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.

Peptide-drug conjugate designated for targeted delivery to HER2-expressing cancer cells.

Targeted therapy of the highest globally incident breast cancer shall resolve the issue of off-target toxicity concurring with augmented killing of specific diseased cells. Thus, the goal of this study was to prepare a peptide-drug conjugate targeting elevated expression of HER2 receptors in breast cancer. Towards this, the rL-A9 peptide was conjugated with the chemotherapeutic drug doxorubicin (DOX) through a N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) linker. The synthesized peptide-drug conjugate, rL-A9-DOX, was characterized by mass spectrometry. Molecular docking studies, based on binding energy data, suggested a stronger interaction of rL-A9-DOX with the HER2 receptor in comparison to the unconjugated peptide, rL-A9. The cytotoxic effect of the rL-A9-DOX conjugate was observed to be higher in HER2-positive SKOV3 cells compared to HER2-negative MDA-MB-231 cells, indicating selective cell killing. Cellular internalization of the rL-A9-DOX conjugate was evident from the flow cytometry analysis, where a noticeable shift in mean fluorescent intensity (MFI) was observed for the conjugate compared to the control group. This data was further validated by confocal microscopy, where the fluorescent signal ascertained nuclear accumulation of rL-A9-DOX. The present studies highlight the promising potential of rL-A9-DOX for targeted delivery of the drug into a defined group of cancer cells.

c-Fos expression after neonatal handling in social brain regions: Distinctive profile of RHA-rat schizophrenia model on a social preference test.

Neonatal handling (NH) is an environmental manipulation that induces long-lasting changes in behavioural, neuroendocrine, and neuroanatomical processes in rodents. We have previously reported that NH treatment increases social interaction preference in an animal model of schizophrenia-relevant features, the Roman high-avoidance (RHA) rats. The present study was aimed at evaluating whether the increase of social behaviour/preference due to NH treatment in RHA rats is associated with differences in c-Fos expression levels in some of the brain areas that integrate the "social brain". To this aim, we evaluated the performance of adult male rats from both Roman rat strains (RHA vs. RLA -Roman low-avoidance- rats), either untreated (control) or treated with NH (administered during the first 21 days of life) in a social interaction task. For the analyses of c-Fos activation untreated and NH-treated animals were divided into three different experimental conditions: undisturbed home cage controls (HC); rats exposed to the testing set-up context (CTX); and rats exposed to a social interaction (SI) test. It was found that, compared with their RLA counterparts, NH treatment increased social behaviour in RHA rats, and also specifically enhanced c-Fos expression in RHA rats tested for SI in some brain areas related to social behaviour, i.e. the infralimbic cortex (IL) and the medial posterodorsal amygdala (MePD) regions.

Atypical antipsychotics attenuate MK801-induced social withdrawal and hyperlocomotion in the RHA rat model of schizophrenia-relevant features.

RATIONALE: The administration of NMDA receptor (NMDAR) antagonists constitutes a widely used model that produce both positive (e.g., hyperactivity) and negative (e.g., social withdrawal) symptoms relevant for schizophrenia in rodents. These effects can be reversed with the administration of atypical (second and third generation) antipsychotics. OBJECTIVES: In this study we combined the NMDAR-antagonist model with the Roman High-Avoidance (RHA) strain, a psychogenetically selected model of schizophrenia-relevant features. We also studied whether some atypical antipsychotic drugs (clozapine, ziprasidone, and aripiprazole) would be able to attenuate or reverse the behavioural alterations induced by MK801 and whether such effects might be dependent on the rat strain. METHODS: MK801 dose-response study was conducted in RHA and Roman Low-Avoidance (RLA) male rats. After that, the 0.15 mg/kg MK801 dose was selected to carry out pharmacological studies versus atypical antipsychotics. RESULTS: In the first experiment we establish that MK801 (dizocilpine), a NMDAR antagonist, produces dose-related hyperactivity and social withdrawal, which are more marked in RHA than RLA rats. The administration of the atypical antipsychotics clozapine (2.5 mg/kg) or ziprasidone (2.5 mg/kg) partially reversed or attenuated some of the social behaviour deficits and hyperactivity induced by the administration of MK801. Aripiprazole (3 mg/kg), a third-generation antipsychotic, reversed or attenuated the social preference deficit, the hyperactivity and the impairment of social latency induced by MK801. CONCLUSIONS: These results seem to be in line with previous studies with the NMDAR-antagonist model and add face (MK801-induced social withdrawal and hyperactivity) and predictive (attenuation of MK801-induced effects by atypical antipsychotics) validity to the RHA rat strain as a model of schizophrenia-relevant features.

Establishment and validation of a nomogram for predicting perioperative complications of retroperitoneal laparoscopic adrenalectomy.

Background: While laparoscopic adrenalectomy (LA) represents a gold standard for treating most adrenal lesions, no effective visual model for the prediction of perioperative complications of retroperitoneal laparoscopic adrenalectomy (RLA) exists. Methods: A retrospective study was conducted involving all consecutive patients underwent unilateral RLA for adrenal disease from January 2012 to December 2021. The entire cohort was randomly divided into 2 subsets (70% of the data for training, 30% for validation). Subsequently, a Least Absolute Shrinkage Selection Operator (LASSO) regression was performed to select the predictor variables, which were further consolidated via random forest (RF) and Boruta algorithm. Then the nomogram was established using the bivariate logistic regression analysis. Eventually, the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were employed to evaluate discrimination, calibration and clinical usefulness of the model, respectively. Results: A total of 610 patients underwent unilateral RLA for adrenal diseases were enrolled. After machine learning analyses, a weighted nomogram was established with 7 factors associated with complications including operative time, lesion laterality, intraoperative blood loss, pheochromocytoma, body mass index (BMI) and 2 preoperative comorbidities [respiratory diseases, cardiovascular diseases (CVD)]. The model displayed a fine calibration curve for perioperative complications evaluation in both the training dataset (P=0.847) and validation dataset (P=0.248). ROC with area under the curve (AUC) revealed excellent discrimination in the training dataset (0.817, 95% CI: 0.758-0.875) and validation dataset (0.794, 95% CI: 0.686-0.901). DCA curves showed that using this nomogram provided a more net benefit where threshold probabilities lay in the range of 0.1 to 0.9. Conclusions: An effective nomogram that incorporating 7 predictors was established in this study to identify patients at high risk of perioperative complications for RLA. It would contribute to the improvement of perioperative strategy due to its accuracy and convenience.

Avoidance and inhibitory control are possible transdiagnostic traits? A systematic review in animal models.

In clinical research, aberrant avoidance behavior and inhibitory control deficit have a high comorbidity in different psychopathological disorders. Therefore, avoidance and impulsive and/or compulsive behaviors might be classified as transdiagnostic traits, where the assessment through animal models could address evidence of their contribution as neurobehavioral mechanisms in psychopathology. The objective of the present review has been to assess the avoidance trait and the implication of inhibitory control behaviors, through studies using passive and active avoidance tests in rodents, and a preclinical model using selective breeding of high- or low-avoidance Roman rats (RHA, RLA). A systematic search strategy was carried out in the PubMed and Web of Science databases, where a total of 40 studies were accepted in the qualitative synthesis. The results of the different studies reviewed pointed to a relation between a reduced avoidance profile in passive avoidance (PA) with impulsive decision making and novelty-seeking behaviors; an increased avoidance profile in PA with compulsive drinking; a high active avoidance profile, including RHA rats, with different types of impulsivity and novelty- seeking behaviors; and regarding compulsivity depending on its measure, a low active avoidance profile, including RLA rats, has been associated with increased anxiety in the EPM and increased grooming, while a high active avoidance profile, including RHA rats, has been associated with increased rearing, compulsive drinking including alcohol, and cognitive inflexibility. The results have been discussed in terms of environmental factors and the underlying mechanisms between these possible transdiagnostic traits in psychopathology.

Comparison of the retroperitoneal laparoscopic adrenalectomy versus transperitoneal laparoscopic adrenalectomy for large (≥6cm) pheochromocytomas: A single-centre retrospective study.

Objectives: To compare the efficacy and safety of retroperitoneal laparoscopic adrenalectomy (RLA) and transperitoneal laparoscopic adrenalectomy (TLA) in the treatment of large (≥6cm) adrenal pheochromocytomas. Methods: We retrospectively collected the clinical data of 130 patients with large pheochromocytoma who underwent RLA or TLA in our hospital from 2012 to 2022. The perioperative parameters and follow-up outcomes of the two groups were compared, and univariate and multivariate analyses were used to evaluate the risk factors of hemodynamic instability (HI). Results: A total of 57 patients underwent TLA and 73 underwent RLA. There was no difference in demographic characteristics such as age, sex and tumor size between the two groups. Compared with the TLA group, patients in the RLA group had shorter operation time (P<0.001) and less estimated blood loss (EBL) (P<0.001). The time to ambulation, time to oral food and time to removal of drainage of RLA group were earlier than those of TLA group. In addition, the hospital stay was shorter in the RLA group than in the TLA group. There were no differences in HI, complications, or blood pressure (BP) improvement between the two groups. The mean follow-up time was 61.4 and 65.5 months, respectively, during which no tumors recurred or metastasized. Multivariate analysis showed that elevated hormone levels and larger tumor size were independent risk factors for HI. Conclusions: Both RLA and TLA are effective treatment methods for large pheochromocytomas, but the perioperative outcomes of RLA are better than that of TLA. Our study demonstrates the superiority of RLA for the treatment of large pheochromocytomas.

Dopamine, Erectile Function and Male Sexual Behavior from the Past to the Present: A Review.

Early and recent studies show that dopamine through its neuronal systems and receptor subtypes plays different roles in the control of male sexual behavior. These studies show that (i) the mesolimbic/mesocortical dopaminergic system plays a key role in the preparatory phase of sexual behavior, e.g., in sexual arousal, motivation and reward, whereas the nigrostriatal system controls the sensory-motor coordination necessary for copulation, (ii) the incertohypothalamic system is involved in the consummatory aspects of sexual behavior (penile erection and copulation), but evidence for its role in sexual motivation is also available, (iii) the pro-sexual effects of dopamine occur in concert with neural systems interconnecting the hypothalamus and preoptic area with the spinal cord, ventral tegmental area and other limbic brain areas and (iv) D2 and D4 receptors play a major role in the pro-sexual effects of dopamine. Despite some controversy, increases or decreases, respectively, of brain dopamine activity induced by drugs or that occur physiologically, usually improves or worsens, respectively, sexual activity. These findings suggest that an altered central dopaminergic tone plays a role in mental pathologies characterized by aberrant sexual behavior, and that pro-erectile D4 receptor agonists may be considered a new strategy for the treatment of erectile dysfunction in men.

Different maturation patterns for sensorimotor gating and startle habituation deficits in male and female RHA vs RLA rats.

Neurodevelopmental anomalies are thought to play a crucial role in the emergence of schizophrenia. The Roman high-avoidance (RHA) rats exhibit impaired prepulse inhibition (PPI), as well as other behavioral and cognitive singularities related to schizophrenia syndromes compared to the Roman low-avoidance (RLA) rats. In the present study, we aimed at elucidating whether PPI deficits in the RHA rats take place during prepubescence, adolescence, or adulthood. Thus, we evaluated the levels of PPI of both strains and both sexes during these three developmental phases. Additionally, we also investigated the onset of startle habituation deficits in the same groups. The results showed that male RHA rats exhibit a clear-cut PPI reduction compared to their RLA counterparts in adulthood. In female RHA rats, we observed lower levels of PPI since adolescence and through adulthood. We also found no differences between PPI percentages among the three ages in RHA male rats. Contrarily, in male RLA rats, PPI levels were increased in adults compared to their adolescent and prepubescent counterparts. Finally, a deficit in startle habituation was observed in adulthood of both male and female RHA rats, although in the latter case the disturbance in startle habituation was more profound. These results further the description of the maturational trajectory of cognitive markers relevant to schizophrenia prodrome and they add face validity to the RHA rats as a model of schizophrenia-relevant phenotypes.

Modeling & implementation of DRLA based partially shaded solar system integration with 3-ϕ conventional grid using constant current controller.

Renewable Energy Resources (RERs) are widely used on the concern of global environment protection. Solar energy systems play an important role in the generation of electrical energy, remarkably minimize the utilization of nonrenewable fuel sources. Solar energy can be extracted and transformed into electrical energy via solar photovoltaic process. Several traditional, soft computing, heuristic, and meta-heuristic maximum power point tracking (MPPT) techniques have been developed to extract Maximum Energy Point (MEP) from the solar photovoltaic modules under different atmospheric conditions. In this manuscript, the combination of reinforcement learning algorithm (RLA) and deep learning algorithm (DLA) called deep Reinforcement Learning Algorithm based MPPT (DRLAMPPT) is proposed under partial shading conditions (PSC) of the solar system. DRLAMPPT can deal with continuous state spaces, in contrast to RL it can be operated only with discrete action state spaces. In this proposed DRLAMPPT, deep deterministic policy gradient (DDPG) solves the problem of continuous state spaces are involved to reach the GMEP in photovoltaic systems especially under PSC. In DRLAMPPT, the representative's strategy is parameterized by an artificial neural network (ANN), which uses sensory information as input and directly sends out control signals. This work develops a 2 kW solar photovoltaic power plant comprises of a photovoltaic array, DC/DC step-up converter, 3-Φ Pulse Width Modulated Voltage Source Inverter (PWM-VSI) integrated with conventional power grid using Constant Current Controller (CCC Effectiveness of the proposed DRLAMPPT with CCC can be validated through an experimental setup and with MATLAB. Simulation and tested at different input conditions of solar irradiance. Experimental results prove that, in comparison to existing MPPTs, suggested DRLAMPPT not only attains the best efficiency and also adopts the change in environmental conditions of the photovoltaic system at a much faster rate and able to reach the GMEP within 0.8 s under PSC. Experimental and simulation results also prove that suggested CCC with LC filter makes the inverter output voltage and the grid voltage are in phase at the lower value of THD i.e. 1.1% and 0.98% respectively.

Social preference in Roman rats: Age and sex variations relevance for modeling negative schizophrenia-like features.

Social withdrawal is one of the most relevant negative symptoms of schizophrenia. Animal models that mimic schizophrenia's symptoms, in general, and negative symptoms, in particular, are difficult to develop because of the high complexity of symptoms and neurochemical disturbances that schizophrenia patients display throughout their lives. In recent years we have shown that Roman High-Avoidance (RHA) rats exhibit some phenotypes that are thought to represent positive symptoms, cognitive/attentional symptoms, as well as some negative symptoms of the disease. In the present study, we aimed at elucidating whether the social interaction (SI) deficits exhibited by adult male RHA rats, compared to their Roman Low-Avoidance (RLA) counterparts, are also present during adolescence, as well as whether there are between-strain differences in adolescent and adult female rats. The results of the present study show that adult male RHA rats exhibited a deficit in social preference compared to their RLA counterparts. Such a deficit was not observed in adolescent RHA rats or female rats of any age. The results also show that the adult male rats of both strains had significant decreases in social preference compared to the adolescent male rats. Additionally, we also show that female adult RHA rats have greater social preference than their male counterparts. These results seem to be in line with previous rodent and human studies and add face validity to the RHA rats as a model of schizophrenia.

Unraveling agglomeration and deagglomeration in aqueous colloidal dispersions of very small tin dioxide nanoparticles.

HYPOTHESIS: Understanding deagglomeration, agglomerate formation and structure for very small nanoparticles (NPs), due to their more facile agglomeration, is critical for processing or tailoring agglomerates for nanostructured materials. We propose that by controlling and fine-tuning the interplay of agglomeration (colloidal interaction) and deagglomeration (hydrodynamic forces), the design of agglomerate size, microstructure and morphology is possible even for very small NPs. EXPERIMENTS: Here, we investigate very small SnO2 NPs (10 nm) generated in the gas phase as model system. Small-angle X-ray scattering (SAXS) and dynamic light scattering (DLS) are used to study dispersions in aqueous media across the entire pH range (2-12) at various NaCl concentrations treated with ultrasound. Parallel to size and size distribution, agglomerate morphology and microstructure are analyzed by means of the mass fractal dimension, dm and modeled with ab initio shape simulations. The critical coagulation concentration (CCC) is determined for the alkaline region where the SnO2 NPs are highly charged. FINDINGS: Quantitative analysis of SAXS and DLS data reveals that size and size distribution of the agglomerates depend similarly on the electrostatic interaction influenced by pH and salinity as observed by the zeta potential. In contrast dm is mainly influenced by the salt concentration. Ab initio shape simulations support these experimental findings.

Decreased social interaction in the RHA rat model of schizophrenia-relevant features: Modulation by neonatal handling.

The Roman-Low (RLA) and High-Avoidance (RHA) rat strains have been bidirectionally selected and bred, respectively, for extremely poor vs. rapid acquisition of the two-way active avoidance task. Over 50 years of selective breeding have led to two strains displaying many differential specific phenotypes. While RLAs display anxious-related behaviours, RHA rats show impulsivity, and schizophrenia-like positive and cognitive symptoms or phenotypes. Neonatal handling (NH) is an environmental treatment with long-lasting anxiolytic-like and anti-stress effects. NH also reduces symptoms related to schizophrenia, such as pre-pulse inhibition (PPI) impairment and latent inhibition (LI) deficits, and improves spatial working memory and cognitive flexibility. The present work was aimed at exploring whether RHAs also display negative schizophrenia-like symptoms (or phenotypes), such as lowered preference for social interaction (i.e. asociality), and whether NH would reduce these deficits. To this aim, we evaluated naïve inbred RHA and RLA rats in a social interaction (SI) test after either long- or short-term habituation to the testing set up (studies 1-2). In Study 3 we tested untreated and NH-treated RHA and RLA rats in novel object exploration (NOE) and SI tests. Compared with RHAs, RLA rats displayed increased anxiety-related behaviours in the NOE (i.e. higher behavioural inhibition, lesser exploration of the novel object) and SI (i.e. higher levels of self-grooming) tests which were dramatically reduced by NH treatment, thus supporting the long-lasting anxiolytic-like effect of NH. Remarkably, RHA rats showed decreased social preference in the SI test compared with RLAs, evidencing that RHAs would present a relative asociality, which is thought to model some negative symptomatology (i.e. social withdrawal) of schizophrenia. NH increased absolute levels of social behaviour in both strains, but with a more marked effect in RHA rats, especially in the first 5 min of the SI test. Thus, it is hypothesized that, apart from its effects on anxiety-related behaviours, NH might have long-lasting positive effects on behavioural and neurobiological processes that are impaired in schizophrenia.

Strict Assembly Restriction of Peptides from Rabbit Hemorrhagic Disease Virus Presented by Rabbit Major Histocompatibility Complex Class I Molecule RLA-A1.

Rabbits are pivotal domestic animals for both the economy and as an animal model for human diseases. A large number of rabbits have been infected by rabbit hemorrhagic disease virus (RHDV) in natural and artificial pandemics in the past. Differences in presentation of antigenic peptides by polymorphic major histocompatibility complex (MHC) molecules to T-cell receptors (TCR) on T lymphocytes are associated with viral clearance in mammals. Here, we screened and identified a series of peptides derived from RHDV binding to the rabbit MHC class I molecule, RLA-A1. The small, hydrophobic B and F pockets of RLA-A1 capture a peptide motif analogous to that recognized by human class I molecule HLA-A*0201, with more restricted aliphatic anchors at P2 and PΩ positions. Moreover, the rabbit molecule is characterized by an uncommon residue combination of Gly53, Val55, and Glu56, making the 310 helix and the loop between the 310 and α1 helices closer to the α2 helix. A wider A pocket in RLA-A1 can induce a special conformation of the P1 anchor and may play a pivotal role in peptide assembly and TCR recognition. Our study broadens the knowledge of T-cell immunity in domestic animals and also provides useful insights for vaccine development to prevent infectious diseases in rabbits.IMPORTANCE We screened rabbit MHC class I RLA-A1-restricted peptides from the capsid protein VP60 of rabbit hemorrhagic disease virus (RHDV) and determined the structures of RLA-A1 complexed with three peptides, VP60-1, VP60-2, and VP60-10. From the structures, we found that the peptide binding motifs of RLA-A1 are extremely constraining. Thus, there is a generally restricted peptide selection for RLA-A1 compared to that for human HLA-A*0201. In addition, uncommon residues Gly53, Val55, and Glu56 of RLA-A1 are located between the 310 helix and α1 helix, which makes the steric position of the 310 helix in RLA-A1 much closer to the α2 helix than that found in other mammalian MHC class I molecules. This special conformation between the 310 helix and α1 helix plays a pivotal role in rabbit MHC class I assembly. Our results provide new insights into MHC class I molecule assembly and peptide presentation of domestic mammals. Furthermore, these data also broaden our knowledge on T-cell immunity in rabbits and may also provide useful information for vaccine development to prevent infectious diseases in rabbits.

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.

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.

Rats selectively bred for showing divergent behavioral traits in response to stress or novelty or spontaneous yawning with a divergent frequency show similar changes in sexual behavior: the role of dopamine.

Sexual behavior plays a fundamental role for reproduction in mammals and other animal species. It is characterized by an anticipatory and a consummatory phase, and several copulatory parameters have been identified in each phase, mainly in rats. Sexual behavior varies significantly across rats even when they are of the same strain and reared under identical conditions. This review shows that rats of the same strain selectively bred for showing a divergent behavioral trait when exposed to stress or novelty (i.e. Roman high and low avoidance rats, bred for their different avoidance response to the shuttle box, and high and low novelty exploration responders rats, bred for their different exploratory response to a novel environment) or a spontaneous behavior with divergent frequency (i.e. low and high yawning frequency rats, bred for their divergent yawning frequency) show similar differences in sexual behavior, mainly in copulatory pattern, but also in sexual motivation. As shown by behavioral pharmacology and intracerebral microdialysis experiments carried out mainly in Roman rats, these sexual differences may be due to a more robust dopaminergic tone present in the mesocorticolimbic dopaminergic system of one of the two sub-lines (e.g. high avoidance, high novelty exploration, and low yawning rat sub-lines). Thus, differences in genotype and/or in prenatal/postnatal environment lead not only to individual differences in temperament and environmental/emotional reactivity but also in sexual behavior. Because of the highly conserved mechanisms controlling reproduction in mammals, this may occur not only in rats but also in humans.

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 ±â€¯0.9 and 36.4 ±â€¯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.

Effects of morphine on place conditioning and ERK1/2 phosphorylation in the nucleus accumbens of psychogenetically selected Roman low- and high-avoidance rats.

RATIONALE: Extracellular signal-regulated kinase (ERK1/2) phosphorylation is critical for neuronal and behavioural functions; in particular, phosphorylated ERK1/2 (pERK1/2) expression in the nucleus accumbens (Acb) of the rat is stimulated by addictive drugs with the exception of morphine, which decreases accumbal ERK1/2 phosphorylation in the Sprague-Dawley and Wistar rats. The psychogenetically selected Roman low- (RLA) and high-avoidance (RHA) rats differ behaviourally and neurochemically in many responses to addictive drugs. In particular, morphine elicits a greater increment in locomotor activity and in dopamine transmission in the Acb of RHA vs RLA rats. However, the effects of morphine on place conditioning (conditioned place preference (CPP)) and ERK1/2 phosphorylation in the Roman lines remain unknown. OBJECTIVES AND METHODS: To characterize in the Roman lines the reinforcing properties of morphine (i.e. morphine-elicited CPP acquisition) and the relationship between these properties and its effects on ERK1/2 phosphorylation in the Acb, the behavioural effects of morphine were evaluated in a place-conditioning apparatus and ERK1/2 phosphorylation was assessed by immunohistochemistry in the shell and core subregions of the Acb of rats both acutely administered with morphine or undergoing conditioning. RESULTS: Morphine elicited CPP in both Roman lines and decreased pERK1/2 expression in the Acb of RLA but not RHA rats. Such decrease was prevented by conditioning. CONCLUSIONS: These findings indicate that the selective breeding of the Roman lines has generated a divergence, in terms of morphine-elicited pERK1/2 expression but not of morphine-elicited CPP, between RLA and RHA rats and sustain the observation that changes in pERK1/2 expression in the Acb are not a requisite for the reinforcing effects of morphine.

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.