic" DA system has purely anatomical connotations and that a more specific terminology (e.g., meso-central amygdaloid nuclear) would express the functional organization of this system more accurately.
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Amígdala del Cerebelo/fisiología , Dopamina/fisiología , Mesencéfalo/fisiología , Neuronas/fisiología , Adenilil Ciclasas/metabolismo , Amígdala del Cerebelo/citología , Amígdala del Cerebelo/efectos de los fármacos , Animales , Apomorfina/farmacología , Haloperidol/farmacología , Mesencéfalo/citología , Mesencéfalo/efectos de los fármacos , Neuronas/efectos de los fármacos , Receptores Dopaminérgicos/efectos de los fármacos , Receptores Dopaminérgicos/fisiología , Transducción de SeñalRESUMEN
The present study sought to map the distribution of dopamine (DA) synthesis-modulating autoreceptors on DA nerve terminals innervating the amygdala and other limbic structures of the rat brain at a level of anatomic resolution (i.e., discrete component nuclei) commensurate with the functional organization of such structures. The biochemically estimated response of mesoamygdaloid and other limbic DA neuronal populations to conditions of minimal (gammabutyrolactone administration or surgical axotomy) and maximal (low-dose apomorphine administration) activation of nerve terminal DA autoreceptors was examined and compared to the response of mesostriatal and mesocortical DA neurons. In contrast to the caudate nucleus, nucleus accumbens, and olfactory tubercle, neither gammabutyrolactone (GBL) nor axotomy increased biochemically estimated DA synthesis (DOPA accumulation) in any of the amygdaloid nuclei, the anterior amygdaloid area, septal nuclei, or subdivisions of the interstitial (bed) nucleus of the stria terminalis. These results indicate that, similar to the medial prefrontal cortex and median eminence, DA synthesis in mesoamygdaloid and other subcortical limbic DA neuronal populations is not under the regulatory influence of tonically active, nerve terminal-localized autoreceptors. Both GBL and axotomy increased DOPA accumulation in the anterior cingulate cortex, but not in allocortical projection fields. In contrast to the differential distribution of DA synthesis-modulating terminal autoreceptors, the end-product inhibition of tyrosine hydroxylase activity appears to be a ubiquitously expressed regulatory property of DA neurons. The decrease in DA metabolism produced by the administration of a low, presumably auto-receptor-selective, dose of apomorphine exhibited a DA neuronal population distribution distinctly unlike that of the aforementioned effects of GBL or axotomy on DOPA accumulation. These results reinforce the DA neuronal population-selective distribution of synthesis-modulating autoreceptors and indicate that nerve terminal-localized autoreceptors are operative in regulating DA synthesis in only a minority of DA-innervated brain structures. Further, the demonstration of such autoreceptors is dependent upon the preparation, pharmacological tools, and functional endpoints chosen for study.