RHA) And Low-avoidance Research Articles

Contrasting Effects of Oxytocin on MK801-Induced Social and Non-Social Behavior Impairment and Hyperactivity in a Genetic Rat Model of Schizophrenia-Linked Features.

Social withdrawal in rodents is a measure of asociality, an important negative symptom of schizophrenia. The Roman high- (RHA) and low-avoidance (RLA) rat strains have been reported to exhibit differential profiles in schizophrenia-relevant behavioral phenotypes. This investigation was focused on the study of social and non-social behavior of these two rat strains following acute administration of dizocilpine (MK801, an NMDA receptor antagonist), a pharmacological model of schizophrenia-like features used to produce asociality and hyperactivity. Also, since oxytocin (OXT) has been proposed as a natural antipsychotic and a potential adjunctive therapy for social deficits in schizophrenia, we have evaluated the effects of OXT administration and its ability to reverse the MK801-impairing effects on social and non-social behavior and MK801-induced hyperactivity. MK801 administration produced hyperlocomotion and a decrease in social and non-social behavior in both rat strains, but these drug effects were clearly more marked in RHA rats. OXT (0.04 mg/kg and 0.2 mg/kg) attenuated MK801-induced hyperlocomotion in both rat strains, although this effect was more marked in RHA rats. The MK801-decreasing effect on exploration of the "social hole" was moderately but significantly attenuated only in RLA rats. This study is the first to demonstrate the differential effects of OXT on MK801-induced impairments in the two Roman rat strains, providing some support for the potential therapeutic effects of OXT against schizophrenia-like symptoms, including both a positive-like symptom (i.e., MK801-induced hyperlocomotion) and a negative-like symptom (i.e., MK801 decrease in social behavior), while highlighting the importance of the genetic background (i.e., the rat strain) in influencing the effects of both MK801 and oxytocin.

Activation of the mPFC-NAc Pathway Reduces Motor Impulsivity but Does Not Affect Risk-Related Decision-Making in Innately High-Impulsive Male Rats.

Attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUD) are characterized by exacerbated motor and risk-related impulsivities, which are associated with decreased cortical activity. In rodents, the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) have been separately implicated in impulsive behaviors, but studies on the specific role of the mPFC-NAc pathway in these behaviors are limited. Here, we investigated whether heightened impulsive behaviors are associated with reduced mPFC activity in rodents and determined the involvement of the mPFC-NAc pathway in motor and risk-related impulsivities. We used the Roman High- (RHA) and Low-Avoidance (RLA) rat lines, which display divergent phenotypes in impulsivity. To investigate alterations in cortical activity in relation to impulsivity, regional brain glucose metabolism was measured using positron emission tomography and [18F]-fluorodeoxyglucose ([18F]FDG). Using chemogenetics, the activity of the mPFC-NAc pathway was either selectively activated in high-impulsive RHA rats or inhibited in low-impulsive RLA rats, and the effects of these manipulations on motor and risk-related impulsivity were concurrently assessed using the rat gambling task. We showed that basal [18F]FDG uptake was lower in the mPFC and NAc of RHA compared to RLA rats. Activation of the mPFC-NAc pathway in RHA rats reduced motor impulsivity, without affecting risk-related decision-making. Conversely, inhibition of the mPFC-NAc pathway had no effect in RLA rats. Our results suggest that the mPFC-NAc pathway controls motor impulsivity, but has limited involvement in risk-related decision-making in our current model. Our findings suggest that reducing fronto-striatal activity may help attenuate motor impulsivity in patients with impulse control dysregulation.

Dissociable Roles of the mPFC-to-VTA Pathway in the Control of Impulsive Action and Risk-Related Decision-Making in Roman High- and Low-Avoidance Rats.

Impulsive action and risk-related decision-making (RDM) are associated with various psychiatric disorders, including drug abuse. Both behavioral traits have also been linked to reduced frontocortical activity and alterations in dopamine function in the ventral tegmental area (VTA). However, despite direct projections from the medial prefrontal cortex (mPFC) to the VTA, the specific role of the mPFC-to-VTA pathway in controlling impulsive action and RDM remains unexplored. We used positron emission tomography with [18F]-fluorodeoxyglucose to evaluate brain metabolic activity in Roman high- (RHA) and low-avoidance (RLA) rats, which exhibit innate differences in impulsive action and RDM. Notably, we used a viral-based double dissociation chemogenetic strategy to isolate, for the first time to our knowledge, the role of the mPFC-to-VTA pathway in controlling these behaviors. We selectively activated the mPFC-to-VTA pathway in RHA rats and inhibited it in RLA rats, assessing the effects on impulsive action and RDM in the rat gambling task. Our results showed that RHA rats displayed higher impulsive action, less optimal decision-making, and lower cortical activity than RLA rats at baseline. Chemogenetic activation of the mPFC-to-VTA pathway reduced impulsive action in RHA rats, whereas chemogenetic inhibition had the opposite effect in RLA rats. However, these manipulations did not affect RDM. Thus, by specifically targeting the mPFC-to-VTA pathway in a phenotype-dependent way, we reverted innate patterns of impulsive action but not RDM. Our findings suggest a dissociable role of the mPFC-to-VTA pathway in impulsive action and RDM, highlighting its potential as a target for investigating impulsivity-related disorders.

Schizophrenia-relevant social, attentional and cognitive traits in female RHA vs. RLA rats: effects of neonatal handling

The Roman high- (RHA) and low-avoidance (RLA) rats were bidirectionally selected and bred for, respectively, their rapid vs. extremely poor acquisition in the two-way active avoidance task. Consistent between-strain neurobehavioural differences have been found in anxiety- and stress-linked traits, as well as in schizophrenia-related phenotypes. RLAs display enhanced anxious- and stress-related phenotypes, whereas RHA rats show impulsivity, hyperactivity and attention/cognition-related impairments. Many of these typical behavioural phenotypes have been reported to be positively modulated by environmental treatments such as neonatal handling (NH). However, most studies on the Roman rat strains have been carried out in males. Thus, the present study for the first time focused on the joint evaluation of differences in novel object exploration (NOE), social interaction (SI), prepulse inhibition of the startle response (PPI), and cognitive performance and flexibility in various spatial tasks (using the Morris water maze, MWM) in females of both Roman rat strains. We also aimed at evaluating the long-lasting effects of NH treatment on the RHA vs. RLA profiles in these tests/tasks. Results show that anxiety-related behavior, as measured by the NOE test and self-grooming in the SI test, was increased in RLA rats, and dramatically reduced by NH. In the SI test RLA rats displayed diminished social interaction, which was rescued by NH. RHA females exhibited a deficit of PPI, which was not affected by NH. Spatial tasks in the MWM showed impairments of working memory, reference learning/memory and spatial reversal learning (i.e., cognitive flexibility) in RHA females. Spatial reference learning and cognitive flexibility (i.e., reversal task) showed some improvement in rats (mainly in RHAs) that had received NH during the first three weeks of life. With the exception of the SI test, the pattern of differences between female RHA vs. RLA profiles was overall consistent with what has previously been found in males of both strains, and NH treatment was able to enduringly improve some emotion-related and (spatial) cognitive outcomes in both strains.

Neuroplastic changes in c-Fos, ΔFosB, BDNF, trkB, and Arc expression in the hippocampus of male Roman rats: differential effects of sexual activity.

Sexual activity causes differential changes in the expression of markers of neural activation (c‐Fos and ΔFosB) and neural plasticity (Arc and BDNF/trkB), as determined either by Western Blot (BDNF, trkB, Arc, and ΔFosB) or immunohistochemistry (BDNF, trkB, Arc, and c‐Fos), in the hippocampus of male Roman high (RHA) and low avoidance (RLA) rats, two psychogenetically selected rat lines that display marked differences in sexual behavior (RHA rats exhibit higher sexual motivation and better copulatory performance than RLA rats). Both methods showed (with some differences) that sexual activity modifies the expression levels of these markers in the hippocampus of Roman rats depending on: (i) the level of sexual experience, that is, changes were usually more evident in sexually naïve than in experienced rats; (ii) the hippocampal partition, that is, BDNF and Arc increased in the dorsal but tended to decrease in the ventral hippocampus; (iii) the marker considered, that is, in sexually experienced animals BDNF, c‐Fos, and Arc levels were similar to those of controls, while ΔFosB levels increased; and (iv) the rat line, that is, changes were usually larger in RHA than RLA rats. These findings resemble those of early studies in RHA and RLA rats showing that sexual activity influences the expression of these markers in the nucleus accumbens, medial prefrontal cortex, and ventral tegmental area, and show for the first time that also in the hippocampus sexual activity induces neural activation and plasticity, events that occur mainly during the first phase of the acquisition of sexual experience and depend on the genotypic/phenotypic characteristics of the animals.

Prepulse inhibition deficits in inbred and outbred rats and between-strain differences in startle habituation do not depend on startle reactivity levels

The acoustic startle response and prepulse inhibition (PPI) of startle are measures related to information processing, which is impaired in schizophrenia. Some studies have provided inconclusive patterns of association between both measures in rodents. We assessed the influence of baseline startle response on PPI in large samples of Roman high-(RHA) and low-avoidance (RLA) rat strains and in genetically heterogeneous stock (HS) rats. Results show that RHAs exhibit a PPI deficit compared to RLA rats, which is present regardless of the startle response levels. HS rats were stratified in two sub-samples according to their high or low PPI (HS-highPPI or HS-lowPPI, respectively) scores, and then they were grouped by their differential baseline startle amplitude (high reactivity –HR- or low reactivity –LR-) within each sub-sample. Differences between high- and low-PPI-stratified HS rats remained regardless of their high or low startle amplitude scores. Thus, the impairments in %PPI found in both RHA and HS-LowPPI rats are present irrespective of the relatively high or low levels of startle amplitude in pulse-alone trials. Another objective of the present study was to evaluate whether habituation to the startling stimulus (i.e., pulse) depends on the initial baseline startle response. RLA rats habituated to the startling stimulus more effectively than RHAs regardless of their baseline startle responses. Conversely, there were no differences in startle habituation in the HS rats grouped by their extreme scores of baseline startle. Altogether, these findings suggest a deficit in information processing in RHA rats, which along with evidence indicating that this strain displays other attentional/cognitive impairments, strengthens the validity of the RHA strain as a putative model of schizophrenia-relevant features.

A Genetic Model of Impulsivity, Vulnerability to Drug Abuse and Schizophrenia-Relevant Symptoms With Translational Potential: The Roman High- vs. Low-Avoidance Rats.

The bidirectional selective breeding of Roman high- (RHA) and low-avoidance (RLA) rats for respectively rapid vs. poor acquisition of active avoidant behavior has generated two lines/strains that differ markedly in terms of emotional reactivity, with RHA rats being less fearful than their RLA counterparts. Many other behavioral traits have been segregated along the selection procedure; thus, compared with their RLA counterparts, RHA rats behave as proactive copers in the face of aversive conditions, display a robust sensation/novelty seeking (SNS) profile, and show high impulsivity and an innate preference for natural and drug rewards. Impulsivity is a multifaceted behavioral trait and is generally defined as a tendency to express actions that are poorly conceived, premature, highly risky or inappropriate to the situation, that frequently lead to unpleasant consequences. High levels of impulsivity are associated with several neuropsychiatric conditions including attention-deficit hyperactivity disorder, obsessive-compulsive disorder, schizophrenia, and drug addiction. Herein, we review the behavioral and neurochemical differences between RHA and RLA rats and survey evidence that RHA rats represent a valid genetic model, with face, construct, and predictive validity, to investigate the neural underpinnings of behavioral disinhibition, novelty seeking, impulsivity, vulnerability to drug addiction as well as deficits in attentional processes, cognitive impairments and other schizophrenia-relevant traits.

Schizophrenia-like reduced sensorimotor gating in intact inbred and outbred rats is associated with decreased medial prefrontal cortex activity and volume.

Prepulse inhibition (PPI) of startle response is a measure of sensorimotor gating that is impaired in schizophrenia and in many other clinical conditions. Rat models using pharmacological or surgical strategies reveal that PPI is modulated by the cortico-striatal-pallido-thalamic (CSPT) circuit. Here, we explore whether spontaneous variation in PPI in intact inbred and outbred rats is associated with functional and structural differences in the CSPT circuit. Inbred Roman High-(RHA) and Low-avoidance (RLA) and outbred heterogeneous stock (HS) rats were assessed for PPI, brain activity, andbrain volume. Brain activity was assessed by c-Fos expression and brain volume by magnetic resonance imaging. Relevant structures of the CSPT circuit were evaluated, such as the medial prefrontal cortex (mPFC), cingulate cortex, hippocampus (HPC), amygdala, nucleus accumbens (NAc), and dorsal striatum. RHA showed lower PPI than RLA rats, while HS rats were stratified by their PPI levels in three groups. Reduced PPI was accompanied by decreased mPFC activity in Roman and HS rats and increased NAc shell activity in HS rats. Low PPI was also associated with decreased mPFC and HPC volumes in Roman and HS rats. This study reports a consistent relationship between decreased function and volume of the mPFC and spontaneous low-PPI levels in inbred and outbred intact rats. Moreover, our findings suggest that, apart from a hypoactive and smaller mPFC, a hyperactive NAc and smaller HPC may underlie reduced PPI levels. Our results support the notion that sensorimotor gating is modulated by forebrain structures and highlight the importance of the mPFC in its regulation.

Differential involvement of D2 and D3 receptors during reinstatement of cocaine-seeking behavior in the Roman high- and low-avoidance rats.

Roman high- (RHA) and low-avoidance (RLA) rats have been used as a model for drug-addiction, showing, respectively, high- and low-responding to psychostimulants, and low versus high dopamine D2/3 receptors (D2/3R) striatal density. Previous studies indicated a major involvement of D2/3R on reinstatement of cocaine seeking, although the respective role of the two receptor subtypes is not clear. Here, we investigated sensitivity to cocaine self-administration (SA) through a dose-response protocol in RHAs and RLAs, and reinstatement of drug-seeking behavior at 15 days and 5 weeks following withdrawal. Compared to RLAs, RHAs confirmed a higher vulnerability to cocaine SA that was not related to a difference in sensitivity to the drug, as highlighted by the dose-response analysis. Both at early and late withdrawal, RHAs showed higher susceptibility than RLAs to reinstatement of drug-seeking when cocaine was used as a primer, but the two sublines did not differ when primed with the D2/3R agonist quinpirole. Moreover, while the specific D2R antagonist L741,626 blocked, the specific D3R antagonist SB-277011A failed to impair cocaine-primed relapse. The higher vulnerability of RHA versus RLA rats to cocaine-primed relapse, which contrasts with their similar vulnerability to quinpirole-primed relapse, suggests that the different propensity of both sublines to relapse likely relies on presynaptic rather than postsynaptic mechanisms. Moreover, our study challenges the involvement of D3R in the mechanisms underlying relapse to cocaine addiction, at least in conditions that may involve high levels of dopaminergic stimulation, and supports a major role of postsynaptic D2R over D3R in the vulnerability to relapse. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Neurobiology of sensorimotor gating deficits in the Roman rat strains: Studies of c-Fos expression and COMT activity

The present study was aimed at evaluating whether the differences between the Roman high- (RHA) and low-avoidance (RLA) rat strains in novelty-induced behavioural inhibition/disinhibition, sensorimotor gating (i.e., prepulse inhibition, PPI) and spatial learning/memory parallel differences in the volume of brain areas related to those behavioural phenotypes. To this aim, we conducted two experiments. In Experiment 1, we evaluated the performance of adult rats from both strains, either untreated (controls) or treated with neonatal handling (NH; administered during the first 21 days of life), in a novel object exploration test (NOE), in the elevated zero-maze test (ZM) of anxiety, and in a PPI test; moreover, magnetic resonance imaging (MRI) was used to measure the volume of limbic and cortical brain regions (amygdala -Am-, hippocampus -Hc-, striatum -St-, medial prefrontal cortex -mPFc-, anterior cingulate cortex -ACC-, nucleus accumbens -NAc-) and lateral ventricles -LV-. In Experiment 2, adult rats neonatally exposed to NH and their naïve controls were submitted to the NOE and PPI tests, and to several spatial learning/memory tasks using the Morris water maze. It was found that, compared with their RLA counterparts, RHA rats show increased exploration of the novel object in the NOE test, lowered anxiety in the ZM and impaired PPI, whereas RLAs display better spatial reference learning and memory and better cognitive flexibility in a reversal task. Furthermore, MRI measurements revealed that the volume of Hc, Am and mPFc is larger in RLA vs. RHA rats, whereas the latter have dramatically enlarged lateral ventricles. NH treatment markedly enhanced exploration in the NOE test in RLA rats, improved PPI in RHA rats but impaired it in their RLA counterparts, and produced beneficial effects on spatial working memory mainly in RHA rats. Finally, exposure to NH decreased the volume of Hc and Am in the RLA strain. The results are discussed in terms of the possible relationships between strain-related volumetric brain differences and the behavioral (anxiety-related and schizophrenia-relevant) traits that distinguish RHA from RLA rats, and highlighting the finding that, in RLA rats, NH is for the first time shown to enduringly reduce the volume of Hc and Am in parallel to the decrease of anxiety and the impairment of sensorimotor gating.

Volumetric brain differences between the Roman rat strains: Neonatal handling effects, sensorimotor gating and working memory

The present study was aimed at evaluating whether the differences between the Roman high- (RHA) and low-avoidance (RLA) rat strains in novelty-induced behavioural inhibition/disinhibition, sensorimotor gating (i.e., prepulse inhibition, PPI) and spatial learning/memory parallel differences in the volume of brain areas related to those behavioural phenotypes. To this aim, we conducted two experiments. In Experiment 1, we evaluated the performance of adult rats from both strains, either untreated (controls) or treated with neonatal handling (NH; administered during the first 21 days of life), in a novel object exploration test (NOE), in the elevated zero-maze test (ZM) of anxiety, and in a PPI test; moreover, magnetic resonance imaging (MRI) was used to measure the volume of limbic and cortical brain regions (amygdala -Am-, hippocampus -Hc-, striatum -St-, medial prefrontal cortex -mPFc-, anterior cingulate cortex -ACC-, nucleus accumbens -NAc-) and lateral ventricles -LV-. In Experiment 2, adult rats neonatally exposed to NH and their naïve controls were submitted to the NOE and PPI tests, and to several spatial learning/memory tasks using the Morris water maze. It was found that, compared with their RLA counterparts, RHA rats show increased exploration of the novel object in the NOE test, lowered anxiety in the ZM and impaired PPI, whereas RLAs display better spatial reference learning and memory and better cognitive flexibility in a reversal task. Furthermore, MRI measurements revealed that the volume of Hc, Am and mPFc is larger in RLA vs. RHA rats, whereas the latter have dramatically enlarged lateral ventricles. NH treatment markedly enhanced exploration in the NOE test in RLA rats, improved PPI in RHA rats but impaired it in their RLA counterparts, and produced beneficial effects on spatial working memory mainly in RHA rats. Finally, exposure to NH decreased the volume of Hc and Am in the RLA strain. The results are discussed in terms of the possible relationships between strain-related volumetric brain differences and the behavioral (anxiety-related and schizophrenia-relevant) traits that distinguish RHA from RLA rats, and highlighting the finding that, in RLA rats, NH is for the first time shown to enduringly reduce the volume of Hc and Am in parallel to the decrease of anxiety and the impairment of sensorimotor gating.

Active avoidance learning differentially activates ERK phosphorylation in the primary auditory and visual cortices of Roman high- and low-avoidance rats

Understanding the mechanisms underlying conditioned avoidance is a critical step toward the development of novel treatments of anxiety. In this context, the two-way active avoidance (2WAA) task is a validated paradigm to investigate uncontrolled avoidance, a hallmark of anxiety disorders. The outbred Roman high- (RHA) and low-avoidance (RLA) rat lines are selected for respectively rapid vs. poor acquisition of active avoidant behavior, and emotional reactivity appears to be the most prominent behavioral difference between the two lines, with RLA rats being more fearful/anxious than their RHA counterparts. This study was aimed at assessing the relationship between the different performance of RHA and RLA rats in the 2WAA task and the number of phosphorylated ERK positive (pERK+) neurons in the primary auditory and visual cortices, in three sub-nuclei of the amygdala, as well as in the nucleus accumbens, and the prefrontal cortex. The results indicate that: (1) RHA rats, but not their RLA counterparts, learn very rapidly to avoid mild electric foot-shocks by crossing to the opposite compartment of the shuttle-box during the presentation of the conditioned stimulus and (2) the different behavior of the Roman lines during active avoidance training is associated with differential changes in the number of pERK+ neurons in the primary auditory and visual cortices (where the proactive coping of RHA rats is associated with increased ERK phosphorylation), but not in the other brain areas examined. These results are consistent with the hypothesis that the activation of the ERK signaling cascade in the auditory and visual cortices may be involved in the acquisition of aversive learning in RHA rats.

C-Fos, ΔFosB, BDNF, trkB and Arc Expression in the Limbic System of Male Roman High- and Low-Avoidance Rats that Show Differences in Sexual Behavior: Effect of Sexual Activity

Male Roman High- (RHA) and Low-Avoidance (RLA) rats display significant differences in sexual behavior (RHA rats exhibit higher sexual motivation and better copulatory performance than RLA rats). These differences are very evident in sexually naïve rats (which copulate with a receptive female rat for the first time), and are still present, although reduced, after five copulatory tests, when sexual experience has been acquired. Since sexual activity is a natural reward that induces neural activation and synaptic plastic changes in limbic brain areas, we studied whether the differences in sexual activity between these rat lines are accompanied by changes in the expression of markers of neural activation and plasticity, i.e., c-Fos, ΔFosB (a truncated form of FosB), Brain-Derived Neurotrophic Factor (BDNF) and its tyrosine kinase receptor B (trkB) and Activity regulated cytoskeleton-associated (Arc) protein in the ventral tegmental area (VTA), nucleus accumbens (Acb) (core and shell) and medial prefrontal cortex (mPFC) of sexually naïve and experienced RHA and RLA rats by Western Blot and/or immunohistochemistry. This study shows that these markers changed differentially in the VTA, Acb and mPFC of RHA and RLA rats, after sexual activity. In both rat lines, the changes were very evident in naïve rats, tended to disappear in experienced rats and were higher in RHA than RLA rats. These findings confirm that sexual activity induces neural activation in limbic brain areas involved in motivation and reward, leading to changes in synaptic plasticity with sexual experience acquisition, and show that these depend on the animals’ genotypic/phenotypic characteristics.

Distinct phenotypes of spontaneous activity and induction of amphetamine sensitization in inbred Roman high- and low-avoidance rats: Vulnerability and protection

The psychogenetically selected Roman high- (RHA) and low-avoidance (RLA) rats are being proposed as a valuable animal model of individual vulnerability to the two distinct neurobiological mechanisms of behavioral sensitization to psychostimulants, namely induction and expression. Most hallmarks of their divergent phenotypes are also found in the inbred RHA (RHA-I) and RLA (RLA-I) strains. For instance, they differ in the expression of sensitization to amphetamine. However, the pattern of spontaneous activity of the inbred rats seems to differ from that of outbred Roman strains. The present work shows the relevance of analyzing spontaneous activity as a covariant in order to determine the significance of day effect in the induction of behavioral sensitization to amphetamine (regime: 11 days, 1 mg/kg, i.p.) in the inbred strains and, for comparison, the standard low activity Sprague-Dawley (SD) strain. Our results also confirm that, in parallel to the outbred strains, only inbred RHA rats showed sensitization during the induction phase, here detectable from day 9 of treatment, while RLA-I and SD strains did not. Inbred RLA rats provide an interesting model to study individual resistance to sensitization, with nuances due to their underlying high spontaneous activity phenotype.

The Roman high- and low-avoidance rats differ in the sensitivity to shock-induced suppression of drinking and to the anxiogenic effect of pentylenetetrazole

The Roman high- (RHA) and low-avoidance (RLA) outbred rat lines are selected for respectively rapid vs. poor acquisition of active avoidant behavior. Emotional reactivity appears to be the most prominent behavioral difference between the two lines, with RLA rats being more fearful/anxious than their RHA counterparts. Accordingly, here we show that shock-induced inhibition of drinking behavior in the Vogel's test is significantly more pronounced in RLA than RHA rats. Thus, unpunished drinking activity is similar in both lines (38.1 ± 0.9 and 36.4 ± 0.6 licking periods/3 min in RLA and RHA rats, respectively), whereas under punished conditions (0.05–1.00 mA electric shocks delivered through the drinking tube) a more robust decrease in drinking behavior is observed in RLA vs. RHA rats. Moreover, fear-related behaviors like freezing and self-grooming are more frequent in RLA than RHA rats throughout the test. Similar results are obtained with the inbred RHA-I and RLA-I rats, which have been selected and bred through brother/sister mating of the outbred lines. In keeping with the above findings, we also show that, compared with their RHA counterparts, the outbred RLA rats are similarly responsive to the anticonflict effect of diazepam but more responsive to the proconflict effect of pentylenetetrazole in the Vogel's test. Collectively, these results reveal another behavioral trait distinguishing RHA from RLA rats and add experimental support to the view that the Roman lines/strains are a valid genetic model for the study of the neural underpinnings of fear/anxiety- and stress-related behaviors.

Expression of BDNF and trkB in the hippocampus of a rat genetic model of vulnerability (Roman low-avoidance) and resistance (Roman high-avoidance) to stress-induced depression.

IntroductionThe selective breeding of Roman High‐ (RHA) and Low‐Avoidance (RLA) rats for, respectively, rapid versus poor acquisition of the active avoidance response has generated two distinct phenotypes differing in many behavioral traits, including coping strategies to aversive conditions. Thus, RLA rats are considered as a genetic model of vulnerability to stress‐induced depression whereas RHA rats are a model of resilience to that trait. Besides the monoamine hypothesis of depression, there is evidence that alterations in neuronal plasticity in the hippocampus and other brain areas are critically involved in the pathophysiology of mood disorders.Materials and MethodsWestern blot (WB) and immunohistochemistry were used to investigate the basal immunochemical occurrence of brain‐derived neurotrophic factor (BDNF) and its high‐affinity tyrosine‐kinase receptor trkB in the dorsal and ventral hippocampus of adult RHA and RLA rats.Results WB analysis indicated that the optical density of BDNF‐ and trkB‐positive bands in the dorsal hippocampus is, respectively, 48% and 25% lower in RLA versus RHA rats. Densitometric analysis of BDNF‐ and trkB‐like immunoreactivity (LI) in brain sections showed that BDNF‐LI is 24% to 34% lower in the different sectors of the Ammon's horn of RLA versus RHA rats, whereas line‐related differences are observed in the dentate gyrus (DG) only in the ventral hippocampus. As for trkB‐LI, significant differences are observed only in the dorsal hippocampus, where density is 23% lower in the DG of RLA versus RHA rats, while no differences across lines occur in the Ammon's horn.ConclusionThese findings support the hypothesis that a reduced BDNF/trkB signaling in the hippocampus of RLA versus RHA rats may contribute to their more pronounced vulnerability to stress‐induced depression.

Dopamine, Noradrenaline and Differences in Sexual Behavior between Roman High and Low Avoidance Male Rats: A Microdialysis Study in the Medial Prefrontal Cortex.

Roman High- (RHA) and Low-Avoidance (RLA) outbred rats, which differ for a respectively rapid vs. poor acquisition of the active avoidance response in the shuttle-box, display differences in sexual activity when put in the presence of a sexually receptive female rat. Indeed RHA rats show higher levels of sexual motivation and copulatory performance than RLA rats, which persist also after repeated sexual activity. These differences have been correlated to a higher tone of the mesolimbic dopaminergic system of RHA rats vs. RLA rats, revealed by the higher increase of dopamine found in the dialysate obtained from the nucleus accumbens of RHA than RLA rats during sexual activity. This work shows that extracellular dopamine and noradrenaline (NA) also, increase in the dialysate from the medial prefrontal cortex (mPFC) of male RHA and RLA rats put in the presence of an inaccessible female rat and more markedly during direct sexual interaction. Such increases in dopamine (and its main metabolite 3,4-dihydroxyphenylacetic acid, DOPAC) and NA were found in both sexually naïve and experienced animals, but they were higher: (i) in RHA than in RLA rats; and (ii) in sexually experienced RHA and RLA rats than in their naïve counterparts. Finally, the differences in dopamine and NA in the mPFC occurred concomitantly to those in sexual activity, as RHA rats displayed higher levels of sexual motivation and copulatory performance than RLA rats in both the sexually naïve and experienced conditions. These results suggest that a higher dopaminergic tone also occurs in the mPFC, together with an increased noradrenergic tone, which may be involved in the different copulatory patterns found in RHA and RLA rats, as suggested for the mesolimbic dopaminergic system.

Differential effects of antipsychotic and propsychotic drugs on prepulse inhibition and locomotor activity in Roman high- (RHA) and low-avoidance (RLA) rats.

Animal models with predictive and construct validity are necessary for developing novel and efficient therapeutics for psychiatric disorders. We have carried out a pharmacological characterization of the Roman high- (RHA-I) and low-avoidance (RLA-I) rat strains with different acutely administered propsychotic (DOI, MK-801) and antipsychotic drugs (haloperidol, clozapine), as well as apomorphine, on prepulse inhibition (PPI) of startle and locomotor activity (activity cages). RHA-I rats display a consistent deficit of PPI compared with RLA-I rats. The typical antipsychotic haloperidol (dopamine D2 receptor antagonist) reversed the PPI deficit characteristic of RHA-I rats (in particular at 65 and 70dB prepulse intensities) and reduced locomotion in both strains. The atypical antipsychotic clozapine (serotonin/dopamine receptor antagonist) did not affect PPI in either strain, but decreased locomotion in a dose-dependent manner in both rat strains. The mixed dopamine D1/D2 agonist, apomorphine, at the dose of 0.05mg/kg, decreased PPI in RHA-I, but not RLA-I rats. The hallucinogen drug DOI (5-HT2A agonist; 0.1-1.0mg/kg) disrupted PPI in RLA-I rats in a dose-dependent manner at the 70dB prepulse intensity, while in RHA-I rats, only the 0.5mg/kg dose impaired PPI at the 80dB prepulse intensity. DOI slightly decreased locomotion in both strains. Finally, clozapine attenuated the PPI impairment induced by the NMDA receptor antagonist MK-801 only in RLA-I rats. These results add experimental evidence to the view that RHA-I rats represent a model with predictive and construct validity of some dopamine and 5-HT2A receptor-related features of schizophrenia.

Density of acetylcholine esterase (AchE) and tyrosine hydroxylase (TH) containing fibers in the amygdala of roman high- and low-avoidance rats

The cholinergic and dopaminergic innervation of the amygdala plays an important role in attention, emotional arousal, aversive forms of associative learning, conditioned responses, and stress responsivity. Roman High- (RHA) and Low-Avoidance (RLA) rats are an ideal model to study the potential impact of this innervation on behavioral responses, because they were selected bidirectionally for differences in their two-way active avoidance performance. RHA rats are known to quickly acquire two-way active avoidance and show indications of enhanced impulsive behavior, novelty seeking, and vulnerability to substance abuse, whereas RLA rats exhibit a passive coping style with high levels of immobility and enhanced stress responsivity. In the present study, the density of acetylcholine esterase (AchE)-positive cholinergic fibers and tyrosine hydroxylase immunoreactive (TH-ir) fibers were analyzed in various amygdala nuclei. In comparison to RLA rats, RHA rats displayed a significantly higher density of AchE-positive fibers in the lateral nucleus (La), the major sensory input area of the amygdala. In contrast, RLA rats showed a higher density of TH-ir fibers in the lateral division of the central nucleus (CeL), which modulates amygdala output and is known to contain more corticotropin-releasing hormone (CRH) positive neurons in RLA than in RHA rats. The findings suggest that a higher density of AchE-positive fibers in the La of RHA rats may facilitate attentional mechanisms and aversive forms of associative learning in RHA rats, whereas the increased density of TH-ir fibers in the CeL of RLA rats may be involved in the regulation of enhanced CRH expression and stress responsivity.

Involvement of dopamine in the differences in sexual behaviour between Roman high and low avoidance rats: An intracerebral microdialysis study

Outbred Roman high- (RHA) and low-avoidance (RLA) rats are selected for respectively rapid vs. poor acquisition of the active avoidance response and display different copulatory patterns when exposed to a sexually receptive female, with RHA rats showing more robust sexual motivation and better performance than RLA rats also after repeated sexual activity. Here we show that the distinct patterns of sexual behaviour of the Roman lines are correlated with differences in the activity of the dopaminergic mesolimbic system, which plays a key role in sexual motivation and copulatory performance. Thus, differential increases in the concentrations of dopamine and its main metabolite 3,4-dihydroxyphenylacetic acid, occurred in dialysates obtained from the nucleus accumbens shell of naïve and sexually experienced Roman rats during the anticipatory and consummatory phases of sexual activity. These differences were particularly evident between sexually naïve RHA and RLA rats and tended to diminish but still persisted between sexually experienced rats, as did the differences in sexual behaviour. Analysis of the biochemical and behavioural findings showed that, while in RHA rats sexual experience caused a shift in the changes in both the dopaminergic activity and copulation towards the first period of the sexual test, in RLA rats sexual experience increased dopaminergic activity and copulation throughout the entire test. Therefore, this study adds experimental support to the view that the different sexual patterns of the Roman lines are due, at least in part, to a more robust functional tone of the mesolimbic dopaminergic system of RHA rats.