RESUMEN
The amygdala, medial hypothalamus, dorsal periaqueductal gray (dPAG), superior and inferior colliculus together constitutes the encephalic aversion system which has been considered the main neural substrate for the integration of unconditioned aversive behavioral states. Within the amygdala the basolateral nucleus (BLA) is thought to act as a filter for innate and learned aversive information to higher structures, whereas the central nucleus (CeA) is considered the main output for the expression of fear reactions through projections to limbic and brainstem regions. Although neurokinin (NK) receptors are abundant in the amygdala, their role in the processing and expression of fear is yet unclear. In this study, we examined the role of SP/NK1 receptor system of the CeA and BLA on the expression of defensive responses elaborated by Wistar rats submitted to elevated plus maze (EPM) and to electrical stimulation (ES) of the dPAG. For EPM test, cannulae were implanted in the CeA and BLA for injections of substance P (SP - 10 and 100pmol/0.2µL) and spantide (SPA - 10, 100 and 500pmol/0.2µL). For ES of dPAG, aversive thresholds for freezing and escape responses as well as post-stimulation freezing (PSF) were measured in rats treated with PBS and SPA (100pmol/0.2µL) in CeA. Injections of SP into the CeA, but not the BLA, produced anxiogenic-like effects in the EPM test. SPA injected into the CeA had no effect on the exploratory behavior of rats submitted to the EPM but blocked the effects of SP. The duration of dPAG-PSF was also reduced significantly following injection of SPA in CeA but had no effect on thresholds for freezing and escape responses. The EPM gives the animal a control over its environment i.e. the option to choose or not to enter into the open arm and dPAG-PSF is thought to reflect a period when the animal evaluates the significance of dPAG-evoked aversion once the unconditioned responses of freezing and escape were elicited. The data indicate that SP may be involved in mediating responses of the animal in only certain types of aversive behavior and suggests a differential participation of the NK1 receptors in the processing of distinct types of fear in the amygdala.
Asunto(s)
Amígdala del Cerebelo/fisiología , Reacción de Fuga/fisiología , Conducta Exploratoria/fisiología , Miedo/fisiología , Receptores de Neuroquinina-1/fisiología , Amígdala del Cerebelo/efectos de los fármacos , Animales , Reacción de Prevención/efectos de los fármacos , Reacción de Prevención/fisiología , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Reacción de Fuga/efectos de los fármacos , Conducta Exploratoria/efectos de los fármacos , Miedo/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Receptores de Neuroquinina-1/agonistas , Sustancia P/análogos & derivados , Sustancia P/farmacologíaRESUMEN
Electrical stimulation of midbrain tectum structures, particularly the dorsal periaqueductal gray (dPAG) and inferior colliculus (IC), produces defensive responses, such as freezing and escape behavior. Freezing also ensues after termination of dPAG stimulation (post-stimulation freezing). These defensive reaction responses are critically mediated by γ-aminobutyric acid and 5-hydroxytryptamine mechanisms in the midbrain tectum. Neurokinins (NKs) also play a role in the mediation of dPAG stimulation-evoked fear, but how NK receptors are involved in the global processing and expression of fear at the level of the midbrain tectum is yet unclear. The present study investigated the role of NK-1 receptors in unconditioned defensive behavior induced by electrical stimulation of the dPAG and IC of male Wistar rats. Spantide (100 pmol/0.2 μL), a selective NK-1 antagonist, injected into these midbrain structures had anti-aversive effects on defensive responses and distress ultrasonic vocalizations induced by stimulation of the dPAG but not of the IC. Moreover, intra-dPAG injections of spantide did not influence post-stimulation freezing or alter exploratory behavior in rats subjected to the elevated plus maze. These results suggest that NK-1 receptors are mainly involved in the mediation of defensive behavior organized in the dPAG. Dorsal periaqueductal gray-evoked post-stimulation freezing was not affected by intra-dPAG injections of spantide, suggesting that NK-1-mediated mechanisms are only involved in the output mechanisms of defensive behavior and not involved in the processing of ascending aversive information from the dPAG.
Asunto(s)
Animales , Masculino , Ratas , Ansiedad/fisiopatología , Reacción de Fuga/fisiología , Miedo/fisiología , Colículos Inferiores/efectos de los fármacos , Neuroquinina A/farmacología , Sustancia Gris Periacueductal/efectos de los fármacos , Receptores de Neuroquinina-1/antagonistas & inhibidores , Sustancia P/análogos & derivados , Reacción de Prevención , Estimulación Eléctrica , Colículos Inferiores/fisiología , Sustancia Gris Periacueductal/fisiología , Ratas Wistar , Sustancia P/farmacología , Vocalización AnimalRESUMEN
Electrical stimulation of midbrain tectum structures, particularly the dorsal periaqueductal gray (dPAG) and inferior colliculus (IC), produces defensive responses, such as freezing and escape behavior. Freezing also ensues after termination of dPAG stimulation (post-stimulation freezing). These defensive reaction responses are critically mediated by γ-aminobutyric acid and 5-hydroxytryptamine mechanisms in the midbrain tectum. Neurokinins (NKs) also play a role in the mediation of dPAG stimulation-evoked fear, but how NK receptors are involved in the global processing and expression of fear at the level of the midbrain tectum is yet unclear. The present study investigated the role of NK-1 receptors in unconditioned defensive behavior induced by electrical stimulation of the dPAG and IC of male Wistar rats. Spantide (100 pmol/0.2 µL), a selective NK-1 antagonist, injected into these midbrain structures had anti-aversive effects on defensive responses and distress ultrasonic vocalizations induced by stimulation of the dPAG but not of the IC. Moreover, intra-dPAG injections of spantide did not influence post-stimulation freezing or alter exploratory behavior in rats subjected to the elevated plus maze. These results suggest that NK-1 receptors are mainly involved in the mediation of defensive behavior organized in the dPAG. Dorsal periaqueductal gray-evoked post-stimulation freezing was not affected by intra-dPAG injections of spantide, suggesting that NK-1-mediated mechanisms are only involved in the output mechanisms of defensive behavior and not involved in the processing of ascending aversive information from the dPAG.
Asunto(s)
Ansiedad/fisiopatología , Reacción de Fuga/fisiología , Miedo/fisiología , Colículos Inferiores/efectos de los fármacos , Neuroquinina A/farmacología , Antagonistas del Receptor de Neuroquinina-1 , Sustancia Gris Periacueductal/efectos de los fármacos , Sustancia P/análogos & derivados , Animales , Reacción de Prevención , Estimulación Eléctrica , Colículos Inferiores/fisiología , Masculino , Sustancia Gris Periacueductal/fisiología , Ratas , Ratas Wistar , Sustancia P/farmacología , Vocalización AnimalRESUMEN
The dorsal periaqueductal gray (dPAG) is the main output structure for the defensive response to proximal aversive stimulation. Panic-like responses, such as freezing and escape behaviors, often result when this structure is electrically stimulated. Freezing also ensues after termination of the dPAG stimulation (post-stimulation freezing (PSF)). GABA and 5-HT have been proposed as the main neuromediators of these defense reactions. Neurokinins (NKs) also play a role in the defense reaction; however, it is unclear how the distinct types of NK receptors are involved in the expression of these fear responses. This study investigated the role of NK-1 and NK-3 receptors in the unconditioned defensive behaviors induced by electrical stimulation of the dPAG of rats, with and without previous experience with contextual fear conditioning (CFC). Spantide (100 ρmol/0.2 µl) and SB 222200 (50 and 100 ρmol/0.2 µl), selective antagonists of NK-1 and NK-3 receptors, respectively, were injected into the dPAG. Injection of spantide had antiaversive effects as determined by stimulation of the dPAG in naive animals and in animals subjected previously to CFC. SB 222200 also increased these aversive thresholds but only at doses that caused a motor deficit. Moreover, neither spantide nor SB 222200 influenced the PSF. The results suggest that NK-1 receptors are mainly involved in the mediation of the defensive behaviors organized in the dPAG. Because dPAG-evoked PSF was not affected by intra-dPAG injections of either spantide or SB 222200, it is suggested that neurokinin-mediated mechanisms are not involved in the processing of ascending aversive information from the dPAG.
Asunto(s)
Reacción de Prevención/efectos de los fármacos , Reacción de Fuga/efectos de los fármacos , Antagonistas del Receptor de Neuroquinina-1 , Sustancia Gris Periacueductal/fisiología , Quinolinas/farmacología , Receptores de Neuroquinina-3/antagonistas & inhibidores , Sustancia P/análogos & derivados , Análisis de Varianza , Animales , Biofisica , Condicionamiento Clásico/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica/efectos adversos , Conducta Exploratoria/efectos de los fármacos , Reacción Cataléptica de Congelación/efectos de los fármacos , Masculino , Microinyecciones , Actividad Motora/efectos de los fármacos , Ratas , Ratas Wistar , Sustancia P/farmacologíaRESUMEN
Ritalin (methylphenidate hydrochloride, MP) is a non-amphetamine psychostimulant and is the drug of choice to treat children and adults diagnosed with the attention deficit hyperactivity disorder (ADHD). Several studies have demonstrated that rats treated with MP during early developmental stage exhibit alterations in anxiety-related processes such as an increased response to stressful stimuli and elevated plasma levels of corticosterone. Accordingly, the present study was designed to further characterize the neural and behavioral consequences of withdrawal from MP in adult rats and its influence on the neural reactivity of the dorsal midbrain. After initial exposure to an elevated plus-maze (EPM), brainstem neural activation, elicited by exposure to EPM aversive cues, was analyzed using a Fos-protein immunolabeling technique. Additional independent groups of animals were submitted to electrical stimulation of the dorsal column (DPAG) or the startle response procedure, in order to verify the influence of withdrawal from MP on the expression of unconditioned fear induced by DPAG activation and the effects of or withdrawal from MP on motor response, respectively. Our results provide new findings about the influence of MP treatment in adult rats, showing that, after a sudden MP treatment-break, increased anxiety, associated with the neural sensitization of anxiety-related regions, ensues.