RESUMEN
It has been shown that fear conditioning improves the steady-state evoked potentials driven by a long lasting amplitude modulated tone in the inferior colliculus. In this work we tested the hypothesis that the amygdala modulates this effect, since it plays a crucial role in assessing the biological relevance of environmental stimuli. We inhibited the basolateral nucleus of the amygdala of rats by injecting a GABAa receptor agonist (muscimol) before the recall test session of an auditory fear conditioning paradigm and recorded the evoked activity in the central nucleus of the inferior colliculus. According to our results, the treatment with muscimol decreased the expression of freezing behavior during the recall test session, but did not impair the entrainment of the evoked activity in the inferior colliculus induced by fear conditioning. We repeated the injection protocol with another group of rats but without pairing the tone to an aversive stimulus and observed that the inhibition of the basolateral amygdala enhances the stimulus-driven activity in the inferior colliculus regardless of the conditioning task. Our findings suggest that the basolateral amygdala exerts a tonic modulation over the encoding of sensory information at the early stages of the sensory pathway.
Asunto(s)
Amígdala del Cerebelo/fisiología , Condicionamiento Clásico/fisiología , Potenciales Evocados/fisiología , Miedo/fisiología , Colículos Inferiores/fisiología , Estimulación Acústica , Amígdala del Cerebelo/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Condicionamiento Clásico/efectos de los fármacos , Potenciales Evocados/efectos de los fármacos , Agonistas de Receptores de GABA-A/farmacología , Colículos Inferiores/efectos de los fármacos , Masculino , Muscimol/farmacología , Ratas , Ratas WistarRESUMEN
BACKGROUND: Gamma-aminobutyric acid (GABA)ergic and opioid systems play a crucial role in the neural modulation of innate fear organised by the inferior colliculus (IC). In addition, the IC is rich in GABAergic fibres and opioid neurons, which are also connected to other mesencephalic structures, such as the superior colliculus and the substantia nigra. However, the contribution of distinct opioid receptors (ORs) in the IC during the elaboration and expression of innate fear and panic-like responses is unclear. The purpose of the present work was to investigate a possible integrated action exerted by ORs and the GABAA receptor-mediated system in the IC on panic-like responses. METHODS: The effect of the blockade of either µ1- or κ-ORs in the IC was evaluated in the unconditioned fear-induced responses elicited by GABAA antagonism with bicuculline. Microinjections of naloxonazine, a µ1-OR antagonist, or nor-binaltorphimine (nor-BNI), a κ-OR antagonist, were made into the IC, followed by intramesencephalic administration of the GABAA-receptor antagonist bicuculline. The defensive behaviours elicited by the treatments in the IC were quantitatively analysed, recording the number of escapes expressed as running (crossing), jumps, and rotations, over a 30-min period in a circular arena. The exploratory behaviour of rearing was also recorded. RESULTS: GABAA-receptor blockade with bicuculline in the IC increased defensive behaviours. However, pretreatment of the IC with higher doses (5 µg) of naloxonazine or nor-BNI followed by bicuculline resulted in a significant decrease in unconditioned fear-induced responses. CONCLUSIONS: These findings suggest a role played by µ1- and κ-OR-containing connexions and GABAA receptor-mediated neurotransmission on the organisation of panic attack-related responses elaborated by the IC neurons.
Asunto(s)
Conducta Animal/efectos de los fármacos , Colículos Inferiores/efectos de los fármacos , Mesencéfalo/efectos de los fármacos , Antagonistas de Narcóticos/farmacología , Pánico/efectos de los fármacos , Receptores Opioides kappa/antagonistas & inhibidores , Receptores Opioides mu/antagonistas & inhibidores , Animales , Bicuculina/farmacología , Conducta Exploratoria/efectos de los fármacos , Antagonistas de Receptores de GABA-A/farmacología , Masculino , Naloxona/análogos & derivados , Naloxona/farmacología , Naltrexona/análogos & derivados , Naltrexona/farmacología , Neuronas/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
BACKGROUND: The endogenous opioid peptide system has been implicated in the neural modulation of fear and anxiety organised by the dorsal midbrain. Furthermore, previous results indicate a fundamental role played by inferior colliculus (IC) opioid mechanisms during the expression of defensive behaviours, but the involvement of the IC µ1-opioid receptor in the modulation of anxiety- and panic attack-related behaviours remains unclear. Using a prey-versus-snake confrontation paradigm, we sought to investigate the effects of µ1-opioid receptor blockade in the IC on the defensive behaviour displayed by rats in a dangerous situation. METHODS: Specific pathogen-free Wistar rats were treated with microinjection of the selective µ1-opioid receptor antagonist naloxonazine into the IC at different concentrations (1.0, 3.0 and 5.0 µg/0.2 µL) and then confronted with rattlesnakes ( Crotalus durissus terrificus). The defensive behavioural repertoire, such as defensive attention, flat back approach (FBA), startle, defensive immobility, escape or active avoidance, displayed by rats either during the confrontations with wild snakes or during re-exposure to the experimental context without the predator was analysed. RESULTS: The blockade of µ1-opioid receptors in the IC decreased the expression of both anxiety-related behaviours (defensive attention, FBA) and panic attack-related responses (startle, defensive immobility and escape) during the confrontation with rattlesnakes. A significant decrease in defensive attention was also recorded during re-exposure of the prey to the experimental apparatus context without the predator. CONCLUSION: Taken together, these results suggest that a decrease in µ1-opioid receptor signalling activity within the IC modulates anxiety- and panic attack-related behaviours in dangerous environments.
Asunto(s)
Ansiedad/prevención & control , Conducta Animal/efectos de los fármacos , Miedo , Colículos Inferiores/efectos de los fármacos , Antagonistas de Narcóticos/farmacología , Trastorno de Pánico/prevención & control , Receptores Opioides mu/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Animales , Crotalus , Modelos Animales de Enfermedad , Cadena Alimentaria , Naloxona/análogos & derivados , Naloxona/farmacología , Ratas , Ratas WistarRESUMEN
BACKGROUND: There is a controversy regarding the key role played by opioid peptide neurotransmission in the modulation of panic-attack-related responses. AIMS: Using a prey versus rattlesnakes paradigm, the present work investigated the involvement of the endogenous opioid peptide-mediated system of the inferior colliculus in the modulation of panic attack-related responses. METHODS: Wistar rats were pretreated with intracollicular administration of either physiological saline or naloxone at different concentrations and confronted with rattlesnakes ( Crotalus durissus terrificus). The prey versus rattlesnake confrontations were performed in a polygonal arena for snakes. The defensive behaviors displayed by prey (defensive attention, defensive immobility, escape response, flat back approach and startle) were recorded twice: firstly, over a period of 15 min the presence of the predator and a re-exposure was performed 24 h after the confrontation, when animals were exposed to the experimental enclosure without the rattlesnake. RESULTS: The intramesencephalic non-specific blockade of opioid receptors with microinjections of naloxone at higher doses decreased both anxiety- (defensive attention and flat back approach) and panic attack-like (defensive immobility and escape) behaviors, evoked in the presence of rattlesnakes and increased non-defensive responses. During the exposure to the experimental context, there was a decrease in duration of defensive attention. CONCLUSIONS: These findings suggest a panicolytic-like effect of endogenous opioid receptors antagonism in the inferior colliculus on innate (panic attack) and conditioned (anticipatory anxiety) fear in rats threatened by rattlesnakes.
Asunto(s)
Miedo/efectos de los fármacos , Colículos Inferiores/efectos de los fármacos , Naloxona/farmacología , Péptidos Opioides/fisiología , Trastorno de Pánico/tratamiento farmacológico , Animales , Reacción de Prevención/efectos de los fármacos , Crotalus , Mecanismos de Defensa , Reacción de Fuga/efectos de los fármacos , Miedo/psicología , Colículos Inferiores/fisiología , Masculino , Péptidos Opioides/antagonistas & inhibidores , Ratas , Ratas WistarRESUMEN
Auditory-evoked potentials (AEPs) can be modified by associative learning, where the appearance of learned compensatory responses (CCRs) may result in the emergence of drug withdrawal symptoms and relapse. Although CCRs' influence on later attentive and cognitive domains has been extensively examined, contextual conditioned tolerance occurring in preattentive mechanisms operating at earlier stages of information processing has remained largely unexplored. To extend our knowledge on this subject, compensatory changes on the motor and emotional aspects of behavior evoked by contextual cues were investigated with an electronic open field in morphine-pretreated rats challenged with two morphine overdoses (40 and 80â¯mg/kg). CCRs influence on the AEPs recorded in the central nucleus of the inferior colliculus (CIC) was analyzed with the help of a field potential recording device and a two-chamber shuttle box placed inside a Faraday cage system. The emergence of electrophysiological CCRs was analyzed by recording AEP latency and amplitude elicited in the central nucleus of the IC (CIC) with the aid of a field potential recording device and a two-chamber shuttle box placed inside a Faraday cage system. Behavioral analysis indicated that CCRs ensue in non-familiar contexts. Electrophysiological data revealed increases in the amplitude of AEPs evoked in a non-familiar context. Our results indicate that behavioral learning responses emerge following Pavlovian conditioning even with the use of low and regular doses of morphine over a short-term treatment. Changes in the CIC electrophysiology may indicate that the development of drug dependence occurs covertly in the early stages of sensory information processing.
Asunto(s)
Condicionamiento Clásico/efectos de los fármacos , Potenciales Evocados Auditivos/efectos de los fármacos , Colículos Inferiores/efectos de los fármacos , Colículos Inferiores/fisiología , Morfina/administración & dosificación , Refuerzo en Psicología , Animales , Conducta Animal/efectos de los fármacos , Señales (Psicología) , Masculino , Ratas WistarRESUMEN
Abstract Introduction: Salicylate at high doses induces tinnitus in humans and experimental animals. However, the mechanisms and loci of action of salicylate in inducing tinnitus are still not well known. The expression of Immediate Early Genes (IEG) is traditionally associated with long-term neuronal modifications but it is still not clear how and where IEGs are activated in animal models of tinnitus. Objectives: Here we investigated the expression of c-fos and Egr-1, two IEGs, in the Dorsal Cochlear Nucleus (DCN), the Inferior Colliculus (IC), and the Posterior Ventral Cochlear Nucleus (pVCN) of rats. Methods: Rats were treated with doses known to induce tinnitus in rats (300 mg/kg i.p. daily, for 3 days), and c-fos and Egr-1 protein expressions were analyzed using western blot and immunocytochemistry. Results: After administration of salicylate, c-fos protein expression increased significantly in the DCN, pVCN and IC when assayed by western blot. Immunohistochemistry staining showed a more intense labeling of c-fos in the DCN, pVCN and IC and a significant increase in c-fos positive nuclei in the pVCN and IC. We did not detect increased Egr-1 expression in any of these areas. Conclusion: Our data show that a high dose of salicylate activates neurons in the DCN, pVCN and IC. The expression of these genes by high doses of salicylate strongly suggests that plastic changes in these areas are involved in the genesis of tinnitus.
Resumo Introdução: Salicilato em doses elevadas induz zumbido nos seres humanos e em animais experimentais. No entanto, os mecanismos e loci de ação do salicilato na indução de zumbido ainda não são bem conhecidos. A expressão dos genes precoces imediatos (GPIs) está tradicionalmente associada a alterações neuronais em longo prazo, mas ainda não está claro como e onde os GPIs são ativados em modelos animais de zumbido. Objetivos: No presente estudo investigamos a expressão de c-fos e Egr-1, dois GPIs, no núcleo coclear dorsal (NCD), colículo inferior (CI) e núcleo coclear ventral posterior (NCVp) de ratos. Métodos: Os ratos foram tratados com doses que, conhecidamente, induzem zumbido em ratos (300 mg/kg IP/dia, por três dias) e as expressões das proteínas c-fos e Egr-1 foram analisadas por meio de Western blot e imunoistoquímica. Resultados: Após a administração de salicilato, a expressão da proteína c-fos aumentou significativamente no NCD, NCVp e CI, quando analisados por Western blot. A coloração imunoistoquímica mostrou uma marcação mais intensa de c-fos no NCD, NCVp e CI e um aumento significativo de núcleos positivos de c-fos no NCVp e CI. Não detectamos aumento da expressão de Egr-1 em qualquer dessas áreas. Conclusão: Nossos dados mostram que uma dose alta de salicilato ativa neurônios no NCD, NCVp e CI. A expressão desses genes por doses altas de salicilato sugere que as alterações plásticas nessas áreas estão envolvidas na gênese do zumbido.
Asunto(s)
Animales , Masculino , Ratas , Colículos Inferiores/efectos de los fármacos , Salicilatos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Genes Inmediatos-Precoces/efectos de los fármacos , Núcleo Coclear/efectos de los fármacos , Salicilatos/administración & dosificación , Western Blotting , Genes fos/efectos de los fármacos , Ratas Wistar , Relación Dosis-Respuesta a Droga , Proteína 1 de la Respuesta de Crecimiento Precoz/efectos de los fármacosRESUMEN
Dysfunctions of the serotonergic system have been suggested to be important in the neurobiology of schizophrenia. Patients with schizophrenia exhibit deficits in an operational measure of sensorimotor gating: prepulse inhibition (PPI) of startle. PPI is the normal reduction in the startle response caused by a low intensity non-startling stimulus (prepulse) which is presented shortly before the startle stimulus (pulse). The hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI), a 5-hydroxytryptamine(HT)2 receptor agonist disrupted PPI in rats. The inferior colliculus (IC) is a critical nucleus of the auditory pathway mediating acoustic PPI. The activation of the IC by the acoustic prepulse reduces startle magnitude. The present study investigated the role of serotonergic transmission in the IC on the expression of acoustic PPI. For that we investigated whether 5-HT2A receptor activation or blockade would affect this response. Unilateral microinjection of DOI (10µg/0.3µl) into the IC disrupted PPI, while microinjection of the 5-HT2A receptor antagonist ritanserin (4µg/0.3µl), into this structure did not alter PPI. We also examined the ability of the atypical antipsychotic clozapine (5.0mg/kg; I.P.) to reverse the disruption of PPI produced by unilateral microinjections of DOI into the IC of rats. Pretreatment with clozapine blocked DOI-induced disruption of PPI. Altogether, these results suggest that serotonin-mediated mechanisms of the IC are involved in the expression of PPI in rodents and that this response is sensitive to atypical antipsychotic clozapine.
Asunto(s)
Anfetaminas/administración & dosificación , Antipsicóticos/administración & dosificación , Clozapina/administración & dosificación , Colículos Inferiores/efectos de los fármacos , Colículos Inferiores/fisiología , Inhibición Prepulso/efectos de los fármacos , Animales , Masculino , Microinyecciones , Ratas Wistar , Receptor de Serotonina 5-HT2A/fisiología , Ritanserina/administración & dosificación , Agonistas del Receptor de Serotonina 5-HT2/administración & dosificación , Antagonistas del Receptor de Serotonina 5-HT2/administración & dosificaciónRESUMEN
INTRODUCTION: Salicylate at high doses induces tinnitus in humans and experimental animals. However, the mechanisms and loci of action of salicylate in inducing tinnitus are still not well known. The expression of Immediate Early Genes (IEG) is traditionally associated with long-term neuronal modifications but it is still not clear how and where IEGs are activated in animal models of tinnitus. OBJECTIVES: Here we investigated the expression of c-fos and Egr-1, two IEGs, in the Dorsal Cochlear Nucleus (DCN), the Inferior Colliculus (IC), and the Posterior Ventral Cochlear Nucleus (pVCN) of rats. METHODS: Rats were treated with doses known to induce tinnitus in rats (300mg/kg i.p. daily, for 3 days), and c-fos and Egr-1 protein expressions were analyzed using western blot and immunocytochemistry. RESULTS: After administration of salicylate, c-fos protein expression increased significantly in the DCN, pVCN and IC when assayed by western blot. Immunohistochemistry staining showed a more intense labeling of c-fos in the DCN, pVCN and IC and a significant increase in c-fos positive nuclei in the pVCN and IC. We did not detect increased Egr-1 expression in any of these areas. CONCLUSION: Our data show that a high dose of salicylate activates neurons in the DCN, pVCN and IC. The expression of these genes by high doses of salicylate strongly suggests that plastic changes in these areas are involved in the genesis of tinnitus.
Asunto(s)
Núcleo Coclear/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Genes Inmediatos-Precoces/efectos de los fármacos , Colículos Inferiores/efectos de los fármacos , Salicilatos/farmacología , Animales , Western Blotting , Relación Dosis-Respuesta a Droga , Proteína 1 de la Respuesta de Crecimiento Precoz/efectos de los fármacos , Genes fos/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Salicilatos/administración & dosificaciónRESUMEN
It has been shown that electrical stimulation of the mesencephalic tectum (MT) provokes defensive responses in both humans and rodents. During an emotional aversive state, some convergent studies have also demonstrated the existence of a complex interaction between endogenous opioid peptide- and γ-aminobutyric acid (GABA)-containing connections during fear-induced responses. It has been proposed that opioid neurons exert an influence on GABAergic interneurons, which, in turn, exert inhibitory tonic control on the mesencephalic excitatory pathways. Thus, opioid peptides can disinhibit neurons that are tonically inhibited by GABA, therefore, modulating the expression of defensive behavioural reactions. In the present work, we used both electric stimulation and microinjections of the GABAA receptor antagonist bicuculline in the inferior colliculus (IC) of Wistar rats in combination with microinjections of µ- and κ-opioid receptor selective agonists into the dorsal columns of periaqueductal grey matter (dPAG) to evaluate the effects on panic-like behaviours elicited by IC electrical and chemical stimulation. The present results showed that neurochemical lesions of the dPAG caused a significant impairment in the organisation of defensive responses by IC neurons, reducing the duration [t(14)=3.0; p<0.01] of defensive immobility and the duration [t(14)=2.8; p<0.05] and frequency [t(14)=2.5; p<0.05] of escape. Paradoxically, treating the dPAG with the µ-opioid receptor agonist met-enkephalin caused a significant reduction of panic-like behaviours induced by both electrical and chemical stimulation of the IC, increasing the escape behaviour threshold [F(2,23)=13.5; p<0.001] and decreasing the frequency [F(3,36)=11.7; p<0.001] and duration [F(3,36)=11.6; p<0.001] of escape and the duration of defensive immobility [F(3,36)=16.1; p<0.05]. In contrast, treating the dPAG with the κ-opioid receptor agonist salvinorin-A increased the frequency [F(3,36)=12.4; p<0.01] and duration [F(3,34)=16.1; p<0.01] of defensive immobility induced by GABAA receptor blockade in the IC. The present results suggest the existence of a complex neuronal network in the MT in which endogenous opioid peptides and GABAergic pathways interact in the control of fear-related behavioural responses.
Asunto(s)
Analgésicos Opioides/farmacología , Colículos Inferiores/fisiología , Pánico/fisiología , Sustancia Gris Periacueductal/fisiología , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Animales , Bicuculina/farmacología , Diterpenos de Tipo Clerodano/farmacología , Estimulación Eléctrica , Encefalina Metionina/farmacología , Reacción de Fuga/fisiología , Reacción Cataléptica de Congelación/fisiología , Antagonistas de Receptores de GABA-A/farmacología , Ácido Iboténico , Colículos Inferiores/efectos de los fármacos , Masculino , Neuronas/efectos de los fármacos , Neuronas/fisiología , Sustancia Gris Periacueductal/efectos de los fármacos , Ratas Wistar , Receptores de GABA-A/metabolismo , Receptores Opioides kappa/agonistas , Receptores Opioides mu/agonistasRESUMEN
The inferior colliculus (IC) is an important midbrain relay station for the integration of descending and ascending auditory information. In addition, it has also been implicated in the processing of acoustic information of aversive nature, as well as in sensory-motor gating. There is evidence that glutamate-mediated mechanisms at the IC level influence haloperidol-induced catalepsy. The present study investigated the influence of glutamate-mediated mechanisms in the IC on catalepsy induced by intrastriatal microinjection of haloperidol (10 µg/0.5 µl). Male Wistar rats received bilateral intracollicular microinjections of the glutamate receptor agonist NMDA (10 or 20 nmol/0.5 µl), the NMDA receptor antagonists MK-801 (15 or 30 nmol/0.5 µl) or physiological saline (0.5 µl), followed by bilateral microinjections of haloperidol (10 µg/0.5 µl) or vehicle (0.5 µl) into the dorso-rostral or ventro-rostral striatum. The catalepsy test was performed positioning both forepaws of the rats on an elevated horizontal wooden bar and recording the time during which the animal remained in this position. The results showed that the administration of physiological saline in the IC followed by the microinjection of haloperidol in the dorso-rostral region of the striatum was not able to induce catalepsy. However, when the bilateral administration of NMDA into the IC was followed by microinjection of haloperidol into the dorso-rostral striatum, catalepsy was observed. The microinjection of haloperidol into the ventro-rostral striatum induced catalepsy, counteracted by previous administration of MK-801 into the IC. These findings suggest that glutamate-mediated mechanisms in the IC can influence the intrastriatal haloperidol-induced catalepsy and that the IC plays an important role as a sensorimotor interface.
Asunto(s)
Antipsicóticos/efectos adversos , Catalepsia/inducido químicamente , Ácido Glutámico/metabolismo , Haloperidol/efectos adversos , Colículos Inferiores/efectos de los fármacos , Colículos Inferiores/fisiopatología , Animales , Catalepsia/fisiopatología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiopatología , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Masculino , N-Metilaspartato/metabolismo , Ratas Wistar , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiologíaRESUMEN
Chemical and electrical stimulation of the inferior colliculus (IC) causes defensive behavior. Electrical stimulation of the IC at the escape threshold enhances dopamine (DA) release in the prefrontal cortex. Intra-ventral tegmental area injections of quinpirole at doses that act presynaptically reduce the release of DA in the terminal fields of the mesolimbic system and clearly reduce conditioned fear in several animal models of anxiety. However, little is known about the involvement of DA in the mediation of unconditioned fear, such as the reactivity to acute stressors. The present study investigated the neural substrates mediated by DA transmission associated with emotional changes triggered by the activation or inhibition of D2 receptors during conditioned and unconditioned fear. We examined the effects of systemic or local injections of the DA-receptor antagonist and agonist haloperidol and quinpirole, respectively, into the IC in rats subjected to fear-potentiated startle, a Pavlovian paradigm that uses loud sounds as the unconditioned stimulus and light previously paired with footshock as the conditioned stimulus. We also assessed auditory-evoked potentials (AEPs) recorded from electrodes implanted in the IC. Intraperitoneal haloperidol administration dose-dependently enhanced AEPs induced by loud tones and inhibited fear-potentiated startle. Intra-IC injections of quinpirole left AEPs unchanged, suggesting that an optimal level of postsynaptic D2 receptors in the IC may regulate the transmission of aversive information through the midbrain tectum. These findings provide evidence of opposing DA-mediated mechanisms in fear/anxiety processes that depend on the area under study. The activity of the neural substrates of conditioned fear was attenuated by haloperidol, whereas midbrain neural substrates of unconditioned fear were enhanced. Thus, DA appears to regulate unconditioned fear at the midbrain level, likely by reducing the sensory gating of aversive events and reducing conditioned fear by acting at more rostral levels of the brain.
Asunto(s)
Condicionamiento Clásico/efectos de los fármacos , Antagonistas de Dopamina/farmacología , Miedo/efectos de los fármacos , Haloperidol/farmacología , Colículos Inferiores/efectos de los fármacos , Animales , Catalepsia/inducido químicamente , Condicionamiento Clásico/fisiología , Agonistas de Dopamina/farmacología , Antagonistas de los Receptores de Dopamina D2 , Potenciales Evocados Auditivos/efectos de los fármacos , Potenciales Evocados Auditivos/fisiología , Miedo/fisiología , Colículos Inferiores/fisiología , Masculino , Quinpirol/farmacología , Ratas , Ratas Wistar , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/fisiología , Estrés Fisiológico/efectos de los fármacos , Estrés Fisiológico/fisiologíaRESUMEN
Not only is the inferior colliculus (IC) a highly important center of integration within the central auditory pathway, but it may also play a modulatory role in sensory-motor circuitry. Previous evidence from our laboratory relating the IC to motor behavior shows that glutamate-mediated mechanisms within the IC modulate haloperidol-induced catalepsy. The high density of GABAergic receptors in the IC led to this study of a possible link between these receptors, haloperidol-induced catalepsy, and a possible involvement of the blockade of dopaminergic receptors. Catalepsy was evaluated by positioning both forepaws of rats on an elevated horizontal wooden bar and recording the time that the animal maintained this position. The present study shows that haloperidol-induced catalepsy was enhanced by local microinjection into the IC of midazolam (20nmol/0.5µl), a benzodiazepine receptor agonist, whereas animals receiving a microinjection of bicuculline (40 or 80ng/0.5µl), a GABAergic antagonist, showed a reduction in the time of catalepsy. However, the microinjection of haloperidol (2.5 or 5.0µg/0.5µl) bilaterally into the IC did not induce catalepsy. Therefore, our results suggest the involvement of the IC in the modulation of catalepsy induced by haloperidol, even though the dopaminergic mechanisms of the IC are unable to induce catalepsy when blocked by the direct microinjection of haloperidol. It is thus possible that the IC plays a role in sensorimotor gating and that GABA-mediated mechanisms are involved.
Asunto(s)
Catalepsia/metabolismo , Antagonistas de Dopamina/farmacología , Haloperidol/farmacología , Colículos Inferiores/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Animales , Catalepsia/inducido químicamente , Antagonistas de Receptores de GABA-A/farmacología , Colículos Inferiores/efectos de los fármacos , Masculino , Ratas , Ratas WistarRESUMEN
Patients with schizophrenia exhibit deficits in an operational measure of sensorimotor gating: prepulse inhibition (PPI) of startle. PPI is the normal reduction in the startle response caused by a low intensity non-startling stimulus (prepulse) which is presented shortly before the startle stimulus (pulse). MK-801 is an NMDA receptor-antagonist known to produce hyperactivity, deficits in prepulse inhibition and social withdrawal, behaviors which correlate well with some of the positive, cognitive and negative symptoms of schizophrenia. The inferior colliculus (IC) is a critical part of the auditory pathway mediating acoustic PPI. The activation of the IC by the acoustic prepulse reduces startle magnitude. Thus, the purpose of the present study was to elucidate the role of glutamatergic transmission in the IC on the expression of acoustic PPI. For that we investigated whether NMDA receptor stimulation or blockade would affect this response. Unilateral microinjections of NMDA (30 nmol/0.5 µL) into the IC did not alter PPI while microinjections of MK-801 (30 nmol/0.5 µL) into this structure disrupted PPI. We also examined the ability of the atypical antipsychotic olanzapine (5.0mg/kg; i.p.) to reverse the disruption of pre-pulse inhibition produced by unilateral microinjections of MK-801 into the IC of rats. Pretreatment with olanzapine blocked MK-801-induced disruption of PPI. Altogether, these results suggest that glutamate-mediated mechanisms of the IC are involved in the expression of PPI in rodents and that this response is sensitive to atypical antipsychotic olanzapine.
Asunto(s)
Antipsicóticos/farmacología , Benzodiazepinas/farmacología , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Colículos Inferiores/efectos de los fármacos , Filtrado Sensorial/efectos de los fármacos , Estimulación Acústica/métodos , Análisis de Varianza , Animales , Agonistas de Aminoácidos Excitadores/farmacología , Masculino , Microinyecciones , N-Metilaspartato/farmacología , Olanzapina , Psicoacústica , Ratas , Ratas Wistar , Reflejo de Sobresalto/efectos de los fármacosRESUMEN
The inferior colliculus (IC) is a mesencephalic auditory nucleus involved in several functions including the analysis of the frequency and intensity of sounds as well as sound localization. In addition to auditory processes, the IC controls the expression of defensive responses. The objective of the present study was to test the hypothesis that the IC contributes to the maintenance of wakefulness. For this purpose, several experimental approaches were performed in urethane-anesthetized guinea pigs. Electrical or chemical stimulation of the IC resulted in electroencephalographic (EEG) desynchronization, theta rhythm in the hippocampus and an increase in heart rate; all of these effects suggest an arousal reaction. Furthermore, by means of extracellular unit recordings, we determined that most IC neurons increased their spontaneous and tone-evoked responses in association with EEG desynchronization. We also studied the effect on sleep and wakefulness of bilateral acute inhibition of the IC by microinjections of muscimol (a GABAA agonist), as well as the effect of bilateral IC lesions in chronically-instrumented (drug-free) guinea pigs. Acute (via muscimol microinjections), but not chronic (via electrolytic lesions) inhibition of the IC decreased wakefulness., We conclude that the IC plays an active role in the maintenance of wakefulness. Further, we propose that this nucleus may mediate arousal responses induced by biologically significant sounds.
Asunto(s)
Nivel de Alerta/fisiología , Colículos Inferiores/fisiología , Vigilia/fisiología , Potenciales de Acción/efectos de los fármacos , Animales , Nivel de Alerta/efectos de los fármacos , Bicuculina/farmacología , Estimulación Eléctrica , Electroencefalografía , Potenciales Evocados/efectos de los fármacos , Agonistas de Receptores de GABA-A/farmacología , Cobayas , Frecuencia Cardíaca/fisiología , Hipocampo/fisiología , Colículos Inferiores/efectos de los fármacos , Masculino , Microelectrodos , Muscimol/farmacología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Sueño/efectos de los fármacos , Sueño/fisiología , Ritmo Teta/fisiología , Factores de Tiempo , Vigilia/efectos de los fármacosRESUMEN
Stress leads to secretion of the adrenal steroid hormone corticosterone (CORT). The aim of this study was to determine the effects of chronic CORT administration on auditory and visual fear conditioning. Male Sprague-Dawley rats received CORT (400 mg/ml) in their drinking water for 10 consecutive days; this treatment induces stress levels of serum CORT. CORT impaired fear conditioning (F((1,28)) = 11.52, p < 0.01) and extinction (F((1,28)) = 4.86, p < 0.05) of auditory fear learning, but did not affect visual fear conditioning. In addition, we analyzed the CORT effects on the neuronal morphology of the inferior colliculus (flat neurons, auditory mesencephalon, a key brain area for auditory processing) and superior colliculus (wide-field neurons, related to visual processing) by Golgi stain. CORT decreased dendritic arborization of inferior colliculus neurons by approximately 50%, but did not affect superior colliculus neurons. Thus, CORT had more deleterious effects on the auditory fear processing than the visual system in the brain.
Asunto(s)
Corticosterona/farmacología , Colículos Inferiores/efectos de los fármacos , Colículos Inferiores/fisiología , Estimulación Acústica , Animales , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , Corticosterona/sangre , Dendritas/efectos de los fármacos , Dendritas/fisiología , Miedo/efectos de los fármacos , Miedo/fisiología , Colículos Inferiores/anatomía & histología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Modelos Neurológicos , Estimulación Luminosa , Ratas , Ratas Sprague-Dawley , Estrés FisiológicoRESUMEN
The inferior colliculus (IC), a midbrain structure that processes acoustic information of aversive nature, is distinguished from other auditory nuclei in the brainstem by its connections with structures of the motor system. Recent evidence relating the IC to motor behavior shows that glutamate-mediated mechanisms in the neural circuits at the IC level modulate haloperidol-induced catalepsy. It has been shown that N(G)-nitro-L-arginine (L-NOARG), inhibitor of enzyme nitric oxide synthase (NOS), can induce catalepsy after intraperitoneal (ip), intracerebroventricular or intrastriatal administration. The present study examined whether the catalepsy induced by L-NOARG (ip) can be influenced by collicular glutamatergic mechanisms and if a NO-dependent neural substrate into the IC plays a role in this immobility state. L-NOARG-induced catalepsy was challenged with prior intracollicular microinjections of glutamate NMDA receptor antagonists, AP7 (20 or 40 nmol/0.5 µl), or of the NMDA receptor agonist N-methyl-D-aspartate (NMDA, 30 nmol/0.5 µl). Catalepsy was evaluated by positioning both forepaws of the rats on an elevated horizontal wooden bar and recording the time for which the animal maintained this position. The results showed that intracollicular microinjection of AP7 previous to systemic injections of L-NOARG (90 mg/kg) significantly attenuated the catalepsy. Conversely, intracollicular microinjection of NMDA increased the time of catalepsy when administered 10 min before systemic L-NOARG (10 or 45 mg/kg). The microinjection of L-NOARG (50 or 100 nmol) directly into the IC was not able to induce catalepsy. These findings suggest that glutamate-mediated mechanisms in the neural circuits of the IC modulate L-NOARG-induced catalepsy and participate in the regulation of motor activity.
Asunto(s)
Catalepsia/inducido químicamente , Catalepsia/patología , Inhibidores Enzimáticos/toxicidad , Colículos Inferiores/metabolismo , Nitroarginina/toxicidad , Receptores de N-Metil-D-Aspartato/metabolismo , 2-Amino-5-fosfonovalerato/administración & dosificación , 2-Amino-5-fosfonovalerato/análogos & derivados , Animales , Catalepsia/prevención & control , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Interacciones Farmacológicas , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Colículos Inferiores/efectos de los fármacos , Masculino , Microinyecciones , N-Metilaspartato/administración & dosificación , Ratas , Ratas Wistar , Estadísticas no Paramétricas , Factores de TiempoRESUMEN
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
Prepulse inhibition (PPI) is the reduction in the startle response caused by a low intensity non-startling stimulus (prepulse) which is presented shortly before the startle stimulus and is an operational measure of sensorimotor gating. PPI is impaired in schizophrenia patients and in rats with central dopamine (DA) activation. The inferior colliculus (IC) is a critical part of the auditory pathway mediating acoustic PPI. The activation of the IC by the acoustic prepulse reduces startle magnitude. The aim of this study was to elucidate the role of DA transmission of the IC on the development of acoustic PPI. Bilateral microinjections of apomorphine (9.0 µg/0.5 µL), an agonist of D(2) receptors, into the IC disrupted PPI while microinjections of haloperidol (0.5 µg/0.5 µL), an antagonist of D(2) receptors, into this structure did not alter PPI. These results suggest that dopamine-mediated mechanisms of the IC are involved in the expression of PPI in rodents.
Asunto(s)
Apomorfina/administración & dosificación , Apomorfina/farmacología , Haloperidol/administración & dosificación , Haloperidol/farmacología , Colículos Inferiores/efectos de los fármacos , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/fisiología , Estimulación Acústica , Animales , Dopamina/metabolismo , Agonistas de Dopamina/administración & dosificación , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/administración & dosificación , Antagonistas de Dopamina/farmacología , Antagonistas de los Receptores de Dopamina D2 , Colículos Inferiores/fisiología , Masculino , Microinyecciones , Ratas , Ratas Wistar , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , EsquizofreniaRESUMEN
BACKGROUND: The aim of the present work was to investigate the involvement of the µ1-endogenous opioid peptide receptor-mediated system in post-ictal antinociception. METHODS: Antinociceptive responses were determined by the tail-flick test after pre-treatment with the selective µ1-opioid receptor antagonist naloxonazine, peripherally or centrally administered at different doses. RESULTS: Peripheral subchronic (24 h) pre-treatment with naloxonazine antagonised the antinociception elicited by tonic-clonic seizures. Acute (10 min) pre-treatment, however, did not have the same effect. In addition, microinjections of naloxonazine into the central, dorsal cortical and external cortical nuclei of the inferior colliculus antagonised tonic-clonic seizure-induced antinociception. Neither acute (10-min) peripheral pre-treatment with naloxonazine nor subchronic intramesencephalic blockade of µ1-opioid receptors resulted in consistent statistically significant differences in the severity of tonic-clonic seizures shown by Racine's index (1972), although the intracollicular specific antagonism of µ1-opioid receptor decreased the duration of seizures. CONCLUSION: µ1-Opioid receptors and the inferior colliculus have been implicated in several endogenous opioid peptide-mediated responses such as antinociception and convulsion. The present findings suggest the involvement of µ1-opiate receptors of central and pericentral nuclei of the inferior colliculus in the modulation of tonic-clonic seizures and in the organisation of post-ictal antinociception.