Roger Pobbe | Universidade de São Paulo (original) (raw)
Papers by Roger Pobbe
Neuropharmacology, 2015
The dorsal raphe nucleus (DR), the main source of 5-HT projections to brain areas involved in anx... more The dorsal raphe nucleus (DR), the main source of 5-HT projections to brain areas involved in anxiety regulation, is composed by 5 subnuclei that differ morphologically, functionally and neurochemically. Based on immunohistochemical evidence, it has been proposed that whereas 5-HT cells of the dorsomedial (dmDR) and caudal subnuclei are implicated in the pathophysiology of generalized anxiety disorder (GAD), neurons of the lateral wings (lwDR) are associated with panic disorder (PD). We here tested this hypothesis from a behavioral perspective by investigating the consequences of the non-selective stimulation of neurons within the dmDR and lwDR, or the pharmacological manipulation of 5-HT1A receptors located in these nuclei, of male Wistar rats exposed to the elevated T-maze. This test allows the measurement of both a GAD- (i.e. inhibitory avoidance) and a PD- (i.e. escape) related response in the same animal. Intra-dmDR injection of either the excitatory amino acid kainic acid or the 5-HT1A receptor antagonist WAY-100635 facilitated inhibitory avoidance acquisition, suggesting an anxiogenic effect, and inhibited escape expression, a panicolytic-like effect. Microinjection of the 5-HT1A receptor agonist 8-OH-DPAT caused the opposite effect. Administration of the same drugs into the lwDR only altered escape performance. Whereas kainic acid and 8-OH-DPAT facilitated its expression, WAY-100635 inhibited it. At higher doses, kainic acid administration evoked vigorous escape reactions as measured in an open-field. These findings implicate 5-HT neurons of the dmDR in the regulation of both GAD- and PD-related defensive behaviors. They also support a primary role of the lwDR in the mediation of PD-associated responses.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, Jan 17, 2015
A wealth of evidence implicates the BDNF-TRKB system in the therapeutic effects of antidepressant... more A wealth of evidence implicates the BDNF-TRKB system in the therapeutic effects of antidepressant drugs (ADs) on mood disorders. However, little is known about the involvement of this system in the panicolytic property also exerted by these compounds. In the present study we evaluated the participation of the BDNF-TRKB system of the dorsal periaqueductal gray matter (DPAG), a core structure involved in the pathophysiology of panic disorder, in AD-induced panicolytic-like effects in rats. The results showed that short- (3 days) or long-term (21 days) systemic treatment with the tricyclic ADs imipramine, clomipramine or desipramine increased BDNF levels in the DPAG. Only longterm treatment with the selective serotonin reuptake inhibitor fluoxetine was able to increase BDNF levels in this structure. After 21-day treatment, fluoxetine and the three tricyclic ADs used also increased BDNF concentration in the hippocampus, a key area implicated in their mood-related actions. Neither in the...
Physiology & Behavior, 2012
The development of tasks measuring behaviors specific to the three major symptom categories for a... more The development of tasks measuring behaviors specific to the three major symptom categories for autism makes it possible to differentiate mouse models of autism spectrum disorders (ASD) in terms of changes in these specific categories. Prior studies indicate that BTBR T+tf/J mice, the strain that has been evaluated most extensively, show autism-relevant changes in all three symptom categories; reciprocal social interactions; communication; and repetitive, ritualized behaviors. This report reviews the behaviors of oxytocin receptor (Oxtr) and Mecp2(308/Y) wild-type (WT) and knockout (KO) mice, in a number of tests specifically designed to provide information on behaviors that may show functional parallels to the core symptoms of ASD. Oxtr KO mice show robust decreases in reciprocal social interactions, and reduced levels of communication, but no changes in repetitive, ritualized behaviors; whereas Mecp2(308/Y) KO mice show a slight but consistent enhancement of social behavior and communication, and no changes in repetitive, ritualized behaviors. This data base, although small, strongly indicates that mouse models can sort the diagnostic symptoms of autism, and suggests that biological and physiological analyses of these strains may be capable of providing differential information on the brain systems involved in particular symptoms of this disorder. Profiles of behavioral changes in other mouse models of ASD should provide additional specificity in the search for biomarkers associated with particular ASD symptoms and symptom clusters.
European Neuropsychopharmacology, 2006
European Neuropsychopharmacology, 2003
Neuroscience Letters, 2010
Chemical stimulation of the lateral nucleus of the habenula (LHb), an area implicated in the regu... more Chemical stimulation of the lateral nucleus of the habenula (LHb), an area implicated in the regulation of serotonergic activity in raphe nuclei, affects the acquisition of inhibitory avoidance and escape expression of rats submitted to the elevated T-maze test of anxiety. Here, we investigated whether facilitation of 5-HT-mediated neurotransmission in the dorsal periaqueductal gray (dPAG) accounts for the behavioral consequences
European Neuropsychopharmacology, 2011
Previous findings point to the involvement of the dorsal raphe nucleus (DRN) and dorsal periaqued... more Previous findings point to the involvement of the dorsal raphe nucleus (DRN) and dorsal periaqueductal gray (dPAG) serotonergic receptors in the mediation of defensive responses that are associated with specific subtypes of anxiety disorders. These studies have mostly been conducted with rats tested in the elevated T-maze, an experimental model of anxiety that was developed to allow the measurement, in
Behavioural Brain Research, 2010
Electrical or chemical stimulation of the dorsal periaqueductal gray matter (DPAG) evokes escape,... more Electrical or chemical stimulation of the dorsal periaqueductal gray matter (DPAG) evokes escape, a defensive behavior that has been related to panic attacks. Injection of 5-HT1A or 5-HT2A receptor agonists into this midbrain area inhibits this response. It has been proposed that the impairment of 5-HT mechanisms controlling escape at the level of the DPAG may underlie the susceptibility to
Hormones and Behavior, 2000
A wealth of studies has implicated oxytocin (Oxt) and its receptors (Oxtr) in the mediation of so... more A wealth of studies has implicated oxytocin (Oxt) and its receptors (Oxtr) in the mediation of social behaviors and social memory in rodents. It has been suggested that failures in this system contribute to deficits in social interaction that characterize autism spectrum disorders (ASD). In the current analyses, we investigated the expression of autism-related behaviors in mice that lack the
Handbook of Behavioral Neuroscience, 2008
Preclinical animal models are utilized in the study of unconditioned states related to fear and a... more Preclinical animal models are utilized in the study of unconditioned states related to fear and anxiety. They are used to screen novel pharmaceuticals, study behavioral phenomena, and understand underlying etiology. In this chapter, we will present a brief overview of the most prevalently used models, discuss their various applications, and state their main behavioral indices. We will conclude by discussing
Life Sciences, 2008
Recently obtained evidence points to the involvement of the lateral habenular nuclei (LHb) in the... more Recently obtained evidence points to the involvement of the lateral habenular nuclei (LHb) in the mediation of coping defensive responses to threatening/stressful stimuli. Nevertheless, the role of this brain area in the regulation of defensive responses that have been associated with specific subtypes of anxiety disorders recognized in clinical settings is presently unknown. To address this question, we investigated the
Psychopharmacology, 2005
Rationale: It has been proposed that the serotonergic pathway that connects the dorsal raphe nucl... more Rationale: It has been proposed that the serotonergic pathway that connects the dorsal raphe nucleus (DRN) to the dorsal periaqueductal gray (DPAG) is implicated in the regulation of escape, a behavior that has been related to panic. Objectives: We further evaluated this hypothesis by investigating whether intra-DRN injection of the 5-HT1A receptor antagonist WAY-100635 changes the escape response of rats
Physiology & Behavior, 2015
Analyses of the behavioral reactions of rodents to predators have greatly contributed to the unde... more Analyses of the behavioral reactions of rodents to predators have greatly contributed to the understanding of defense-related human psychopathologies such as anxiety and panic. We here investigated the behavioral consequences of exposing male Wistar rats to a live cat using the elevated T-maze test of anxiety. This test allows the measurement of two defensive responses: inhibitory avoidance and escape, which in terms of pathology have been associated with generalized anxiety and panic disorders, respectively. For comparative reasons, the effects of exposure to the cat were also assessed in the elevated plus-maze. The results showed that a 5-min exposure to the cat selectively facilitated inhibitory avoidance acquisition, an anxiogenic effect, without affecting escape expression in the elevated T-maze. This was seen immediately but not thirty minutes after contact with the predator. This short-lived anxiogenic effect was also detected in the elevated plus-maze. Previous administration of the benzodiazepine anxiolytic diazepam (2mg/kg) decreased the immediate avoidance response to the predator and the neophobic reaction to a dummy cat used as a control stimulus. The drug also impaired inhibitory avoidance acquisition in the elevated T-maze, indicating an anxiolytic effect, without affecting escape performance. The results indicate that the state of anxiety evoked during contact with the predator generalizes to both elevated plus- and T-mazes, impacting on defensive responses associated with generalized anxiety disorder.
Chronic administration of antidepressants such as fluoxetine and imipramine increases the respons... more Chronic administration of antidepressants such as fluoxetine and imipramine increases the responsiveness of 5-HT 1A receptors in dorsal periaqueductal grey matter (DPAG), a midbrain area consistently implicated in the pathogenesis of panic disorder. This effect has been related to the clinically relevant antipanic action of these drugs. In this study we determined whether long-term administration of fluoxetine also affects 5-HT efflux in DPAG. As a comparison, the effect of chronic treatment with the anxiolytic 5-HT 1A receptor agonist buspirone on DPAG 5-HT levels was assessed. We also investigated whether the inhibitory effect of chronic fluoxetine on escape behaviour in the rat elevated T-maze, considered as a panicolytic-like effect, is counteracted by intra-DPAG injection of the 5-HT 1A receptor antagonist WAY 100635. Male Wistar rats were treated (1 or 21 d, i.p.) with fluoxetine, buspirone or vehicle, once daily. After treatment, 5-HT in DPAG was measured by in-vivo microdialysis coupled to HPLC. In another study, rats treated (21 d, i.p.) with either fluoxetine or vehicle also received intra-DPAG injection of WAY 100635 or saline 10 min before being tested in the elevated T-maze. Chronic, but not acute, administration of fluoxetine significantly raised extracellular levels of 5-HT in DPAG. Long-term treatment with buspirone was ineffective. In the elevated T-maze, intra-DPAG injection of WAY 100635 fully blocked the anti-escape effect of chronic administration of fluoxetine. Therefore, chronic fluoxetine facilitates 5-HT 1Amediated neurotransmission within DPAG and this effect accounts for the panicolytic-like effect of this antidepressant in the elevated T-maze.
Behavioural brain research, Jan 15, 2014
A wealth of evidence indicates that changes in procedural parameters and/or environmental conditi... more A wealth of evidence indicates that changes in procedural parameters and/or environmental conditions may exert a remarkable influence on the basal expression of defensive behaviors in different animal tests of anxiety. The goal of the current study was to further investigate the influence of procedural factors upon inhibitory avoidance acquisition and escape expression of male Wistar rats exposed to the elevated T-maze. These responses have been related in terms of psychopathology to generalized anxiety and panic disorders, respectively. Our results showed that the expression of these behaviors is not affected by prior handling of the animals or by increasing the illumination level of the experimental room from 60 to 580lx. They also showed that enhancing the number of avoidance trials from 3 to 6 favors the acquisition of this behavior. Under this condition, both diazepam (2mg/kg) and clonazepam (1-4mg/kg) caused anxiolytic effects, but only the latter benzodiazepine impaired escap...
Psychopharmacology, 2005
Rationale: It has been proposed that the serotonergic pathway that connects the dorsal raphe nucl... more Rationale: It has been proposed that the serotonergic pathway that connects the dorsal raphe nucleus (DRN) to the dorsal periaqueductal gray (DPAG) is implicated in the regulation of escape, a behavior that has been related to panic. Objectives: We further evaluated this hypothesis by investigating whether intra-DRN injection of the 5-HT 1A receptor antagonist WAY-100635 changes the escape response of rats submitted to the elevated T-maze. This test also measures inhibitory avoidance, which has been associated with generalized anxiety disorder. We also investigated whether the 5-HT 1A and 5-HT 2A receptors in the DPAG mediate the behavioral consequences induced by the injection of WAY-100635 into the DRN. Results: Intra-DRN injection of WAY-100635 facilitated inhibitory avoidance, while impairing escape. The same effect was obtained after intra-DRN injection of the glutamate receptor agonist kainic acid. Preadministration of WAY-100635 into the DPAG counteracted the effect induced by intra-DRN injection of WAY-100635 and of kainic acid on escape, but not on inhibitory avoidance. Preadministration of the preferential 5-HT 2A receptor antagonist ketanserin into the DPAG abolished the effects of intra-DRN injection of WAY-100635 on both elevated T-maze tasks. Conclusion: The results are indicative that 5-HT 1A autoreceptors in the DRN are under tonic inhibitory influence by endogenous 5-HT. The effects of 5-HT release in the DPAG after intra-DRN injection of WAY-100635 and kainic acid on inhibitory avoidance and escape involve different 5-HT receptor subtypes. Whereas 5-HT 2A receptors in the DPAG seem to mediate the effect of 5-HT on both behaviors, 5-HT 1A receptors are only involved in the regulation of escape.
Pharmacological Research, 2004
Sibutramine is an anorexiant drug that inhibits the reuptake of noradrenaline and serotonin, a ph... more Sibutramine is an anorexiant drug that inhibits the reuptake of noradrenaline and serotonin, a pharmacological property shared with drugs clinically effective in treating anxiety pathologies. However, the effects of this compound on experimental and clinical anxiety have not been assessed yet. In this study, we evaluated the effects of sibutramine on anxiety-related behaviours which have been related to specific anxiety disorders. Acute injection of sibutramine (5, 10 or 20 mg kg −1 ; intraperitoneally) in male Wistar rats impaired inhibitory avoidance in the elevated T-maze (ETM) and in the light/dark transition test, indicative of an anxiolytic effect. The drug also inhibited one-way escape in the ETM. Sibutramine, however, was ineffective in changing rat performance in the elevated plus-maze. Therefore, sibutramine decreased the expression of defensive behaviours that have been associated with generalized anxiety disorder (inhibitory avoidance) and with panic disorder (one-way escape). Yet, in contrast to what has been reported with drugs such as the tricyclic anti-depressants that also inhibit monoamine reuptake, the anxiolytic effects of sibutramine were revealed after a single administration.
Neuroscience & Biobehavioral Reviews, 2011
Risk assessment is a pattern of activities involved in detection and analysis of threat stimuli a... more Risk assessment is a pattern of activities involved in detection and analysis of threat stimuli and the situations in which the threat is encountered. It is a core process in the choice of specific defenses, such as flight, freezing, defensive threat and defensive attack, that counter the threat and minimize the danger it poses. This highly adaptive process takes into account important characteristics, such as type and location (including distance from the subject) of the threat, as well as those (e.g. presence of an escape route or hiding place) of the situation, combining them to predict which specific defense is optimal with that particular combination of threat and situation. Risk assessment is particularly associated with ambiguity either of the threat stimulus or of the outcome of available defensive behaviors. It is also crucial in determining that threat is no longer present, permitting a return to normal, nondefensive behavior. Although risk assessment has been described in detail in rodents, it is also a feature of human defensive behavior, particularly in association with ambiguity. Rumination may be a specifically human form of risk assessment, more often expressed by women, and highly associated with anxiety.
Neuroscience & Biobehavioral Reviews, 2012
BTBR T+tf/J (BTBR) mice have emerged as strong candidates to serve as models of a range of autism... more BTBR T+tf/J (BTBR) mice have emerged as strong candidates to serve as models of a range of autism-relevant behaviors, showing deficiencies in social behaviors; reduced or unusual ultrasonic vocalizations in conspecific situations; and enhanced, repetitive self grooming. Recent studies have described their behaviors in a seminatural Visible Burrow System (VBS); a social proximity test in which avoidance of a conspecific is impossible; and in an object approach and investigation test evaluating attention to specific objects and potential stereotypies in the order of approaching/ investigating objects. VBS results confirmed strong BTBR avoidance of conspecifics and in the social proximity test, BTBR showed dramatic differences in several close-in behaviors, including specific avoidance of a nose-to-nose contact that may potentially be related to gaze-avoidance. Diazepam normalized social avoidance by BTBRs in a three-chamber test, and some additional behaviors -but not nose to nose avoidance-in the social proximity test. BTBR also showed higher levels of preference for particular objects, and higher levels of sequences investigating 3-or 4objects in the same order. Heparan sulfate (HS) associated with fractal structures in the subventricular zone of the lateral ventricles was severely reduced in BTBR. HS may modulate the functions of a range of growth and guidance factors during development, and HS abnormalities are associated with relevant brain (callosal agenesis) and behavioral (reductions in sociality) changes; suggesting the value of examination of the dynamics of the HS system in the context of autism.
Hormones and Behavior, 2012
A wealth of studies has implicated oxytocin (Oxt) and its receptors (Oxtr) in the mediation of so... more A wealth of studies has implicated oxytocin (Oxt) and its receptors (Oxtr) in the mediation of social behaviors and social memory in rodents. It has been suggested that failures in this system contribute to deficits in social interaction that characterize autism spectrum disorders (ASD). In the current analyses, we investigated the expression of autism-related behaviors in mice that lack the ability to synthesize the oxytocin receptor itself, Oxtr knockout (KO) mice, as compared to their wild-type (WT) littermates. In the visible burrow system, Oxtr KO mice showed robust reductions in frontal approach, huddling, allo-grooming, and flight, with more time spent alone, and in self-grooming, as compared to WT. These results were corroborated in the three-chambered test: unlike WT, Oxtr KO mice failed to spend more time in the side of the test box containing an unfamiliar CD-1 mouse. In the social proximity test, Oxtr KO mice showed clear reductions in nose to nose and anogenital sniff behaviors oriented to an unfamiliar C57BL/6J (B6) mouse. In addition, our study revealed no differences between Oxtr WT and KO genotypes in the occurrence of motor and cognitive stereotyped behaviors. A significant genotype effect was found in the scent marking analysis, with Oxtr KO mice showing a decreased number of scent marks, as compared to WT. Overall, the present data indicate that the profile for Oxtr KO mice, including consistent social deficits, and reduced levels of communication, models multiple components of the ASD phenotype. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.
Neuropharmacology, 2015
The dorsal raphe nucleus (DR), the main source of 5-HT projections to brain areas involved in anx... more The dorsal raphe nucleus (DR), the main source of 5-HT projections to brain areas involved in anxiety regulation, is composed by 5 subnuclei that differ morphologically, functionally and neurochemically. Based on immunohistochemical evidence, it has been proposed that whereas 5-HT cells of the dorsomedial (dmDR) and caudal subnuclei are implicated in the pathophysiology of generalized anxiety disorder (GAD), neurons of the lateral wings (lwDR) are associated with panic disorder (PD). We here tested this hypothesis from a behavioral perspective by investigating the consequences of the non-selective stimulation of neurons within the dmDR and lwDR, or the pharmacological manipulation of 5-HT1A receptors located in these nuclei, of male Wistar rats exposed to the elevated T-maze. This test allows the measurement of both a GAD- (i.e. inhibitory avoidance) and a PD- (i.e. escape) related response in the same animal. Intra-dmDR injection of either the excitatory amino acid kainic acid or the 5-HT1A receptor antagonist WAY-100635 facilitated inhibitory avoidance acquisition, suggesting an anxiogenic effect, and inhibited escape expression, a panicolytic-like effect. Microinjection of the 5-HT1A receptor agonist 8-OH-DPAT caused the opposite effect. Administration of the same drugs into the lwDR only altered escape performance. Whereas kainic acid and 8-OH-DPAT facilitated its expression, WAY-100635 inhibited it. At higher doses, kainic acid administration evoked vigorous escape reactions as measured in an open-field. These findings implicate 5-HT neurons of the dmDR in the regulation of both GAD- and PD-related defensive behaviors. They also support a primary role of the lwDR in the mediation of PD-associated responses.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, Jan 17, 2015
A wealth of evidence implicates the BDNF-TRKB system in the therapeutic effects of antidepressant... more A wealth of evidence implicates the BDNF-TRKB system in the therapeutic effects of antidepressant drugs (ADs) on mood disorders. However, little is known about the involvement of this system in the panicolytic property also exerted by these compounds. In the present study we evaluated the participation of the BDNF-TRKB system of the dorsal periaqueductal gray matter (DPAG), a core structure involved in the pathophysiology of panic disorder, in AD-induced panicolytic-like effects in rats. The results showed that short- (3 days) or long-term (21 days) systemic treatment with the tricyclic ADs imipramine, clomipramine or desipramine increased BDNF levels in the DPAG. Only longterm treatment with the selective serotonin reuptake inhibitor fluoxetine was able to increase BDNF levels in this structure. After 21-day treatment, fluoxetine and the three tricyclic ADs used also increased BDNF concentration in the hippocampus, a key area implicated in their mood-related actions. Neither in the...
Physiology & Behavior, 2012
The development of tasks measuring behaviors specific to the three major symptom categories for a... more The development of tasks measuring behaviors specific to the three major symptom categories for autism makes it possible to differentiate mouse models of autism spectrum disorders (ASD) in terms of changes in these specific categories. Prior studies indicate that BTBR T+tf/J mice, the strain that has been evaluated most extensively, show autism-relevant changes in all three symptom categories; reciprocal social interactions; communication; and repetitive, ritualized behaviors. This report reviews the behaviors of oxytocin receptor (Oxtr) and Mecp2(308/Y) wild-type (WT) and knockout (KO) mice, in a number of tests specifically designed to provide information on behaviors that may show functional parallels to the core symptoms of ASD. Oxtr KO mice show robust decreases in reciprocal social interactions, and reduced levels of communication, but no changes in repetitive, ritualized behaviors; whereas Mecp2(308/Y) KO mice show a slight but consistent enhancement of social behavior and communication, and no changes in repetitive, ritualized behaviors. This data base, although small, strongly indicates that mouse models can sort the diagnostic symptoms of autism, and suggests that biological and physiological analyses of these strains may be capable of providing differential information on the brain systems involved in particular symptoms of this disorder. Profiles of behavioral changes in other mouse models of ASD should provide additional specificity in the search for biomarkers associated with particular ASD symptoms and symptom clusters.
European Neuropsychopharmacology, 2006
European Neuropsychopharmacology, 2003
Neuroscience Letters, 2010
Chemical stimulation of the lateral nucleus of the habenula (LHb), an area implicated in the regu... more Chemical stimulation of the lateral nucleus of the habenula (LHb), an area implicated in the regulation of serotonergic activity in raphe nuclei, affects the acquisition of inhibitory avoidance and escape expression of rats submitted to the elevated T-maze test of anxiety. Here, we investigated whether facilitation of 5-HT-mediated neurotransmission in the dorsal periaqueductal gray (dPAG) accounts for the behavioral consequences
European Neuropsychopharmacology, 2011
Previous findings point to the involvement of the dorsal raphe nucleus (DRN) and dorsal periaqued... more Previous findings point to the involvement of the dorsal raphe nucleus (DRN) and dorsal periaqueductal gray (dPAG) serotonergic receptors in the mediation of defensive responses that are associated with specific subtypes of anxiety disorders. These studies have mostly been conducted with rats tested in the elevated T-maze, an experimental model of anxiety that was developed to allow the measurement, in
Behavioural Brain Research, 2010
Electrical or chemical stimulation of the dorsal periaqueductal gray matter (DPAG) evokes escape,... more Electrical or chemical stimulation of the dorsal periaqueductal gray matter (DPAG) evokes escape, a defensive behavior that has been related to panic attacks. Injection of 5-HT1A or 5-HT2A receptor agonists into this midbrain area inhibits this response. It has been proposed that the impairment of 5-HT mechanisms controlling escape at the level of the DPAG may underlie the susceptibility to
Hormones and Behavior, 2000
A wealth of studies has implicated oxytocin (Oxt) and its receptors (Oxtr) in the mediation of so... more A wealth of studies has implicated oxytocin (Oxt) and its receptors (Oxtr) in the mediation of social behaviors and social memory in rodents. It has been suggested that failures in this system contribute to deficits in social interaction that characterize autism spectrum disorders (ASD). In the current analyses, we investigated the expression of autism-related behaviors in mice that lack the
Handbook of Behavioral Neuroscience, 2008
Preclinical animal models are utilized in the study of unconditioned states related to fear and a... more Preclinical animal models are utilized in the study of unconditioned states related to fear and anxiety. They are used to screen novel pharmaceuticals, study behavioral phenomena, and understand underlying etiology. In this chapter, we will present a brief overview of the most prevalently used models, discuss their various applications, and state their main behavioral indices. We will conclude by discussing
Life Sciences, 2008
Recently obtained evidence points to the involvement of the lateral habenular nuclei (LHb) in the... more Recently obtained evidence points to the involvement of the lateral habenular nuclei (LHb) in the mediation of coping defensive responses to threatening/stressful stimuli. Nevertheless, the role of this brain area in the regulation of defensive responses that have been associated with specific subtypes of anxiety disorders recognized in clinical settings is presently unknown. To address this question, we investigated the
Psychopharmacology, 2005
Rationale: It has been proposed that the serotonergic pathway that connects the dorsal raphe nucl... more Rationale: It has been proposed that the serotonergic pathway that connects the dorsal raphe nucleus (DRN) to the dorsal periaqueductal gray (DPAG) is implicated in the regulation of escape, a behavior that has been related to panic. Objectives: We further evaluated this hypothesis by investigating whether intra-DRN injection of the 5-HT1A receptor antagonist WAY-100635 changes the escape response of rats
Physiology & Behavior, 2015
Analyses of the behavioral reactions of rodents to predators have greatly contributed to the unde... more Analyses of the behavioral reactions of rodents to predators have greatly contributed to the understanding of defense-related human psychopathologies such as anxiety and panic. We here investigated the behavioral consequences of exposing male Wistar rats to a live cat using the elevated T-maze test of anxiety. This test allows the measurement of two defensive responses: inhibitory avoidance and escape, which in terms of pathology have been associated with generalized anxiety and panic disorders, respectively. For comparative reasons, the effects of exposure to the cat were also assessed in the elevated plus-maze. The results showed that a 5-min exposure to the cat selectively facilitated inhibitory avoidance acquisition, an anxiogenic effect, without affecting escape expression in the elevated T-maze. This was seen immediately but not thirty minutes after contact with the predator. This short-lived anxiogenic effect was also detected in the elevated plus-maze. Previous administration of the benzodiazepine anxiolytic diazepam (2mg/kg) decreased the immediate avoidance response to the predator and the neophobic reaction to a dummy cat used as a control stimulus. The drug also impaired inhibitory avoidance acquisition in the elevated T-maze, indicating an anxiolytic effect, without affecting escape performance. The results indicate that the state of anxiety evoked during contact with the predator generalizes to both elevated plus- and T-mazes, impacting on defensive responses associated with generalized anxiety disorder.
Chronic administration of antidepressants such as fluoxetine and imipramine increases the respons... more Chronic administration of antidepressants such as fluoxetine and imipramine increases the responsiveness of 5-HT 1A receptors in dorsal periaqueductal grey matter (DPAG), a midbrain area consistently implicated in the pathogenesis of panic disorder. This effect has been related to the clinically relevant antipanic action of these drugs. In this study we determined whether long-term administration of fluoxetine also affects 5-HT efflux in DPAG. As a comparison, the effect of chronic treatment with the anxiolytic 5-HT 1A receptor agonist buspirone on DPAG 5-HT levels was assessed. We also investigated whether the inhibitory effect of chronic fluoxetine on escape behaviour in the rat elevated T-maze, considered as a panicolytic-like effect, is counteracted by intra-DPAG injection of the 5-HT 1A receptor antagonist WAY 100635. Male Wistar rats were treated (1 or 21 d, i.p.) with fluoxetine, buspirone or vehicle, once daily. After treatment, 5-HT in DPAG was measured by in-vivo microdialysis coupled to HPLC. In another study, rats treated (21 d, i.p.) with either fluoxetine or vehicle also received intra-DPAG injection of WAY 100635 or saline 10 min before being tested in the elevated T-maze. Chronic, but not acute, administration of fluoxetine significantly raised extracellular levels of 5-HT in DPAG. Long-term treatment with buspirone was ineffective. In the elevated T-maze, intra-DPAG injection of WAY 100635 fully blocked the anti-escape effect of chronic administration of fluoxetine. Therefore, chronic fluoxetine facilitates 5-HT 1Amediated neurotransmission within DPAG and this effect accounts for the panicolytic-like effect of this antidepressant in the elevated T-maze.
Behavioural brain research, Jan 15, 2014
A wealth of evidence indicates that changes in procedural parameters and/or environmental conditi... more A wealth of evidence indicates that changes in procedural parameters and/or environmental conditions may exert a remarkable influence on the basal expression of defensive behaviors in different animal tests of anxiety. The goal of the current study was to further investigate the influence of procedural factors upon inhibitory avoidance acquisition and escape expression of male Wistar rats exposed to the elevated T-maze. These responses have been related in terms of psychopathology to generalized anxiety and panic disorders, respectively. Our results showed that the expression of these behaviors is not affected by prior handling of the animals or by increasing the illumination level of the experimental room from 60 to 580lx. They also showed that enhancing the number of avoidance trials from 3 to 6 favors the acquisition of this behavior. Under this condition, both diazepam (2mg/kg) and clonazepam (1-4mg/kg) caused anxiolytic effects, but only the latter benzodiazepine impaired escap...
Psychopharmacology, 2005
Rationale: It has been proposed that the serotonergic pathway that connects the dorsal raphe nucl... more Rationale: It has been proposed that the serotonergic pathway that connects the dorsal raphe nucleus (DRN) to the dorsal periaqueductal gray (DPAG) is implicated in the regulation of escape, a behavior that has been related to panic. Objectives: We further evaluated this hypothesis by investigating whether intra-DRN injection of the 5-HT 1A receptor antagonist WAY-100635 changes the escape response of rats submitted to the elevated T-maze. This test also measures inhibitory avoidance, which has been associated with generalized anxiety disorder. We also investigated whether the 5-HT 1A and 5-HT 2A receptors in the DPAG mediate the behavioral consequences induced by the injection of WAY-100635 into the DRN. Results: Intra-DRN injection of WAY-100635 facilitated inhibitory avoidance, while impairing escape. The same effect was obtained after intra-DRN injection of the glutamate receptor agonist kainic acid. Preadministration of WAY-100635 into the DPAG counteracted the effect induced by intra-DRN injection of WAY-100635 and of kainic acid on escape, but not on inhibitory avoidance. Preadministration of the preferential 5-HT 2A receptor antagonist ketanserin into the DPAG abolished the effects of intra-DRN injection of WAY-100635 on both elevated T-maze tasks. Conclusion: The results are indicative that 5-HT 1A autoreceptors in the DRN are under tonic inhibitory influence by endogenous 5-HT. The effects of 5-HT release in the DPAG after intra-DRN injection of WAY-100635 and kainic acid on inhibitory avoidance and escape involve different 5-HT receptor subtypes. Whereas 5-HT 2A receptors in the DPAG seem to mediate the effect of 5-HT on both behaviors, 5-HT 1A receptors are only involved in the regulation of escape.
Pharmacological Research, 2004
Sibutramine is an anorexiant drug that inhibits the reuptake of noradrenaline and serotonin, a ph... more Sibutramine is an anorexiant drug that inhibits the reuptake of noradrenaline and serotonin, a pharmacological property shared with drugs clinically effective in treating anxiety pathologies. However, the effects of this compound on experimental and clinical anxiety have not been assessed yet. In this study, we evaluated the effects of sibutramine on anxiety-related behaviours which have been related to specific anxiety disorders. Acute injection of sibutramine (5, 10 or 20 mg kg −1 ; intraperitoneally) in male Wistar rats impaired inhibitory avoidance in the elevated T-maze (ETM) and in the light/dark transition test, indicative of an anxiolytic effect. The drug also inhibited one-way escape in the ETM. Sibutramine, however, was ineffective in changing rat performance in the elevated plus-maze. Therefore, sibutramine decreased the expression of defensive behaviours that have been associated with generalized anxiety disorder (inhibitory avoidance) and with panic disorder (one-way escape). Yet, in contrast to what has been reported with drugs such as the tricyclic anti-depressants that also inhibit monoamine reuptake, the anxiolytic effects of sibutramine were revealed after a single administration.
Neuroscience & Biobehavioral Reviews, 2011
Risk assessment is a pattern of activities involved in detection and analysis of threat stimuli a... more Risk assessment is a pattern of activities involved in detection and analysis of threat stimuli and the situations in which the threat is encountered. It is a core process in the choice of specific defenses, such as flight, freezing, defensive threat and defensive attack, that counter the threat and minimize the danger it poses. This highly adaptive process takes into account important characteristics, such as type and location (including distance from the subject) of the threat, as well as those (e.g. presence of an escape route or hiding place) of the situation, combining them to predict which specific defense is optimal with that particular combination of threat and situation. Risk assessment is particularly associated with ambiguity either of the threat stimulus or of the outcome of available defensive behaviors. It is also crucial in determining that threat is no longer present, permitting a return to normal, nondefensive behavior. Although risk assessment has been described in detail in rodents, it is also a feature of human defensive behavior, particularly in association with ambiguity. Rumination may be a specifically human form of risk assessment, more often expressed by women, and highly associated with anxiety.
Neuroscience & Biobehavioral Reviews, 2012
BTBR T+tf/J (BTBR) mice have emerged as strong candidates to serve as models of a range of autism... more BTBR T+tf/J (BTBR) mice have emerged as strong candidates to serve as models of a range of autism-relevant behaviors, showing deficiencies in social behaviors; reduced or unusual ultrasonic vocalizations in conspecific situations; and enhanced, repetitive self grooming. Recent studies have described their behaviors in a seminatural Visible Burrow System (VBS); a social proximity test in which avoidance of a conspecific is impossible; and in an object approach and investigation test evaluating attention to specific objects and potential stereotypies in the order of approaching/ investigating objects. VBS results confirmed strong BTBR avoidance of conspecifics and in the social proximity test, BTBR showed dramatic differences in several close-in behaviors, including specific avoidance of a nose-to-nose contact that may potentially be related to gaze-avoidance. Diazepam normalized social avoidance by BTBRs in a three-chamber test, and some additional behaviors -but not nose to nose avoidance-in the social proximity test. BTBR also showed higher levels of preference for particular objects, and higher levels of sequences investigating 3-or 4objects in the same order. Heparan sulfate (HS) associated with fractal structures in the subventricular zone of the lateral ventricles was severely reduced in BTBR. HS may modulate the functions of a range of growth and guidance factors during development, and HS abnormalities are associated with relevant brain (callosal agenesis) and behavioral (reductions in sociality) changes; suggesting the value of examination of the dynamics of the HS system in the context of autism.
Hormones and Behavior, 2012
A wealth of studies has implicated oxytocin (Oxt) and its receptors (Oxtr) in the mediation of so... more A wealth of studies has implicated oxytocin (Oxt) and its receptors (Oxtr) in the mediation of social behaviors and social memory in rodents. It has been suggested that failures in this system contribute to deficits in social interaction that characterize autism spectrum disorders (ASD). In the current analyses, we investigated the expression of autism-related behaviors in mice that lack the ability to synthesize the oxytocin receptor itself, Oxtr knockout (KO) mice, as compared to their wild-type (WT) littermates. In the visible burrow system, Oxtr KO mice showed robust reductions in frontal approach, huddling, allo-grooming, and flight, with more time spent alone, and in self-grooming, as compared to WT. These results were corroborated in the three-chambered test: unlike WT, Oxtr KO mice failed to spend more time in the side of the test box containing an unfamiliar CD-1 mouse. In the social proximity test, Oxtr KO mice showed clear reductions in nose to nose and anogenital sniff behaviors oriented to an unfamiliar C57BL/6J (B6) mouse. In addition, our study revealed no differences between Oxtr WT and KO genotypes in the occurrence of motor and cognitive stereotyped behaviors. A significant genotype effect was found in the scent marking analysis, with Oxtr KO mice showing a decreased number of scent marks, as compared to WT. Overall, the present data indicate that the profile for Oxtr KO mice, including consistent social deficits, and reduced levels of communication, models multiple components of the ASD phenotype. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.