RESUMEN
Nitric oxide (NO) release in the right medial prefrontal cortex (RmPFC) produces anxiogenesis. In the bed nucleus of the stria terminalis (BNST), a region that receives neuronal projections from the mPFC, NO provokes anxiety, an effect that is blocked by local injections of corticotrophin-releasing factor type 1 receptor (CRF1) or n-methyl-d-aspartate receptor (NMDAr) antagonist. Anxiety is also enhanced by social defeat stress, and chronic stress impairs and facilitates, respectively, PFC and BNST roles in modulating behavioral responses to aversive situations. This study investigated whether the (i) chronic social defeat stress (CSDS) increases NO signaling in the mPFC; and/or (ii) anxiogenic effects provoked by the intra-RmPFC injection of NOC-9 (an NO donor) or by CSDS are prevented by intra-BNST injections of AP-7 (0.05 nmol) or CP 376395 (3.0 nmol), respectively, NMDAr and CRF1 antagonists, in male Swiss-Webster mice exposed to the elevated plus-maze (EPM). Results showed that (a) CSDS increased anxiety (i.e., reduced open-arm exploration) and repeatedly activated nNOS-containing neurons, as measured by ΔFosB (a stable nonspecific marker of neural activity) + nNOS double-labeling, in the right (but not left) mPFC, (b) NOC-9 in the RmPFC also increased anxiety, and (c) both CSDS and NOC-9 effects were reversed by injections of AP-7 or CP 376395 into the BNST. These results suggest that NMDA and CRF1 receptors located in BNST play an important role in the modulation of anxiety provoked by NO in the RmPFC, as well as by chronic social defeat in mice.
Asunto(s)
Ansiedad/metabolismo , Óxido Nítrico/metabolismo , Corteza Prefrontal/metabolismo , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Núcleos Septales/metabolismo , Derrota Social , Aminopiridinas/administración & dosificación , Animales , Ansiedad/inducido químicamente , Ansiedad/psicología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Microinyecciones , Óxido Nítrico/toxicidad , Corteza Prefrontal/efectos de los fármacos , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Núcleos Septales/efectos de los fármacos , Triazenos/administración & dosificaciónRESUMEN
It has been suggested that the left medial prefrontal cortex (LmPFC) has an inhibitory role in controlling the right mPFC (RmPFC), thereby reducing the deleterious effects of stressors on emotional states. Here, we investigated the effects on anxiety of bilateral or unilateral injections of NOC-9 [a nitric oxide (NO) donor] and cobalt chloride (CoCl2; a synaptic inhibitor) into the mPFC of mice exposed to the elevated plus-maze (Experiments 1 and 2). The effects of restraint or social defeat on anxiety in undrugged mice were recorded at 5 min or 24 h after exposure to the stress (Experiment 3). Experiment 4 investigated the effects of LmPFC injection of CoCl2 combined with restraint or social defeat on anxiety, which was recorded 24 h later. Although intra-RmPFC NOC-9 produced anxiogenesis, its injection into the LmPFC, or bilaterally, did not change anxiety. Intra-RmPFC or -LmPFC injection of CoCl2 produced anxiolytic- and anxiogenic-like effects, respectively. Both restraint and social defeat produced anxiogenesis at 5 min, but defeated mice did not display anxiety 24 h after the stress. Although intra-LmPFC CoCl2 did not change anxiety, which was recorded 24 h later in non-stressed mice, this synaptic inhibitor produced a clear, anxiogenic-like effect in defeated (but not restrained) mice. These results suggest that (i) nitrergic activation of the RmPFC increases anxiety, which in turn is inhibited by NO production within the LmPFC; (ii) neuronal inhibition of the RmPFC or LmPFC elicits anxiolysis and anxiogenesis, respectively; and (iii) inactivation of the LmPFC results in recrudescence of anxiety induced by social defeat stress.
Asunto(s)
Ansiedad/metabolismo , Lateralidad Funcional/fisiología , Óxido Nítrico/fisiología , Corteza Prefrontal/fisiología , Animales , Ansiolíticos/administración & dosificación , Ansiedad/inducido químicamente , Ansiedad/tratamiento farmacológico , Cobalto/administración & dosificación , Relación Dosis-Respuesta a Droga , Lateralidad Funcional/efectos de los fármacos , Inyecciones Intraventriculares , Masculino , Ratones , Corteza Prefrontal/efectos de los fármacos , Triazenos/administración & dosificaciónRESUMEN
It has been shown that the bed nucleus of the stria terminalis (BNST) of rats contains nitrergic neurons, which are activated during animal exposure to aversive stimuli. The BNST is also populated by glutamatergic and corticotrophin releasing factor (CRFergic) neurons, which in turn are activated under stressful situations. Here we investigated the anxiogenic-like effects of intra-BNST injections of a nitric oxide (NO) donor, NOC-9 in mice. The role of CRFergic and glutamatergic systems on defensive behavior induced by NOC-9 was investigated with previous intra-BNST infusion of different doses of CP376395, a CRF type 1 receptor antagonist (CRF1), or AP-7, an NMDA (N-methyl-D-aspartate) receptor antagonist. Anxiety-like behavior was assessed immediately and 5 min after intra-BNST drug injection, exposing mice to a novel arena and to the elevated plus-maze (EPM; an anxiogenic situation). Results showed that NOC-9 provoked a short period (≈ 150 s) of freezing behavior in the novel arena and increased anxiety in the EPM. Both CP and AP-7 attenuated the anxiogenic-like effects of NOC-9 in the EPM without changing freezing behavior in the novel arena. When given alone (i.e. without prior intra-BNST injection of NOC-9), AP-7 (0.20 nmol), but not CP (0.75, 1.50, or 3.00 nmol), attenuated anxiety in mice exposed to the EPM. These results suggest that CRF1 and NMDA receptors located within the BNST differentially modulate aversive effects induced by NO production in this limbic forebrain structure.
Asunto(s)
Ansiedad/inducido químicamente , Óxido Nítrico/farmacología , Receptores de Hormona Liberadora de Corticotropina/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Núcleos Septales/efectos de los fármacos , Aminopiridinas/farmacología , Animales , Ansiedad/metabolismo , Conducta Animal/efectos de los fármacos , Hormona Liberadora de Corticotropina/metabolismo , Reacción Cataléptica de Congelación/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Estrés Psicológico/inducido químicamente , Estrés Psicológico/metabolismo , Estrés Psicológico/psicología , Triazenos/farmacologíaRESUMEN
The anxiogenic and antinociceptive effects produced by glutamate N-methyl-D-aspartate receptor activation within the dorsal periaqueductal gray (dPAG) matter have been related to nitric oxide (NO) production, since injection of NO synthase (NOS) inhibitors reverses these effects. dPAG corticotropin-releasing factor receptor (CRFr) activation also induces anxiety-like behavior and antinociception, which, in turn, are selectively blocked by local infusion of the CRF type 1 receptor (CRFr1) antagonist, NBI 27914 [5-chloro-4-(N-(cyclopropyl)methyl-N-propylamino)-2-methyl-6-(2,4,6-trichlorophenyl)aminopyridine]. Here, we determined whether i) the blockade of the dPAG by CRFr1 attenuates the anxiogenic/antinociceptive effects induced by local infusion of the NO donor, NOC-9 [6-(2-hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-hexanamine], and ii) the anxiogenic/antinociceptive effects induced by intra-dPAG CRF are prevented by local infusion of Nω-propyl-L-arginine (NPLA), a neuronal NOS inhibitor, in mice. Male Swiss mice (12 weeks old, 25-35 g, N = 8-14/group) were stereotaxically implanted with a 7-mm cannula aimed at the dPAG. Intra-dPAG NOC-9 (75 nmol) produced defensive-like behavior (jumping and running) and antinociception (assessed by the formalin test). Both effects were reversed by prior local infusion of NBI 27914 (2 nmol). Conversely, intra-dPAG NPLA (0.4 nmol) did not modify the anxiogenic/antinociceptive effects of CRF (150 pmol). These results suggest that CRFr1 plays an important role in the defensive behavior and antinociception produced by NO within the dPAG. In contrast, the anxiogenic and antinociceptive effects produced by intra-dPAG CRF are not related to NO synthesis in this limbic midbrain structure.
Asunto(s)
Animales , Masculino , Ratones , Conducta Animal/efectos de los fármacos , Nocicepción/efectos de los fármacos , Sustancia Gris Periacueductal/efectos de los fármacos , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Triazenos/farmacología , Óxido Nítrico Sintasa/farmacología , Óxido Nítrico/farmacología , Sustancia Gris Periacueductal/fisiología , Receptores de Hormona Liberadora de Corticotropina/efectos de los fármacos , Receptores de Hormona Liberadora de Corticotropina/fisiologíaRESUMEN
The anxiogenic and antinociceptive effects produced by glutamate N-methyl-D-aspartate receptor activation within the dorsal periaqueductal gray (dPAG) matter have been related to nitric oxide (NO) production, since injection of NO synthase (NOS) inhibitors reverses these effects. dPAG corticotropin-releasing factor receptor (CRFr) activation also induces anxiety-like behavior and antinociception, which, in turn, are selectively blocked by local infusion of the CRF type 1 receptor (CRFr1) antagonist, NBI 27914 [5-chloro-4-(N-(cyclopropyl)methyl-N-propylamino)-2-methyl-6-(2,4,6-trichlorophenyl)aminopyridine]. Here, we determined whether i) the blockade of the dPAG by CRFr1 attenuates the anxiogenic/antinociceptive effects induced by local infusion of the NO donor, NOC-9 [6-(2-hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-hexanamine], and ii) the anxiogenic/antinociceptive effects induced by intra-dPAG CRF are prevented by local infusion of N(ω)-propyl-L-arginine (NPLA), a neuronal NOS inhibitor, in mice. Male Swiss mice (12 weeks old, 25-35 g, N = 8-14/group) were stereotaxically implanted with a 7-mm cannula aimed at the dPAG. Intra-dPAG NOC-9 (75 nmol) produced defensive-like behavior (jumping and running) and antinociception (assessed by the formalin test). Both effects were reversed by prior local infusion of NBI 27914 (2 nmol). Conversely, intra-dPAG NPLA (0.4 nmol) did not modify the anxiogenic/antinociceptive effects of CRF (150 pmol). These results suggest that CRFr1 plays an important role in the defensive behavior and antinociception produced by NO within the dPAG. In contrast, the anxiogenic and antinociceptive effects produced by intra-dPAG CRF are not related to NO synthesis in this limbic midbrain structure.
Asunto(s)
Conducta Animal/efectos de los fármacos , Nocicepción/efectos de los fármacos , Sustancia Gris Periacueductal/efectos de los fármacos , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Triazenos/farmacología , Animales , Masculino , Ratones , Óxido Nítrico/farmacología , Óxido Nítrico Sintasa/farmacología , Sustancia Gris Periacueductal/fisiología , Receptores de Hormona Liberadora de Corticotropina/efectos de los fármacos , Receptores de Hormona Liberadora de Corticotropina/fisiologíaRESUMEN
A single exposure to the elevated plus-maze test (EPM) increases open arms avoidance and reduces or abolishes the anxiolytic-like effect of benzodiazepines assessed during a second trial, a phenomenon defined as "one-trial tolerance" (OTT). It has been emphasized that the dorsal portion of the midbrain periaqueductal gray (dPAG) plays a role on this enhanced aversion phenomenon in maze-experienced rodents. Given that intra-dPAG injections of a wide range of serotonergic 5-HT(1A), 5-HT(2A) and 5-HT(2C) receptor agonists produce anxiolytic-like effects in maze-naïve rodents, the present study examined the effects of the 5-HT(1A) receptor agonist 8-OH-DPAT (5.6 and 10.0nmol in 0.15microl) the preferential 5-HT(2A) receptor agonist DOI (2.0 and 8.0nmol in 0.1microl) and the preferential 5-HT(2C) receptor agonist MK-212 (21.2 and 63.6nmol in 0.1microl) microinjected into the dPAG prior to Trial 1 and Trial 2 on the behaviour of mice in the EPM. Test sessions were recorded and subsequently scored for anxiety-like behaviour (percentage of open arms entries and time) as well as general locomotor activity (closed arm entries). The results showed a lack of 8-OH-DPAT (5.6 and 10.0nmol) effect on the behaviour of maze-naïve and maze-experienced mice, while intra-dPAG microinfusions of DOI (8nmol) reduced anxiety-like behaviour only in maze-experienced mice that had received a similar treatment prior to Trial 1. Furthermore, intra-dPAG MK-212 (63.6nmol) showed an anxiolytic-like effect on both Trial 1 and Trial 2. Importantly, these effects were observed in the absence of any significant change in closed arm entries, the parameter considered to be a valid index of locomotor activity in the plus-maze. These results support the dPAG as a crucial structure involved in the neurobiology of the OTT phenomenon as well as accounting the role of the 5-HT(2A) and 5-HT(2C) receptors located within this midbrain structure on the emotional state induced by EPM test and retest paradigm mice.
Asunto(s)
Ansiedad/patología , Aprendizaje por Laberinto/fisiología , Sustancia Gris Periacueductal/metabolismo , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2C/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Anfetaminas/farmacología , Análisis de Varianza , Animales , Ansiedad/fisiopatología , Conducta Animal , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Microinyecciones/métodos , Actividad Motora/efectos de los fármacos , Sustancia Gris Periacueductal/efectos de los fármacos , Pirazinas/farmacología , Reproducibilidad de los Resultados , Agonistas del Receptor de Serotonina 5-HT1 , Agonistas del Receptor de Serotonina 5-HT2 , Serotoninérgicos/farmacologíaRESUMEN
In order to investigate the relationship between behaviors elicited by chemical stimulation of the dorsal periaqueductal gray (dorsal PAG) and spontaneous defensive behaviors to a predator, the excitatory amino acid D,L-homocysteic acid (5 nmol in 0.1 micro l), was infused into the dorsal PAG and behavioral responses of mice were evaluated in two different situations, a rectangular novel chamber or the Mouse Defense Test Battery (MDTB) apparatus. During a 1-min period following drug infusion, more jumps were made in the chamber than in the MDTB runway but running time and distance traveled were significantly higher in the runway. Animals were subsequently tested using the standard MDTB procedure (anti-predator avoidance, chase and defensive threat/attack). No drug effects on these measures were significant. In a further test in the MDTB apparatus, the pathway of the mouse during peak locomotion response was blocked 3 times by the predator stimulus (anesthetized rat) to determine if the mouse would avoid contact. Ninety percent of D,L-homocysteic treated animals made direct contact with the stimulus (rat), indicating that D,L-homocysteic-induced running is not guided by relevant (here, threat) stimuli. These results indicate that running as opposed to jumping is the primary response in mice injected with D,L-homocysteic into the dorsal PAG when the environment enables flight. However, the lack of responsivity to the predator during peak locomotion suggests that D,L-homocysteic-stimulation into the dorsal PAG does not induce normal antipredator flight.
Asunto(s)
Conducta Animal , Sustancia Gris Periacueductal/efectos de los fármacos , Animales , Miedo , Homocisteína/administración & dosificación , Ratones , Sustancia Gris Periacueductal/fisiologíaRESUMEN
We have recently suggested that the elevated T-maze (ETM) is not a useful test to study different types of anxiety in mice if a procedure similar to that originally validated for rats is employed. The present study investigated whether procedural (five exposures in the enclosed arm instead of three as originally described for rats) and structural (transparent walls instead of opaque walls) changes to the ETM leads to consistent inhibitory avoidance acquisition (IAA) and low escape latencies in mice. Results showed that five exposures to the ETM provoked consistent IAA, an effect that was independent of the ETM used. However, the ETM with transparent walls (ETMt) seemed to be more suitable for the study of conditioned anxiety (i.e. IAA) and unconditioned fear (escape) in mice, since IAA (low baseline latency with a gradual increase over subsequent exposures) and escape (low latency) profiles rendered it sensitive to the effects of anxiolytic and anxiogenic drugs. In addition to evaluation of drug effects on IAA and escape, the number of line crossings in the apparatus were used to control for locomotor changes. Results showed that whereas diazepam (1.0-2.0 mg/kg) and flumazenil (10-30 mg/kg) impaired IAA, FG 7142 (10-30 mg/kg) did not provoke any behavioral change. Significantly, none of these benzodiazepine (BDZ) receptor ligands modified escape latencies. The 5-HT1A partial receptor agonist buspirone (1.0-2.0 mg/kg) and the 5-HT releaser fenfluramine (0.15-0.30 mg/kg) impaired IAA and facilitated escape, while the full 5-HT1A receptor agonist, 8-OH-DPAT (0.05-0.1 mg/kg) and the 5-HT(2B/2C) receptor antagonist, SER 082 (0.5-2.0 mg/kg) failed to modify either response. mCPP (0.5-2.0 mg/kg), a 5-HT(2B/2C) receptor agonist, facilitated IAA but did not alter escape latency. Neither antidepressant utilized in the current study, imipramine (1.0-5.0 mg/kg) and moclobemide (3.0-10 mg/kg) affected IAA or escape performance in mice. The well-known anxiogenic drugs yohimbine (2.0-8.0 mg/kg) and caffeine (10-30 mg/kg) did not selectively affect IAA, although caffeine did impair escape latencies. Present results suggest the ETMt is useful for the study of conditioned anxiety in mice. However, upon proximal threats (e.g. open arm exposure), mice do not exhibit escape behavior as an immediate defensive strategy, suggesting that latency to leave open arm is not a useful parameter to evaluate unconditioned fear in this species.
Asunto(s)
Ansiedad/fisiopatología , Reacción de Prevención/fisiología , Reacción de Fuga/fisiología , Aprendizaje por Laberinto/fisiología , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Análisis de Varianza , Animales , Ansiolíticos/uso terapéutico , Antidepresivos/farmacología , Ansiedad/tratamiento farmacológico , Depresores del Apetito/farmacología , Reacción de Prevención/efectos de los fármacos , Cafeína/farmacología , Carbolinas/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Condicionamiento Clásico/efectos de los fármacos , Condicionamiento Clásico/fisiología , Relación Dosis-Respuesta a Droga , Reacción de Fuga/efectos de los fármacos , Imipramina/farmacología , Inhibición Psicológica , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Distribución Aleatoria , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Serotoninérgicos/farmacología , Yohimbina/farmacologíaRESUMEN
Intracerebroventricular (i.c.v.) administration of the novel hypothalamic neuropeptide orexin-A stimulates food intake in rats, and delays the onset of behavioural satiety (i.e. the natural transition from feeding to resting). Furthermore, preliminary findings with the selective orexin-1 receptor antagonist, SB-334867, suggest that orexin-A regulation of food intake is mediated via the orexin-1 receptor. At present, however, little is known about either the intrinsic effects of SB-334867 on the normal structure of feeding behaviour, or its effects upon orexin-A-induced behavioural change. In the present study, we have employed a continuous monitoring technique to characterize the effects of SB-334867 (3-30 mg/kg, i.p.) on the microstructure of rat behaviour during a 1-h test with palatable wet mash. Administered alone, SB-334867 (30 mg/kg, but not lower doses) significantly reduced food intake and most active behaviours (eating, grooming, sniffing, locomotion and rearing), while increasing resting. Although suggestive of a behaviourally nonselective (i.e. sedative) action, the structure of feeding behaviour was well-preserved at this dose level, with the reduction in behavioural output clearly attributable to an earlier onset of behavioural satiety. As previously reported, orexin-A (10 microg per rat i.c.v.) stimulated food intake, increased grooming and delayed the onset of behavioural satiety. Pretreatment with SB-334867 dose-dependently blocked these effects of orexin-A, with significant antagonism evident at dose levels (3-10 mg/kg) below those required to produce intrinsic behavioural effects under present test conditions. Together, these findings strongly support the view that orexin-A is involved in the regulation of feeding patterns and that this influence is mediated through the orexin-1 receptor.
Asunto(s)
Benzoxazoles/farmacología , Proteínas Portadoras/farmacología , Hiperfagia/metabolismo , Péptidos y Proteínas de Señalización Intracelular , Neuropéptidos/farmacología , Receptores de Neuropéptido/antagonistas & inhibidores , Respuesta de Saciedad/efectos de los fármacos , Urea/farmacología , Animales , Conducta Apetitiva/efectos de los fármacos , Peso Corporal , Ingestión de Alimentos/efectos de los fármacos , Hiperfagia/inducido químicamente , Inyecciones Intraventriculares , Masculino , Naftiridinas , Receptores de Orexina , Orexinas , Ratas , Ratas Endogámicas , Receptores Acoplados a Proteínas G , Receptores de Neuropéptido/metabolismo , Urea/análogos & derivadosRESUMEN
Although intracerebroventricular (i.c.v.) administration of orexin-A has been reported to stimulate food intake and/or feeding behaviour in rats, mice and goldfish, little attention has thus far been paid to its effects on normal patterns of feeding. In the present study, a continuous monitoring technique was used to characterise the effects of this novel neuropeptide on the microstructure of rat behaviour during a 1-h test with palatable wet mash. Particular attention was devoted to the behavioural satiety sequence, in which feeding is followed by grooming and resting. Although results confirmed the hyperphagic effects of orexin-A (3.33-30.0 microg i.c. v.), gross behavioural analysis failed to reveal any reliable effects of peptide treatment on eating, drinking, sniffing, grooming, resting, locomotion or rearing. However, microstructural analysis revealed behavioural effects of orexin-A that are both dose- and time-dependent. At lower doses (3.33-10.0 microg), orexin-A primarily delayed behavioural satiety, i.e. the normal transition from eating to resting. In contrast, the 30 microg dose initially induced a sedative-like effect, significantly suppressing eating and other active behaviours for the first 15-20 min of the test period. This sedative-like effect resulted in a phase-shifting of the entire behavioural sequence with higher than control levels of eating, grooming, locomotion, rearing and sniffing observed over the second half of the test session. Present findings illustrate the advantages of microstructural behavioural analysis and suggest that the hyperphagic response to low doses of orexin-A results largely from a delay in behavioural satiety while that seen in response to high doses may occur in rebound to initial behavioural suppression. Further studies will be required to confirm the identity of the specific orexin receptors (i.e. OX(1) or OX(2)) involved in mediating the dose-dependent behavioural effects reported.
Asunto(s)
Conducta Animal/efectos de los fármacos , Proteínas Portadoras/administración & dosificación , Proteínas Portadoras/farmacología , Ingestión de Alimentos/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular , Neuropéptidos/administración & dosificación , Neuropéptidos/farmacología , Respuesta de Saciedad/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ingestión de Líquidos/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Aseo Animal/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Orexinas , Ratas , Ratas Endogámicas , Descanso , Factores de TiempoRESUMEN
RATIONALE: Mice exhibit antinociception after a single experience in the elevated plus maze (EPM), an animal model of anxiety. OBJECTIVE: This study investigated the mechanisms involved in this form of anxiety-induced antinociception. METHODS: Nociception was evaluated by means of the writhing test in mice confined either to the open or enclosed arms of the EPM. The effects of systemic (naloxone, midazolam and 8-OH-DPAT) or intra-amygdala (8-OH-DPAT, NAN-190 and midazolam) drug infusions were investigated in mice previously treated i.p. with 0.6% acetic acid, an algic stimulus that induces abdominal contortions. The effects of these drugs on conventional measures of anxiety (% entries and % time in open arms) in a standard EPM test were also independently investigated. RESULTS: Open-arm confinement resulted in a high-magnitude antinociception (minimum 85%, maximum 450%) compared with enclosed arm confinement. The opiate antagonist naloxone (1 mg/kg and 10 mg/kg) neither blocked this open arm-induced antinociception (OAIA) nor modified indices of anxiety in EPM. Administration of midazolam (0.5-2 mg/kg, s.c.) increased OAIA and produced antinociception in enclosed confined animals, as well as attenuating anxiety in the EPM. The 5-HT(1A) receptor agonist 8-OH-DPAT (0.05-1 mg/kg, s.c.) had biphasic effects on OAIA, antagonising the response at the lowest dose and intensifying it at the highest dose. In addition, low doses of this agent reduced anxiety in the EPM. Although bilateral injections of 8-OH-DPAT (5.6 nmol/0.4 microl) or NAN-190 (5.6 nmol and 10 nmol/0.4 microl) into the amygdala did not alter OAIA, increased anxiety was observed in the EPM. In contrast, intra-amygdala administration of midazolam (10 nmol and 30 nmol/0.4 microl) blocked both OAIA and anxiety. CONCLUSIONS: These results with systemic and intracerebral drug infusion suggest that 5-HT(1A) receptors localised in the amygdala are not involved in the pain inhibitory processes that are "recruited" during aversive situations. However, activation of these receptors does phasically increase anxiety. Although the intrinsic antinociceptive properties of systemically administered midazolam confounded interpretation of its effects on OAIA, intra-amygdala injections of this compound suggest that benzodiazepine receptors in this brain region modulate both the antinociceptive and behavioural (anxiety) responses to the EPM.
Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Amígdala del Cerebelo/fisiología , Analgesia/psicología , Ansiolíticos/farmacología , Ansiedad/psicología , Midazolam/farmacología , Agonistas de Receptores de Serotonina/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin/administración & dosificación , Animales , Ansiolíticos/administración & dosificación , Masculino , Ratones , Microinyecciones , Midazolam/administración & dosificación , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Dimensión del Dolor/efectos de los fármacos , Piperazinas/farmacología , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina 5-HT1 , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/administración & dosificaciónRESUMEN
The elevated T-maze has been developed as an animal model of anxiety to generate both conditioned and unconditioned fears in the same rat. This study explores a version of the elevated T-maze fit for mice. Inhibitory (passive) avoidance- conditioned fear-is measured by recording the latency to leave the enclosed arm during three consecutive trials. One-way escape- unconditioned fear-is measured by recording the time to withdraw from open arms. The results showed that mice do not appear to acquire inhibitory avoidance in the standard T-maze, since their latencies to leave enclosed arm did not increase along trials. Nevertheless, the open arms seemed to be aversive for mice, because the latency to leave the enclosed arm after the first trial was lower in a T-maze with the three enclosed arms than in the standard elevated T-maze. In agreement, the exposure of mice to an elevated T-maze without shield, that reduces the perception of openness, increased significantly the latencies to leave the enclosed arm. However, the absence of the shield also increased the time taken to leave the open arms when compared to that recorded in standard T-maze. Systematic observation of behavioral items in the enclosed arm has shown that risk assessment behavior decreases along trials while freezing increases. In the open arms, freezing did not appear to influence the high latency to leave this compartment, since mice spend only about 8% of their time exhibiting this behavior. These results suggest that mice acquire inhibitory avoidance of the open arms by decreasing and increasing time in risk assessment and freezing, respectively, along three consecutive trials. However, one-way escape could not be characterized. Therefore, there are important differences between mice (present results) and rats (previously reported results) in the performance of behavioral tasks in the elevated T-maze.
Asunto(s)
Trastornos de Ansiedad/psicología , Animales , Reacción de Prevención/fisiología , Conducta Animal/fisiología , Modelos Animales de Enfermedad , Diseño de Equipo , Reacción de Fuga/fisiología , Miedo/psicología , Masculino , Ratones , Psicología/instrumentación , Tiempo de Reacción/fisiologíaRESUMEN
The effect of intraperitoneal injection of clonidine (9-72 microg/kg) on need-free 1.5% NaCl intake and on performance (defined as percent of a complete trial) in the rotarod test, was studied in normovolemic adult male rats. Clonidine (18 and 36 microg/kg) inhibited the 1.5% NaCl intake in a 2-h test at doses that did not alter the performance in the rotarod test. The dose of 36 microg/kg did not inhibit 10% sucrose intake. Only the highest dose (72 microg/kg) of clonidine inhibited the 1.5% NaCl intake and the performance in the rotarod test, and produced signs of sedation. Sedation was determined either by change in posture (immobility or lack of postural tonus) of the animals during the ingestive test or by their performance in the rotarod test. The results suggest that sedation is not a determinant effect on the inhibition of 1.5% NaCl intake induced by clonidine.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Clonidina/farmacología , Sedación Consciente , Conducta Alimentaria/efectos de los fármacos , Cloruro de Sodio Dietético , Agonistas alfa-Adrenérgicos/administración & dosificación , Animales , Apetito/efectos de los fármacos , Clonidina/administración & dosificación , Sacarosa en la Dieta , Masculino , Equilibrio Postural/efectos de los fármacos , Desempeño Psicomotor/efectos de los fármacos , Ratas , Sodio/metabolismoRESUMEN
Recent results from our laboratory have shown that 30-bites social conflict in mice produces a high-intensity, short-term analgesia which is attenuated by systemically injected 5-HT1A receptor agonists, such as BAY R 1531 (6-methoxy-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz((c,d)indole hydrochloride) and gepirone. The present study investigated the effects of these drugs, as well as the 5-HT1A receptor antagonist WAY 100135 (N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2-phenylpropanamide ) injected into the midbrain periaqueductal gray matter of mice on 30-bites analgesia. Four to five days after guide-cannula implantation, each mouse received microinjection of gepirone (30 nmol/0.2 microl), BAY R 1531 (10 nmol/0.2 microl), WAY 100135 (10 nmol/0.2 microl), saline (0.9% NaCl) or vehicle (saline + 4% Tween 80) 5 min before either an aggressive (30 bites) or a non-aggressive interaction. Nociception was assessed by the tail-flick test made before as well as 1, 5, 10 and 20 min after social interaction. The full 5-HT1A receptor agonist BAY R 1531 blocked, whereas, WAY 100135 and gepirone intensified 30-bites analgesia. Neither non-aggressive interaction, per se, nor the three compounds given after this type of social interaction significantly changed nociception. These results indicate that 5-HT1A receptors in the periaqueductal gray inhibit analgesia induced by social conflict in mice.
Asunto(s)
Analgesia , Conflicto Psicológico , Mesencéfalo/fisiología , Sustancia Gris Periacueductal/fisiología , Receptores de Serotonina/fisiología , Agresión/efectos de los fármacos , Animales , Indoles/administración & dosificación , Indoles/farmacología , Masculino , Ratones , Microinyecciones , Piperazinas/administración & dosificación , Piperazinas/farmacología , Pirimidinas/administración & dosificación , Pirimidinas/farmacología , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/administración & dosificación , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/administración & dosificación , Agonistas de Receptores de Serotonina/farmacologíaRESUMEN
Social conflict between mice produces analgesia in the attacked mouse. Both the magnitude and type (opioid or nonopioid) of this analgesia have been related to attack intensity and strain of mouse. In the present study low intensity social conflict (7 bites) did not produce analgesia, whereas high intensity - 30 and 60 bites - interactions produced, respectively, short-lasting (5 min) and very short-lasting (1 min) analgesia in Swiss albino mice, when compared with nonaggressive interaction (0 bite). The 30 bites aggressive interaction induced analgesia (AIIA) was not affected by IP injection of either naloxone (5.0 and 7.5 mg/kg) or diazepam (0.5, 1.0, 2.0 and 4.0 mg/kg). However, this attack-induced analgesia was reduced after IP administration of the 5-HT1A agonists, gepirone (0.3 and 3.0 mg/kg) and BAY R 1531 (0.01 mg/kg). These results indicate that the analgesia induced by 30 bites social conflict in Swiss albino mice does not involve opioid and GABA-benzodiazepine (GABA-BZD) mechanisms. In addition, they suggest that high-intensity social conflict activates serotonergic pain modulatory systems that act through 5-HT1A receptors.
Asunto(s)
Analgesia , Analgésicos Opioides/farmacología , Conflicto Psicológico , Morfina/farmacología , Dolor/fisiopatología , Receptores de Serotonina/fisiología , Análisis de Varianza , Animales , Diazepam/farmacología , Indoles/farmacología , Masculino , Ratones , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Dimensión del Dolor , Pirimidinas/farmacología , Agonistas de Receptores de Serotonina/farmacologíaRESUMEN
Paw edema was induced in male Wistar rats (200-250 g) by intraplantar (ipl) administration of 2.5 micrograms endotoxin (Etx). Etx, like carrageenin, produced two distinct edema formation phases, an early phase (75 min) followed by a late phase (7 h). We showed that the edema formation in the early phase was antagonized by dipyrone (80 mg/kg, i.p.) and indomethacin (1 mg/kg, i.p.) by 52% and 55%, respectively, and that the late phase was resistant to these drugs. These results suggest that in the early phase prostaglandins appear to be involved in the process. However, the activation of the kinin cascade leading to the release of other mediators may be involved in the increase of edema in the late phase. To test this hypothesis, we investigated whether the release of nitric oxide (NO) is involved in the mechanism of endotoxin-induced rat paw edema during the late phase, using N omega-nitro-L-arginine methyl ester (L-NAME) (50 micrograms, ipl) as inhibitor of NO synthase and L-arginine (1 mg, ipl) as substrate of NO synthase. The paw edema induced by Etx was inhibited by L-NAME by 56% and increased by L-arginine by 81%. Furthermore, L-arginine given in combination with L-NAME completely reversed the inhibition of Etx-induced edema produced by L-NAME. These results support the hypothesis that in the late phase NO production is associated with the edema evoked by Etx.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Dipirona/uso terapéutico , Edema/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , NG-Nitroarginina Metil Éster/uso terapéutico , Animales , Arginina , Edema/inducido químicamente , Endotoxinas , Extremidades , Masculino , Ratas , Ratas WistarRESUMEN
1. Microinjection of morphine (0.31, 1.25 and 5.0 micrograms) into the periaqueductal grey area (PAG) of C57BL/6 (C57) and DBA/2 (DBA) mice increased the pain threshold in the tail-flick test. The highest dose also caused a behavioral reaction in both strains characterized by periods of immobility alternating with explosive motor behavior. 2. In the DBA strain, the analgesic effect was demonstrated with all doses of morphine, while in the C57 strain only the highest dose induced analgesia. 3. DBA mice presented a decrease in activity with the lowest dose of morphine, whereas in the C57 strain, this effect was obtained only with the highest dose of morphine. 4. These data corroborate at the PAG level the results of other studies which have shown that central and peripheral injections of morphine produce analgesia and alter motor activity in C57 and DBA strains. They also confirm that these two strains of mice present genotype-dependent differences in sensitivity to opioids as determined after injections of morphine into the PAG.
Asunto(s)
Morfina/farmacología , Sustancia Gris Periacueductal/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Microinyecciones , Morfina/administración & dosificación , Actividad Motora/efectos de los fármacos , Dolor , Especificidad de la EspecieRESUMEN
The present work reviews neurochemical, physiological and behavioral data recorded from the attacked mouse and integrates them into a model of coping mechanisms during social conflict. More specifically, the possible relationships between systems of pain, memory and defense are presented, with special emphasis on the role of endogenous opioid peptides (EOPs). In recipients of attack, decreased beta-endorphin-like immunoreactivity and changes in opiate and benzodiazepine binding characteristics are found in structures of the brain defensive system. EOPs mediate the social conflict-induced increase of dopamine synthesis in the periaqueductal grey and frontal cortex. Social conflict analgesia in attacked mice is under the control of central opioid and nonopioid (e.g., benzodiazepine, glutamate) mechanisms, and is modified by experience (e.g., long-term analgesic reaction; tolerance). EOPs and pain-inhibitory mechanisms participate in the organization of behavioral defense, recuperative behavior and the memory of attack experience. The data are considered in relation to the perceptual-defensive-recuperative model of fear and pain, forwarded by Bolles and Fanselow.