RESUMEN
A wealth of evidence indicates that the activation of 5-HT1A and 5-HT2A receptors in the dorsal periaqueductal grey matter (dPAG) inhibits escape, a panic-related defensive behaviour. Results that were previously obtained with the elevated T-maze test of anxiety/panic suggest that 5-HT1A and µ-opioid receptors in this midbrain area work together to regulate this response. To investigate the generality of this finding, we assessed whether the same cooperative mechanism is engaged when escape is evoked by a different aversive stimulus electrical stimulation of the dPAG. Administration of the µ-receptor blocker CTOP into the dPAG did not change the escape threshold, but microinjection of the µ-receptor agonist DAMGO (0.3 and 0.5 nmol) or the 5-HT1A receptor agonist 8-OHDPAT (1.6 nmol) increased this index, indicating a panicolytic-like effect. Pretreatment with CTOP antagonised the anti-escape effect of 8-OHDPAT. Additionally, combined administration of subeffective doses of DAMGO and 8-OHDPAT increased the escape threshold, indicating drug synergism. Therefore, regardless of the aversive nature of the stimulus, µ-opioid and 5-HT1A receptors cooperatively act to regulate escape behaviour. A better comprehension of this mechanism might allow for new therapeutic strategies for panic disorder.
Asunto(s)
Reacción de Fuga/fisiología , Pánico/fisiología , Sustancia Gris Periacueductal/fisiología , Receptor de Serotonina 5-HT1A/fisiología , Receptores Opioides mu/fisiología , 8-Hidroxi-2-(di-n-propilamino)tetralin/antagonistas & inhibidores , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Animales , Estimulación Eléctrica , Encefalina Ala(2)-MeFe(4)-Gli(5)/farmacología , Reacción de Fuga/efectos de los fármacos , Masculino , Microinyecciones , Pánico/efectos de los fármacos , Sustancia Gris Periacueductal/efectos de los fármacos , Ratas , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT2A , Receptores Opioides mu/antagonistas & inhibidores , Somatostatina/administración & dosificación , Somatostatina/análogos & derivados , Somatostatina/farmacologíaRESUMEN
Although the role of the median raphe nucleus (MRN) in the regulation of anxiety has received less attention than that of the dorsal raphe nucleus (DRN) there is substantial evidence supporting this function. Reported results with different animal models of anxiety in rats show that whereas inactivation of serotonergic neurons in the MRN causes anxiolysis, the stimulation of the same neurons is anxiogenic. In particular, studies using the elevated T-maze comparing serotonergic interventions in the MRN and in the DRN indicate that the former affect only the inhibitory avoidance task, which has been related to generalized anxiety. In contrast, similar operations in the DRN change both the inhibitory avoidance and the one-way escape task, the latter being representative of panic disorder. Simultaneous injections of 5-HT-acting drugs in the MRN and in the dorsal hippocampus (DH) suggest that the MRN-DH pathway mediates the regulatory function of the MRN in anxiety. Overall, the results discussed in this review point to a relevant role of the MRN in the regulation of anxiety, but not panic, through the 5-HT pathway that innervates the DH.
Asunto(s)
Ansiedad/fisiopatología , Núcleos del Rafe/metabolismo , Serotonina/metabolismo , Animales , Reacción de Prevención/fisiología , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Humanos , Aprendizaje por Laberinto/fisiología , Neuronas/metabolismo , Trastorno de Pánico/fisiopatología , RatasRESUMEN
Panic disorder (PD) is a subtype of anxiety disorder in which the core phenomenon is the spontaneous occurrence of panic attacks. Although studies with laboratory animals have been instrumental for the understanding of its neurobiology and treatment, few review articles have focused on the validity of the currently used animal models for studying this psychopathology. Therefore, the aim of the present paper is to discuss the strengths and limits of these models in terms of face, construct and predictive validity. Based on the hypothesis that panic attacks are related to defensive responses elicited by proximal threat, most animal models measure the escape responses induced by specific stimuli. Some apply electrical or chemical stimulation to brain regions proposed to modulate fear and panic responses, such as the dorsal periaqueductal grey or the medial hypothalamus. Other models focus on the behavioural consequences caused by the exposure of rodents to ultrasound or natural predators. Finally, the elevated T-maze associates a one-way escape response from an open arm with panic attacks. Despite some limitations, animal models are essential for a better understanding of the neurobiology and pharmacology of PD and for discovering more effective treatments.
Asunto(s)
Modelos Animales de Enfermedad , Trastorno de Pánico , Animales , Humanos , RoedoresRESUMEN
Previous results with the elevated T-maze (ETM) test indicate that the antipanic action of serotonin (5-HT) in the dorsal periaqueductal grey (dPAG) depends on the activation endogenous opioid peptides. The aim of the present work was to investigate the interaction between opioid- and serotonin-mediated neurotransmission in the modulation of defensive responses in rats submitted to the ETM. The obtained results showed that intra-dPAG administration of morphine significantly increased escape latency, a panicolytic-like effect that was blocked by pre-treatment with intra-dPAG injection of either naloxone or the 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1 piperazinyl] ethyl] -N- 2- pyridinyl-ciclohexanecarboxamide maleate (WAY-100635). In addition, previous administration of naloxone antagonized both the anti-escape and the anti-avoidance (anxiolytic-like) effect of the 5-HT1A agonist (±)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), but did not affect the anti-escape effect of the 5-HT2A agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI). Moreover, the combination of sub-effective doses of locally administered 5-HT and morphine significantly impaired ETM escape performance. Finally, the µ-antagonist D-PHE-CYS-TYR-D-TRP-ORN-THR-PEN (CTOP) blocked the anti-avoidance as well as the anti-escape effect of 8-OHDPAT, and the association of sub-effective doses of the µ-opioid receptor agonist [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin acetate salt (DAMGO) and of 8-OHDPAT had anti-escape and anti-avoidance effects in the ETM. These results suggest a synergic interaction between the 5-HT1A and the µ-opioid receptor at post-synaptic level on neurons of the dPAG that regulate proximal defense, theoretically related to panic attacks.
Asunto(s)
Ansiedad/metabolismo , Pánico/fisiología , Receptor de Serotonina 5-HT1A/metabolismo , Receptores Opioides mu/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Morfina/farmacología , Naloxona/farmacología , Neuronas/metabolismo , Trastorno de Pánico/metabolismo , Sustancia Gris Periacueductal/metabolismo , Ratas , Ratas Wistar , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptores Opioides mu/efectos de los fármacos , Serotonina/administración & dosificación , Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacologíaRESUMEN
Serotonin (5-HT), opioids and the dorsal periaqueductal grey (DPAG) have been implicated in the pathophysiology of panic disorder. In order to study 5-HT-opioid interaction, the opioid antagonist naloxone was injected either systemically (1 mg/kg, i.p.) or intra-DPAG (0.2 µg/0.5 µL) to assess its interference with the effect of chronic fluoxetine (10 mg/kg, i.p., daily for 21 days) or of intra-DPAG 5-HT (8 µg/0.5 µL). Drug effects were measured in the one-escape task of the rat elevated T-maze, an animal model of panic. Pretreatment with systemic naloxone antagonized the lengthening of escape latency caused by chronic fluoxetine, considered a panicolytic-like effect that parallels the drug's therapeutic response in the clinics. Pretreatment with naloxone injected intra-DPAG antagonized both the panicolytic effect of chronic fluoxetine as well as that of 5-HT injected intra-DPAG. Neither the performance of the inhibitory avoidance task in the elevated T-maze, a model of generalized anxiety nor locomotion measured in a circular arena was affected by the above drug treatments. These results indicate that the panicolytic effect of fluoxetine is mediated by endogenous opioids that are activated by 5-HT in the DPAG. They also allow reconciliation between the serotonergic and opioidergic hypotheses of panic disorder pathophysiology.
Asunto(s)
Antidepresivos de Segunda Generación/farmacología , Fluoxetina/farmacología , Péptidos Opioides/fisiología , Trastorno de Pánico/tratamiento farmacológico , Sustancia Gris Periacueductal/fisiología , Serotonina/farmacología , Animales , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Naloxona/farmacología , Sustancia Gris Periacueductal/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
This study aimed to measure, using fMRI, the effect of diazepam on the haemodynamic response to emotional faces. Twelve healthy male volunteers (mean age = 24.83 ± 3.16 years), were evaluated in a randomized, balanced-order, double-blind, placebo-controlled crossover design. Diazepam (10 mg) or placebo was given 1 h before the neuroimaging acquisition. In a blocked design covert face emotional task, subjects were presented with neutral (A) and aversive (B) (angry or fearful) faces. Participants were also submitted to an explicit emotional face recognition task, and subjective anxiety was evaluated throughout the procedures. Diazepam attenuated the activation of right amygdala and right orbitofrontal cortex and enhanced the activation of right anterior cingulate cortex (ACC) to fearful faces. In contrast, diazepam enhanced the activation of posterior left insula and attenuated the activation of bilateral ACC to angry faces. In the behavioural task, diazepam impaired the recognition of fear in female faces. Under the action of diazepam, volunteers were less anxious at the end of the experimental session. These results suggest that benzodiazepines can differentially modulate brain activation to aversive stimuli, depending on the stimulus features and indicate a role of amygdala and insula in the anxiolytic action of benzodiazepines.
Asunto(s)
Amígdala del Cerebelo/efectos de los fármacos , Ira/fisiología , Diazepam/farmacología , Expresión Facial , Miedo/fisiología , Giro del Cíngulo/efectos de los fármacos , Adulto , Amígdala del Cerebelo/fisiología , Estudios Cruzados , Método Doble Ciego , Giro del Cíngulo/fisiología , Humanos , Imagen por Resonancia Magnética , Masculino , Adulto JovenRESUMEN
Oxytocin (OT) is known to be involved in anxiety, as well as cardiovascular and hormonal regulation. The objective of this study was to assess the acute effect of intranasally administered OT on subjective states, as well as cardiovascular and endocrine parameters, in healthy volunteers (n = 14) performing a simulated public speaking test. OT or placebo was administered intranasally 50 min before the test. Assessments were made across time during the experimental session: (1) baseline (-30 min); (2) pre-test (-15 min); (3) anticipation of the speech (50 min); (4) during the speech (1:03 h), post-test time 1 (1:26 h), and post-test time 2 (1:46 h). Subjective states were evaluated by self-assessment scales. Cortisol serum and plasma adrenocorticotropic hormone (ACTH) were measured. Additionally, heart rate, blood pressure, skin conductance, and the number of spontaneous fluctuations in skin conductance were measured. Compared with placebo, OT reduced the Visual Analogue Mood Scale (VAMS) anxiety index during the pre-test phase only, while increasing sedation at the pre-test, anticipation, and speech phases. OT also lowered the skin conductance level at the pre-test, anticipation, speech, and post-test 2 phases. Other parameters evaluated were not significantly affected by OT. The present results show that OT reduces anticipatory anxiety, but does not affect public speaking fear, suggesting that this hormone has anxiolytic properties.
Asunto(s)
Ansiolíticos/farmacología , Oxitocina/farmacología , Habla/efectos de los fármacos , Administración Intranasal , Hormona Adrenocorticotrópica/sangre , Adulto , Miedo/efectos de los fármacos , Humanos , Hidrocortisona/sangreRESUMEN
BACKGROUND: High level piano performance requires complex integration of perceptual, motor, cognitive and emotive skills. Observations in psychology and neuroscience studies have suggested reciprocal inhibitory modulation of the cognition by emotion and emotion by cognition. However, it is still unclear how cognitive states may influence the pianistic performance. The aim of the present study is to verify the influence of cognitive and affective attention in the piano performances. METHODS AND FINDINGS: Nine pianists were instructed to play the same piece of music, firstly focusing only on cognitive aspects of musical structure (cognitive performances), and secondly, paying attention solely on affective aspects (affective performances). Audio files from pianistic performances were examined using a computational model that retrieves nine specific musical features (descriptors)--loudness, articulation, brightness, harmonic complexity, event detection, key clarity, mode detection, pulse clarity and repetition. In addition, the number of volunteers' errors in the recording sessions was counted. Comments from pianists about their thoughts during performances were also evaluated. The analyses of audio files throughout musical descriptors indicated that the affective performances have more: agogics, legatos, pianos phrasing, and less perception of event density when compared to the cognitive ones. Error analysis demonstrated that volunteers misplayed more left hand notes in the cognitive performances than in the affective ones. Volunteers also played more wrong notes in affective than in cognitive performances. These results correspond to the volunteers' comments that in the affective performances, the cognitive aspects of piano execution are inhibited, whereas in the cognitive performances, the expressiveness is inhibited. CONCLUSIONS: Therefore, the present results indicate that attention to the emotional aspects of performance enhances expressiveness, but constrains cognitive and motor skills in the piano execution. In contrast, attention to the cognitive aspects may constrain the expressivity and automatism of piano performances.
Asunto(s)
Estimulación Acústica , Percepción Auditiva/fisiología , Música , Adulto , Cognición , Emociones , Humanos , Destreza Motora , Percepción , Proyectos Piloto , Reproducibilidad de los ResultadosRESUMEN
AIMS: the ß-adrenergic and 5-HT(1A) receptor antagonist pindolol has been used in combination with antidepressant drugs, to shorten the time of onset of clinical efficacy and/or increase the proportion of responders in depressive and anxiety disorders. The aim of this study was to examine the interaction between pindolol and the selective serotonin reuptake inhibitor (SSRI), paroxetine in rats submitted to the elevated T-maze (ETM). MAIN METHODS: for assessing the drug combination effect, rats were administered with pindolol before paroxetine, using oral or intraperitoneal (i.p.) routes of acute administration, and were submitted to the ETM model. KEY FINDINGS: the highest dose of pindolol used (15.0mg/kg, i.p.) increased both inhibitory avoidance and escape latencies in the ETM, probably due to nonspecific motor deficit, since locomotion in a circular arena was also significantly decreased. The highest dose of paroxetine (3.0mg/kg, i.p.) selectively impaired escape, considered a panicolytic effect. Combination of pindolol (5.0mg/kg, i.p.) with an ineffective dose of paroxetine (1.5mg/kg, i.p.) impaired escape, indicating a potentiation of the panicolytic effect of paroxetine. By the oral route, neither paroxetine (3.0mg/kg) nor pindolol (5.0mg/kg) alone were effective, but the combination treatment had a marked panicolytic effect, again indicating drug potentiation. SIGNIFICANCE: the present results show that the combination of the ineffective doses of pindolol and paroxetine significantly increased escape latency, indicating a selective panicolytic effect. These findings give preclinical support for the use of this drug combination in the treatment of panic disorder (PD).
Asunto(s)
Antagonistas Adrenérgicos beta/administración & dosificación , Antidepresivos de Segunda Generación/administración & dosificación , Trastornos de Ansiedad/tratamiento farmacológico , Trastorno de Pánico/tratamiento farmacológico , Paroxetina/administración & dosificación , Pindolol/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Antagonistas Adrenérgicos beta/uso terapéutico , Animales , Antidepresivos de Segunda Generación/uso terapéutico , Combinación de Medicamentos , Interacciones Farmacológicas , Masculino , Paroxetina/uso terapéutico , Pindolol/uso terapéutico , Ratas , Ratas Wistar , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéuticoRESUMEN
Antidepressants are widely used to treat several anxiety disorders, among which generalized anxiety disorder (GAD) and panic disorder (PD). Serotonin (5-HT) is believed to play a key role in the mode of action of these agents, a major question being which pathways and receptor subtypes are involved in each type of anxiety disorder. The dual role of 5-HT in defense hypothesis assumes that 5-HT facilitates defensive responses to potential threat, like inhibitory avoidance, related to anxiety, whereas it inhibits defensive responses to proximal danger, like one-way escape, related to panic. The former action would be exerted at the forebrain, chiefly the amygdala and medial prefrontal cortex (PFC), while the latter would be exerted at the dorsal periaqueductal gray (DPAG) matter of the midbrain. The present review is focused on studies designed to test this hypothesis, performed in animal models of anxiety and panic, as well as in human experimental anxiety tests. The reviewed results suggest that chronic, but not acute, administration of antidepressants suppress panic attacks by increasing the release of 5-HT and enhancing the responsivity of post-synaptic 5-HT1A and 5-HT2A receptors in the DPAG. The attenuation of generalized anxiety, also caused by the same drug treatment, would be due to the desensitization of 5-HT2C receptors and, less certainly, to increased stimulation of 5-HT1A receptors in forebrain structures. This action would result in less activation of the amygdala, medial PFC and insula by warning signals, as shown by the reviewed results obtained with functional neuroimaging in healthy volunteers and patients with anxiety disorders.
Asunto(s)
Antidepresivos/uso terapéutico , Trastornos de Ansiedad/tratamiento farmacológico , Trastornos de Ansiedad/fisiopatología , Trastorno de Pánico/tratamiento farmacológico , Trastorno de Pánico/fisiopatología , Serotonina/fisiología , Animales , Humanos , Transmisión Sináptica/efectos de los fármacosRESUMEN
Emotion and spatial cognitive aspects were assessed in adult and middle-aged rats using the elevated T-maze (ETM) and the Morris water maze (MWM) tasks. Both adult and middle-aged rats were able to acquire inhibitory avoidance behaviour, though the middle-aged subjects showed larger latencies along the trials, including the baseline, which was significantly longer than that showed by adult rats. Further, compared to adult rats, middle-aged rats had longer escape latency. In spite of the worse performance in the second session of the spatial cognitive task, the middle-aged rats were able to learn the task and remember the information along the whole probe trial test. Both thalamic serotonin (5-HT) concentration and amygdala serotonergic activity (5-HIAA/5-HT) are significantly correlated, respectively, to escape latency and behavioural extinction in the MWM only for middle-aged rats. A significant correlation between the 5-HIAA/5-HT ratio in the amygdala and behavioural extinction for middle-aged, but not for adult, rats was observed. This result suggests that serotonergic activity in the amygdala may regulate behavioural flexibility in aged animals. In addition, a significant negative correlation was found between hippocampal 5-HIAA/5-HT ratio and the path length at the second training session of the MWM task, although only for adult subjects. This was the only session where a significant difference between the performance of middle-aged and adult rats has occurred. Although the involvement of the hippocampus in learning and memory is well established, the present work shows, for the first time, a correlation between a serotonergic hippocampal parameter and performance of a spatial task, which is lost with ageing.
Asunto(s)
Afecto , Trastornos del Conocimiento/diagnóstico , Aprendizaje por Laberinto/fisiología , Serotonina/fisiología , Factores de Edad , Animales , Conducta Animal , Trastornos del Conocimiento/epidemiología , Modelos Animales de Enfermedad , Masculino , RatasRESUMEN
Recent theories of panic disorder propose an extensive involvement of limbic system structures, such as the hippocampus, in the pathophysiology of this condition. Despite this, no prior study has examined exclusively the hippocampal neurochemistry in this disorder. The current study used proton magnetic resonance spectroscopy imaging ((1)H-MRSI) to examine possible abnormalities in the hippocampus in panic disorder patients. Participants comprised 25 panic patients and 18 psychiatrically healthy controls. N-acetylaspartate (NAA, a putative marker of neuronal viability) and choline (Cho, involved in the synthesis and degradation of cell membranes) levels were quantified relative to creatine (Cr, which is thought to be relatively stable among individuals and in different metabolic condition) in both right and left hippocampi. Compared with controls, panic patients demonstrated significantly lower NAA/Cr in the left hippocampus. No other difference was detected. This result is consistent with previous neuroimaging findings of hippocampal alterations in panic and provides the first neurochemical evidence suggestive of involvement of this structure in the disorder. Moreover, lower left hippocampal NAA/Cr in panic disorder may possibly reflect neuronal loss and/or neuronal metabolic dysfunction, and could be related to a deficit in evaluating ambiguous cues.
Asunto(s)
Ácido Aspártico/análogos & derivados , Colina/metabolismo , Creatina/metabolismo , Hipocampo/metabolismo , Trastorno de Pánico/fisiopatología , Adulto , Análisis de Varianza , Ácido Aspártico/metabolismo , Femenino , Hipocampo/patología , Humanos , Espectroscopía de Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Protones , Adulto JovenRESUMEN
The present work aimed to evaluate the effects of social separation for 14 days (chronic stress) and of withdrawal from a 14-day treatment with diazepam (acute stress) on the exploratory behaviour of male rats in the elevated plus-maze and on serotonin (5-hydroxytryptamine) turnover in different brain structures. Social separation had an anxiogenic effect, evidenced by fewer entries into, and less time spent on the open arms of the elevated plus-maze. Separation also selectively increased 5-hydroxytryptamine turnover in the hippocampus and median raphe nucleus. Diazepam withdrawal had a similar anxiogenic effect in grouped animals and increased 5-hydroxytryptamine turnover in the same brain structures. Chronic treatment with imipramine during the 14 days of separation prevented the behavioural and neurochemical changes caused by social separation. It is suggested that the increase in anxiety determined by both acute and chronic stress is mediated by the activation of the median raphe nucleus-hippocampal 5-hydroxytryptamine pathway.
Asunto(s)
Ansiedad , Diazepam/toxicidad , Hipocampo/metabolismo , Núcleos del Rafe/metabolismo , Serotonina/metabolismo , Aislamiento Social/psicología , Síndrome de Abstinencia a Sustancias , Enfermedad Aguda , Animales , Ansiolíticos/uso terapéutico , Ansiolíticos/toxicidad , Ansiedad/inducido químicamente , Ansiedad/prevención & control , Ansiedad/psicología , Reacción de Prevención , Enfermedad Crónica , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Imipramina/uso terapéutico , Masculino , Distribución Aleatoria , Ratas , Ratas Wistar , Estrés Psicológico/fisiopatologíaRESUMEN
Estrogen deficiency has been associated with stress, anxiety and depression. Estrogen receptors have been identified in the median raphe nucleus (MRN). This structure is the main source of serotonergic projections to the hippocampus, a forebrain area implicated in the regulation of defensive responses and in the resistance to chronic stress. There is reported evidence indicating that estrogen modulates 5-HT1A receptor function. In the MRN, somatodendritic 5-HT1A receptors control the activity of serotonergic neurones by negative feedback. The present study has evaluated the effect of intra-MRN injection of estradiol benzoate (EB, 600 or 1200 ng/0.2 microl) on the performance of ovariectomized rats submitted to contextual conditioning. Additionally, the same treatment was given after intra-MRN injection of Way 100635 (100 ng/0.2 microl), a 5-HT1A receptor antagonist. Both doses of EB decreased freezing and increased rearing, indicating an anxiolytic effect. Pretreatment with Way 100635 antagonized the anxiolytic effect of estradiol. On the basis of these results, it may be suggested that estrogens modulate anxiety by acting on 5-HT1A receptors localized in the MRN.
Asunto(s)
Condicionamiento Clásico/efectos de los fármacos , Estradiol/análogos & derivados , Estrógenos/farmacología , Núcleos del Rafe/efectos de los fármacos , Análisis de Varianza , Animales , Ansiedad/tratamiento farmacológico , Ansiedad/fisiopatología , Cateterismo , Estradiol/administración & dosificación , Estradiol/farmacología , Estrógenos/administración & dosificación , Femenino , Reacción Cataléptica de Congelación/efectos de los fármacos , Reacción Cataléptica de Congelación/fisiología , Microinyecciones , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Ovariectomía , Piperazinas/administración & dosificación , Piperazinas/farmacología , Piridinas/administración & dosificación , Piridinas/farmacología , Núcleos del Rafe/fisiología , Ratas , Ratas Wistar , Antagonistas de la Serotonina/administración & dosificación , Antagonistas de la Serotonina/farmacología , Factores de TiempoRESUMEN
Evidence from animal models of anxiety has led to the hypothesis that serotonin enhances inhibitory avoidance (related to anxiety) in the forebrain, but inhibits one-way escape (panic) in the midbrain periaqueductal gray (PAG). Stressing the difference between these emotions, neuroendocrinological results indicate that the hypothalamic-pituitary-adrenal axis is activated by anticipatory anxiety, but not by panic attack nor by electrical stimulation of the rat PAG. Functional neuroimaging has shown activation of the insula and upper brain stem (including PAG), as well as deactivation of the anterior cingulated cortex (ACC) during experimental panic attacks. Voxel-based morphometric analysis of brain magnetic resonance images has shown a grey matter volume increase in the insula and upper brain stem, and a decrease in the ACC of panic patients at rest, as compared to healthy controls. The insula and the ACC detect interoceptive stimuli, which are overestimated by panic patients. It is suggested that these brain areas and the PAG are involved in the pathophysiology of panic disorder.
Asunto(s)
Mapeo Encefálico , Encéfalo/fisiopatología , Trastorno de Pánico/fisiopatología , Animales , Modelos Animales de Enfermedad , Humanos , Trastorno de Pánico/complicaciones , Trastorno de Pánico/psicología , Ratas , Estrés Psicológico/complicaciones , Estrés Psicológico/fisiopatologíaRESUMEN
Although abnormalities in brain structures involved in the neurobiology of fear and anxiety have been implicated in the pathophysiology of panic disorder (PD), relatively few studies have made use of voxel-based morphometry (VBM) magnetic resonance imaging (MRI) to determine structural brain abnormalities in PD. We have assessed gray matter volume in 19 PD patients and 20 healthy volunteers using VBM. Images were acquired using a 1.5 T MRI scanner, and were spatially normalized and segmented using optimized VBM. Statistical comparisons were performed using the general linear model. A relative increase in gray matter volume was found in the left insula of PD patients compared with controls. Additional structures showing differential increases were the left superior temporal gyrus, the midbrain, and the pons. A relative gray matter deficit was found in the right anterior cingulate cortex. The insula and anterior cingulate abnormalities may be relevant to the pathophysiology of PD, since these structures participate in the evaluation process that ascribes negative emotional meaning to potentially distressing cognitive and interoceptive sensory information. The abnormal brain stem structures may be involved in the generation of panic attacks.
Asunto(s)
Encéfalo/patología , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , Trastorno de Pánico/patología , Adulto , Nivel de Alerta/genética , Nivel de Alerta/fisiología , Encéfalo/fisiopatología , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Dominancia Cerebral/fisiología , Emociones/fisiología , Femenino , Giro del Cíngulo/patología , Giro del Cíngulo/fisiopatología , Humanos , Masculino , Mesencéfalo/patología , Mesencéfalo/fisiopatología , Persona de Mediana Edad , Trastorno de Pánico/diagnóstico , Trastorno de Pánico/fisiopatología , Trastorno de Pánico/psicología , Puente/patología , Puente/fisiopatología , Lóbulo Temporal/patología , Lóbulo Temporal/fisiopatologíaRESUMEN
This is a comparative study between manual volumetry (MV) and voxel based morphometry (VBM) as methods of evaluating the volume of brain structures in magnetic resonance images. The volumes of the hippocampus and the amygdala of 16 panic disorder patients and 16 healthy controls measured through MV were correlated with the volumes of gray matter estimated by optimized modulated VBM. The chosen structures are composed almost exclusively of gray matter. Using a 4 mm Gaussian filter, statistically significant clusters were found bilaterally in the hippocampus and in the right amygdala in the statistical parametric map correlating with the respective manual volume. With the conventional 12 mm filter,a significant correlation was found only for the right hippocampus. Therefore, narrow filters increase the sensitivity of the correlation procedure, especially when small brain structures are analyzed. The two techniques seem to consistently measure structural volume.
Asunto(s)
Amígdala del Cerebelo/patología , Hipocampo/patología , Imagen por Resonancia Magnética/métodos , Trastorno de Pánico/patología , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los ResultadosRESUMEN
This is a comparative study between manual volumetry (MV) and voxel based morphometry (VBM) as methods of evaluating the volume of brain structures in magnetic resonance images. The volumes of the hippocampus and the amygdala of 16 panic disorder patients and 16 healthy controls measured through MV were correlated with the volumes of gray matter estimated by optimized modulated VBM. The chosen structures are composed almost exclusively of gray matter. Using a 4 mm Gaussian filter, statistically significant clusters were found bilaterally in the hippocampus and in the right amygdala in the statistical parametric map correlating with the respective manual volume. With the conventional 12 mm filter,a significant correlation was found only for the right hippocampus. Therefore,narrowfilters increase the sensitivity of the correlation procedure, especially when small brain structures are analyzed. The two techniques seem to consistently measure structural volume.
Trata-se de estudo comparativo entre a volumetria manual(VM) e a morfometria baseada no vóxel (MBV), como métodos de avaliação do volume de estruturas cerebrais. Os volumes do hipocampo e da amídala de 16 pacientes de pânico e 16 controles sadios medidos através da VM foram correlacionados com os volumes de matéria cinzenta estimados pela MBV.As estruturas escolhidas são constituídas quase exclusivamente de matéria cinzenta. Utilizando um filtro Gaussiano de 4 mm, encontram-se, bilateralmente, aglomerados significativos de correlação nas duas estruturas no mapa estatístico paramétrico, correspondendo ao respectivo volume manual. Com o filtro convencional de 12 mm, apenas uma correlação significativa foi encontrada no hipocampo direito. Portanto, filtros estreitos aumentam a sensibilidade do procedimento de correlação,especialmente quando estruturas pequenas são analisadas. Ambas as técnicas parecem medir consistentemente o volume estrutural.
Asunto(s)
Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Amígdala del Cerebelo/patología , Hipocampo/patología , Imagen por Resonancia Magnética/métodos , Trastorno de Pánico/patología , Estudios de Casos y Controles , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVE: This article focuses on the differential activation of the hypothalamic-pituitary-adrenal axis in generalized anxiety disorder and panic disorder. METHOD: The results of recently reported reviews of the literature are summarized and discussed. RESULTS: The results of experimental studies that assayed adrenocorticotropic hormone, cortisol and prolactin show that real-life panic attacks, as well as those induced by selective panicogenic agents such as lactate and carbon dioxide, do not activate the hypothalamic-pituitary-adrenal axis. Agonists of the cholecystokinin receptor B such as the cholecystokinin-4 peptide and pentagastrin increase stress hormones regardless of the occurrence of a panic attack and, thus, seem to activate the hypothalamic-pituitary-adrenal axis directly. The benzodiazepine antagonist flumazenil does not increase stress hormones, but this agent does not reliably induce panic attacks. Pharmacological agents that increase anxiety in both normal people and panic patients (caffeine, yohimbine, serotonergic agonists) raise stress hormone levels. CONCLUSIONS: In addition to the differences in symptomatology and pharmacological response, generalized anxiety disorder and panic disorder affect stress hormones in distinct ways. While anticipatory anxiety and generalized anxiety disorder activate both the hypothalamic-pituitary-adrenal and the sympathoadrenal axes, panic attack causes major sympathetic activation, but has little effect on the hypothalamic-pituitary-adrenal axis.
Asunto(s)
Sistema Hipotálamo-Hipofisario/fisiopatología , Trastorno de Pánico/fisiopatología , Sistema Hipófiso-Suprarrenal/fisiopatología , Estrés Psicológico/fisiopatología , Hormona Adrenocorticotrópica/metabolismo , Animales , Dióxido de Carbono/metabolismo , Modelos Animales de Enfermedad , Humanos , Sistema Hipotálamo-Hipofisario/metabolismo , Ácido Láctico/metabolismo , Trastorno de Pánico/metabolismo , Trastorno de Pánico/psicología , Sistema Hipófiso-Suprarrenal/metabolismo , Prolactina/metabolismo , Estrés Psicológico/metabolismoRESUMEN
This article reviews reported results about the effects of drugs that act upon the serotonergic neurotransmission measured in three elevated mazes that are animal models of anxiety. A bibliographic search has been performed in MEDLINE using different combinations of the key words X-maze, plus-maze, T-maze, serotonin and 5-HT, present in the title and/or the abstract, with no time limit. From the obtained abstracts, several publications were excluded on the basis of the following criteria: review articles that did not report original results, species other than the rat, intracerebral drug administration alone, genetically manipulated rats, and animals having any kind of experimental pathology. The reported results indicate that the effect of drugs on the inhibitory avoidance task performed in the elevated T-maze and on the spatio temporal indexes of anxiety measured in the X and plus mazes correlate with their effect in patients diagnosed with generalized anxiety disorder. In contrast, the drug effects on the one-way escape task in the elevated T-maze predict the drug response of panic disorder patients. Overall, the drug effects assessed with the avoidance task in the T-maze are more consistent than those measured through the anxiety indexes of the X and plus mazes. Therefore, the elevated T-maze is a promising animal model of generalized anxiety and panic disorder.