Roman Low-avoidance Rats Research Articles

Individual variation in the (patho)physiology of energy balance

There are large individual differences in the susceptibility for metabolic disorders such as obesity, the metabolic syndrome and type 2 diabetes. Unfortunately, most animal studies in this field ignore the importance of individual variation which limits the face validity of these studies for translation to the human situation. We have performed a series of studies that were particularly focused on the individual differences in the (patho)physiology of energy balance. The studies were performed with passive and proactive individuals of two different rat strains: the Roman High and Low Avoidance rats and the Wild type Groningen rat. The data reveal that passive and proactive individuals differ significantly on several parameters, i.e. body composition, Hypothalamic-Pituitary-Adrenal (HPA) axis activity, plasma levels of insulin and leptin, intestinal transit time, systolic blood pressure and meal patterns. We also found that the selection line of the Roman Low Avoidance rat may be considered as a non-obese animal model for the metabolic syndrome, since these rats display, under sedentary conditions, many of the related symptoms such as hypertension, visceral adiposity and insulin resistance during an intravenous glucose tolerance test. These symptoms disappeared when the animals were allowed to exercise voluntarily in a running wheel. We conclude that experiments with passive and proactive individuals are highly relevant for studying the (patho)physiology and behavior of energy balance and the related metabolic disorders.

Effects of antidepressants on the performance in the forced swim test of two psychogenetically selected lines of rats that differ in coping strategies to aversive conditions

The selective breeding of Roman low-avoidance (RLA) and high-avoidance (RHA) rats for, respectively, poor versus rapid acquisition of active avoidance in a shuttle-box has produced two phenotypes that differ drastically in the reactivity to stressful stimuli: in tests used to assess emotionality, RLA rats display passive ("reactive") coping and robust hypothalamus-pituitary-adrenal (HPA) axis reactivity, whereas RHA rats show proactive coping and blunted HPA axis responses. The behavioral and neuroendocrine traits that distinguish these lines suggest that RLA rats may be prone, whereas RHA rats may be resistant to develop depression-like behavior when exposed to stressful experimental conditions. To evaluate the performance of the Roman lines in the forced swim test, immobility, climbing, and swimming were assessed under baseline conditions (i.e., pretest in naïve animals or test after the administration of vehicle), and after subacute treatment with desipramine, fluoxetine, and chlorimipramine. Under baseline conditions, RLA rats displayed greater immobility and fewer climbing counts than RHA rats. In RLA rats, desipramine, fluoxetine, and chlorimipramine decreased immobility; moreover, desipramine and chlorimipramine increased climbing, whereas fluoxetine increased swimming. In RHA rats, none of these drugs affected immobility, swimming, or climbing. RLA and RHA rats represent two divergent phenotypes respectively susceptible and resistant to display depression-like behavior in the forced swim test. Hence, comparative studies in these lines may help to develop novel working hypotheses on the relationships among genotype, temperament traits, and neural mechanisms underlying the vulnerability or resistance to stress-induced depression in humans.

The frequency and power of theta band recorded from dorsal CA1 field of hippocampus are related to individual differences in emotional reactivity of the Roman High (RHA/Verh) and Low Avoidance (RLA/Verh) rats

The frequency and power of theta band recorded from dorsal CA1 field of hippocampus are related to individual differences in emotional reactivity of the Roman High (RHA/Verh) and Low Avoidance (RLA/Verh) rats

The passive coping Roman Low Avoidance rat, a non-obese rat model for insulin resistance

The aim of the study was develop to an animal model that links coping style to insulin resistance. We hypothesized that the psychogenetically selected Roman Low Avoidance (RLA) rats may serve as such a model. To test this hypothesis, we submitted both RLA and Roman High avoidance (RHA) rats to a series of intravenous glucose tolerance tests (IVGTT). These IVGTT were followed by post mortem metabolic characterization of the selection lines. It was found that plasma insulin levels are markedly elevated in the passively coping RLA rat, both in baseline conditions and during the intravenous glucose tolerance tests. The elevation in plasma insulin was accompanied with increased levels of plasma corticosterone, FFA, leptin and triglycerides but not by changes in body weight. We conclude that the passive, highly emotional RLA rat is metabolically different from both the RHA rat and the standard control Wistar rat and may serve as a non-obese animal model for insulin resistance.

P.4.11 Higher histamine synthesis and release in inbred Roman high versus low avoidance rats: a histaminergic hypothesis

ethanol (1 g/kg) or WIN 55,212-2 was administered for 5 days, from PND 28 to PND 32. Such early ethanol exposure decreased (−28% p< 0.05) spontaneous alcohol consumption at adulthood. In contrast, their spontaneous alcohol intake increased (+37% p< 0.05) when C57BL/6J mice had been treated with WIN 55,212-2 at adolescence. In DBA/2J mice, which spontaneously avoid alcohol at adult age, the latter treatment did not significantly affect this behavioural trait. In contrast, early alcohol intake at adolescence regularly increased their spontaneous alcohol consumption under free-choice conditions at adulthood. This augmentation ranged between +34% and +94% (p< 0.001), depending on the dose and duration of early ethanol administration. No changes in 5-HT1A G protein coupling efficacy were generally observed in animals which had been exposed to alcohol at adolescence, except in C57BL/6J mice with an induced decrease in alcohol intake at adulthood (see above) for which 5-carboxamidotryptamine exhibited a 3-fold increased potency (p< 0.05) to enhance [35S]GTP-g-S binding in the hippocampus. These results show that early ethanol and/or cannabis consumption can affect ethanol preference at adulthood. The differences between C57BL/6J and DBA/2J mice indicate that such induced modulations of alcohol intake are under genetic control. The change in 5-HT1A receptor coupling suggests that the critical influence of gene– environment interactions on alcohol preference/avoidance at adulthood may depend-in part-on serotoninergic mechanisms. This research has been supported by grants from INSERM, IREB and MILDT.

Diverse Sensitivity of RHA/Verh and RLA/Verh Rats to Emotional and Spatial Aspects of a Novel Environment as a Result of a Distinct Pattern of Neuronal Activation in the Fear/Anxiety Circuit

Psychogenetically selected Roman high (RHA/Verh) and Roman low (RLA/Verh) avoidance rats constitute a well-recognized model of diverse emotional reactivity. The two Swiss lines display marked behavioral and endocrine differences in reaction to a novel environment. In our study we found that these differences are accompanied by a distinct, line-specific pattern of neuronal activation within the fear/anxiety circuit. We have compared the c-Fos protein expression in the medial prefrontal cortex (mPFC), basolateral (BLA), central (CeA), medial (MeA), and cortical (CoA) nuclei of amygdala, paraventricular nucleus of the hypothalamus (PVN), and CA1, CA2, and CA3 fields of the hippocampus upon exposure to a novel situation of different stressorgeneity (open field with illuminated center, elevated plus maze, hole board test and acute restraint). Profound between-line differences in the sensitivity to emotional and spatial aspects of the behavioral challenge were observed for tests measuring spontaneous behavior. This effect seems to reflect different motivational factors driving the rat behavior, which clearly suggests that the diverse emotional reactivity of RHA/Verh and RLA/Verh rats is a result of different activation of the fear/anxiety circuit.

Regional adaptations in PSD-95, NGFI-A and secretogranin gene transcripts related to vulnerability to behavioral sensitization to amphetamine in the Roman rat strains

Genetically selected for high or low two-way active avoidance, Roman high-avoidance (RHA) and Roman low-avoidance (RLA) rats differ in their central dopaminergic activity, sensation/novelty- and substance-seeking profiles. These animals are, therefore, well suited to identify anatomical and neurochemical concomitants of behavioral sensitization, a phenomenon linked to addictive liability. We submitted inbred RHA (RHA-I), inbred RLA (RLA-I) and Sprague–Dawley-OFA (SD-OFA) rats to a sensitization regimen with amphetamine and studied the behavioral response to an amphetamine challenge after a 2-week withdrawal period. The expression patterns of nerve growth factor inducible clone A (NGFI-A), secretogranin, post-synaptic density protein of 95 Kd (PSD-95), prodynorphin and proenkephalin mRNA were also analyzed using in situ hybridization, after the challenge with amphetamine. RHA-I rats showed stronger sensitization than SD-OFA rats. RLA-I rats did not show sensitization but were hyper-reactive to amphetamine. Expression of behavioral sensitization in RHA-I rats activated secretogranin and PSD-95 mRNA in the nucleus accumbens core. On the other hand, high induction of NGFI-A mRNA in the central amygdala was observed in RLA-I rats when they experienced amphetamine for the first time in the challenge. Our results reveal that 1) the acute locomotor response to amphetamine does not predict vulnerability to behavioral sensitization and 2) differences in vulnerability to sensitization may involve distinctive cellular adaptations at particular brain locations which may be related to addictive vulnerability.

One-way avoidance learning and diazepam in female roman high-avoidance and low-avoidance rats

The goal of this experiment was to study the influence of the time spent in the safe compartment (30 vs. 1 s) and of an intraperitoneal injection of diazepam (1 mg/kg vs. vehicle) on one-way avoidance learning, in inbred female roman high-avoidance and roman low-avoidance rats. Rats learned to run from a danger compartment, where they received a warning signal (88 dB tone) followed by a 1 mA electric footshock, to a safe compartment, where these stimuli were not presented. The number of trials needed to reach 10 consecutive avoidance responses was the dependent variable. Roman low-avoidance rats exposed to 1 s in the safe compartment showed poorer performance than their roman high-avoidance counterparts. These differences were not observed in rats exposed to 30 s in the safe place, and were abolished by the injection of diazepam. These results suggest the importance of fear and reinforcement in one-way avoidance learning and its usefulness for studying emotional processes underlying genetic or pharmacological manipulations.

Successive positive contrast in one-way avoidance behavior with Roman low-avoidance rats

The inbred Roman High - (RHA-I) and Roman Low-Avoidance (RLA-I) rats, psychogenetically selected for rapid (RHA-I) vs. extremely poor (RLA-I) acquisition of two-way active avoidance, exhibit a lower or a higher level of fearfulness, respectively, that can be observed in many laboratory anxiety models. The present study analyzed the performance of female RLA-I and RHA-I rats in a successive positive contrast situation induced during one-way avoidance learning. Three groups of RLA-I and three of RHA-I rats (1–30, 30–30 and 1–1 groups, the numbers stand for the time spent in the safe compartment during the first and second phase of training) were trained to avoid an electric foot-shock administered in a “danger” compartment, by running from this compartment to a “safe” one. Only RLA-I rats showed a significant positive contrast effect, in such a way that the reinforcement increase from the lower (1 s spent in safety) to the higher reward (30 s) led to a response enhancement, surpassing the performance of rats trained with the low (1–1 s) or the high (30–30 s) reward from the beginning of training. The results are discussed in the context of an opponent process theory based upon the interaction between the motivational strength of fear and the incentive value of relief taking place during one-way avoidance learning.

Successive negative contrast in one-way avoidance learning in female roman rats

The inbred RLA (Roman Low-Avoidance) and RHA (Roman High-avoidance) rat strains have been psychogenetically selected for rapid (RHA) vs. extremely poor acquisition (RLA) of two-way active avoidance. As a consequence of this selective breeding, RLA animals exhibit a higher level of emotionality that can be observed in many anxiety models. The present study was conducted in order to analyze the performance of female RLA, RHA and Wistar rats in a behavioral test of anxiety that involves the reduction of the magnitude of an expected reward: the negative contrast effect that is obtained in one-way avoidance learning by reducing the time spent in the safe compartment. To this aim, three groups of animals (30–1/RLA, 30–1/RHA and 30–1/W) were trained to avoid an electric foot-shock administered in a “danger” compartment, by running from this compartment to a “safe” compartment. We observed an impairment of the avoidance response when time spent in the safe compartment was reduced from 30 to 1 s, when 30–1/RLA and 30–1/W groups were compared with control groups that were trained with a constant safe time (1–1/RLA and 1–1/W, respectively). We also obtained significant differences between 30–1/RLA and 30–1/RHA groups in the postshift phase. These results indicate that RLA rats respond more negatively to the frustration triggered by the reduction in time spent in the safe compartment, suggesting that animal models based on negative contrast effects can be useful tools for studying the genetic basis of anxiety.

Differential activation of dopamine release in the nucleus accumbens core and shell after acute or repeated amphetamine injections: A comparative study in the Roman high- and low-avoidance rat lines

The selectively bred Roman high- and low-avoidance rats differ in emotionality and responsiveness to the motor effects of acute and repeated psychostimulant administration. These lines also show drastic differences in the neurochemical responses of their mesolimbic dopamine systems to addictive drugs. The nucleus accumbens is critically involved in the locomotor activation produced by psychostimulants and in the augmentation of this effect observed upon repeated drug administration (i.e. behavioral sensitization), although there is not a general consensus as to whether the nucleus accumbens-core or the nucleus accumbens-shell is preferentially involved in such alterations. This study was designed to evaluate the effects of acute amphetamine (0.20mg/kg, s.c.) on dopamine output in the nucleus accumbens-shell and nucleus accumbens-core of the Roman lines under basal conditions (i.e. naïve rats) and after the repeated administration of amphetamine (1mg/kg, s.c.×10 days) or saline. We show that (1) in naïve rats, amphetamine caused a larger increment in dopamine output in the nucleus accumbens-shell vs the nucleus accumbens-core only in the Roman high-avoidance line; (2) repeated amphetamine elicits behavioral sensitization in Roman high-avoidance, but not Roman low-avoidance, rats; (3) in sensitized Roman high-avoidance rats, amphetamine provokes a larger increment in dopamine output in the nucleus accumbens-core, and an attenuated dopaminergic response in the nucleus accumbens-shell, as compared with Roman high-avoidance rats repeatedly treated with saline; and (4) such neurochemical changes are not observed in the mesoaccumbens dopaminergic system of the sensitization-resistant Roman low-avoidance line. We propose that (1) Roman high-avoidance and Roman low-avoidance rats differ in the vulnerability to develop psychostimulant sensitization, (2) the nucleus accumbens-core and nucleus accumbens-shell subserve distinct functional roles in this phenomenon, and (3) comparative studies in the Roman lines may provide insight into the influence of neural substrates and genetic background on the individual vulnerability to addiction.

Inbred Roman High- and Low-Avoidance Rats: Differences in Anxiety, Novelty-Seeking, and Shuttlebox Behaviors

In the present study, male inbred animals (from the 10th generation of an inbreeding program that has been carried out in parallel to that of the outbred Roman high- and low-avoidance rat lines), were compared for emotionality in different testing situations, exploratory behavior in the holeboard and two-way, active-avoidance acquisition. Compared to the inbred Roman high-avoidance (RHA-I/Verh) rats, inbred Roman low-avoidance (RLA-I-Verh) rats showed higher emotionality in the open field (reduced distance travelled and number of rearings, and increased self-grooming behavior), in the elevated plus-maze test (increased number of total and open-arm entries, reduced distance travelled in the open arms, and increased self-grooming behavior), and during the habituation period in the shuttle box (decreased number of crossings, increased self-grooming behavior and defecations). Results from the hyponeophagia test were not conclusive, probably due to the test-dependent hyperactivity shown by RHA-I/Verh rats. In the holeboard apparatus, RHA-I/Verh rats explored more than RLA-I/Verh rats, especially when novel objects were located beneath the holes. Finally, RHA-I/Verh animals rapidly acquired active, two-way (shuttlebox) avoidance, whereas RLA-I/Verh animals required four 50-trial sessions to achieve an assymptotic level of 30–40% avoidance. Thus, the behavioral patterns of the Roman inbred strains were very similar to those previously reported for the RHA/Verh outbred lines. Differences in locomotor activity, exploratory, and self-grooming behavior were actually greater between the inbred strains than between the outbred lines. Differences in defecation, however, although still significant, were not so pronounced as those noted previously at this laboratory with the outbred lines.

Pharmacological properties of the GABA A receptor complex from brain regions of (hypoemotional) Roman high- and (hyperemotional) low-avoidance rats

The pharmacological properties of benzodiazepine binding sites of the γ-aminobutyric acid (GABA) A receptor complex from cortical, hippocampal and cerebellar membranes of Roman high-avoidance (RHA/Verh) and Roman low-avoidance (RLH/Verh) rats were investigated. No major differences between the two lines were found in the binding parameters of [ 3 H ]flunitrazepam (a non-selective agonist), [ 3 H ]zolpidem (a Type I selective agonist) or [ 3 H ]ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4 H-imidazol[1,5- a]-[1,4]benzodiazepine-3-carboxylate (Ro15-4513) (a partial inverse agonist). Neither the K d values nor the B max for these ligands differed between RHA/Verh and RLA/Verh rats in any of the brain regions studied. As a result, the proportion of Type I binding sites in cortical and hippocampal membranes of RHA/Verh and RLA/Verh rats or the `diazepam-sensitive' and the `diazepam-insensitive' binding sites in cerebellar membranes, calculated from the [ 3 H ]flunitrazepam and [ 3 H ]zolpidem maximal binding sites or from [ 3 H ]Ro15-4513 binding (in the absence or in presence of diazepam), respectively, was also similar. Furthermore, there were no differences between the two rat lines in the allosteric interactions between GABA and the benzodiazepine binding sites (labeled with [ 3 H ]flunitrazepam) in all three areas tested or the Type I binding sites (labeled with [ 3 H ]zolpidem) in the hippocampus. In contrast, RLA/Verh rats showed a significant reduction in the allosteric interactions between GABA and [ 3 H ]zolpidem binding sites in the cortex. As a whole, these results indicate the absence of generalized between-line differences in the GABA A receptor complex showing, at the same time, the existence of some specific differences in allosterism within the GABA A complex. These differences may contribute to the divergent emotional responses which characterize the RHA/Verh and RLA/Verh rat lines.

Acute stress enhances intestinal permeability to intact protein in roman low avoidance rats, but not in roman high avoidance rats, by a cholinergic mechanism

ACUTE STRESS ENHANCES INTESTINAL PERMEABILITY TO INTACT PROTEIN IN ROMAN LOW AVOIDANCE RATS, BUT NOT IN ROMAN HIGH AVOIDANCE RATS, BY A CHOLINERGIC MECHANISM. P.B. Bijlsma, P.R. Saunders*, P. Driscoll**, J.M. Konlhaas***, J.A.J.M. Taminiau, M.H. Perdue*, J.A. Groot. Inst. Neumbiol / Acad. Med. Ctr., Univ. Amsterdam,*** Fac. Biol., Univ. Groningen, The Netherlands; *Dept. Pathol., McMaster Univ. Hamilton, Canada; **ETH ZUrich, Switzerland.

Behavioural and physiological consequences of a single social defeat in Roman high- and low-avoidance rats.

The behavioural and physiological consequences of a single social defeat were studied in Roman high-avoidance (RHA) and Roman low-avoidance (RLA) rats, two rat lines with a genetically determined difference in the way of responding to or coping with stressors. Animals were subjected to social defeat by placing them in the cage of an aggressive male conspecific for 1 h. In both RHA and RLA rats, social defeat induced a profound increase in body temperature during the circadian resting phase, lasting for up to 10 days after the conflict. The increase in resting temperature was paralleled by a slight decrease in spontaneous home cage activity. Food intake and growth were suppressed for a number of days, resulting in a long-lasting lower body weight compared to non-stressed control animals. An open field test 2 days after defeat showed a social stress-induced decrease in locomotion in a novel environment. Despite the well-known differentiation between RHA and RLA rats in their behavioural and neuroendocrine response pattern to acute environmental challenges, the present study did not show major differences in the long-term consequences of social defeat.

Effects of cocaine and morphine in rats from two psychogenetically selected lines: a behavioral and brain dialysis study.

The Swiss sublines of Roman high-avoidance (RHA/Verh) and Roman low-avoidance (RLA/Verh) rats differ in their reactivity to environmental and pharmacological stressors, in their sensitivity to stereotypies elicited by dopamine (DA)-mimetic agents, and in their densities of D1 DA receptors in the terminal field of the mesoaccumbens DAergic projection, an important link in the neural networks involved in the motor effects and reinforcing properties of drugs abused by humans. The present study was therefore designed to compare the behavioral and neurochemical effects of cocaine (5 mg/kg, i.p.) and morphine (0.5 mg/kg, s.c.) in RHA/Verh and RLA/Verh rats. To this aim, we measured motor activity and DA output in the nucleus accumbens as determined by brain microdialysis. The number of counts corresponding to horizontal, vertical, and total motor activities accumulated in basal conditions during the 60-min acclimation period was significantly larger in RHA/Verh than in RLA/Verh rats. Moreover, horizontal, vertical, and total motor activities throughout the 120-min observation period that followed the administration of vehicle tended to be larger in RHA/Verh rats, although the difference between the two lines was not statistically significant. In RHA/Verh rats, locomotion, rearing, and total motor activity were significantly more intense after acute cocaine and morphine challenges than after vehicle administration, whereas no significant differences in motor activity were observed between control and cocaine- or morphine-treated RLA/Verh rats. No line-related differences were detected in the basal DA output, but the effect of cocaine on DA release was more robust in RHA/Verh rats. Likewise, the effect of morphine was more pronounced in RHA/Verh than in RLA/Verh rats. Because the mesoaccumbens DAergic pathway plays a central role in the acquisition of motivational valence by environmental and pharmacological stimuli and, therefore, in operant behavior, our results suggest that comparative behavioral and neurochemical studies in these two lines may provide useful information on the biological correlates of drug dependence.

Biochemical parameters of dopaminergic and GABAergic neurotransmission in the CNS of Roman high-avoidance and Roman low-avoidance rats.

The dopaminergic (DAergic) and GABAergic pathways in the central nervous system (CNS) are involved in the control of emotions, in the reactivity to stressful stimuli, and in the positive and negative reinforcing properties of psychotropic drugs. In the present review, we summarize the differences in a range of neurochemical markers of GABA- and DA-mediated neurotransmission in the CNS of Roman high-avoidance (RHA/Verh) and Roman low-avoidance (RLA/Verh) rats, two psychogenetically selected lines that differ in what may be considered to be level of emotionality. The stimulatory effect of GABA on 36Cl- uptake was less pronounced in the cerebral cortex of RLA/Verh rats compared to RHA/Verh rats. In addition, the binding affinity of [35S]TBPS, a selective ligand of the convulsant site located in the chloride channel of GABAA receptors, was significantly lower in the hippocampus of RLA/Verh rats than in their high-avoidance counterparts. On the other hand, the density of D1 DA receptors labeled with [3H]SCH 23390 was lower in the nucleus accumbens of RLA/Verh rats compared to RHA/Verh rats. Brain microdialysis studies demonstrated that tail-pinch stress and subconvulsant doses of the anxiogenic compound pentylenetetrazol increased the extracellular concentrations of DA in the prefrontal cortex of hypoemotive RHA/Verh rats but not in their hyperemotive RLA/Verh counterparts. These line-dependent differences in GABAergic and DAergic neurotransmission may contribute to the distinct emotionality and responsiveness to centrally active drugs of RHA/Verh and RLA/Verh rats.

The locus of origin of augmenting and reducing of visual evoked potentials in rat brain

Humans who are high sensation seekers and cats who demonstrate comparable behavioral traits show increasing amplitudes of the early components of the cortical visual evoked potential (VEP) to increasing intensities of light flash; low sensation seekers show VEP reducing. Roman high-avoidance (RHA) and Roman low-avoidance (RLA) rats have behavioral traits comparable to human and cat high and low sensation seekers, respectively. Previously, we showed that RHA and RLA rats are cortical VEP augmenters and reducers, respectively. The goal of this study was to determine if augmenting-reducing is in fact a property of the visual cortex or if it originates at the lateral geniculate nucleus and is merely reflected in recordings from the cortex. VEPs to five flash intensities were recorded from the visual cortex and dorsal lateral geniculate of RHA and RLA rats. As in the previous study, the slope of the first cortical component as a function of flash intensity was greater in the RHA than in the RLA rats. The amplitude of the geniculate component that has a latency shorter than the first cortical component was no different in the two lines of rats. The finding from the cortex confirms the earlier finding of augmenting and reducing in RHA and RLA rats, respectively. The major new finding is that the augmenting-reducing difference recorded at the cortex does not occur at the thalamus, indicating that it is truly a cortical phenomenon.

Genetic analysis of the relationships between behavioral and neuroendocrine traits in Roman High and Low Avoidance rat lines.

In order to determine whether the coselection observed between the selection trait (active avoidance behavior) of the Roman High Avoidance (RHA) and Roman Low Avoidance (RLA) rat lines and their neuroendocrine characteristics were genetically determined, we analyzed, in nonsegregating (RHA, RLA, and F1) and segregating (F2 and the two backcrosses) crosses, the inheritance pattern and the phenotypic correlations among behavioral (shuttle-box behavior), physiological (body, adrenal, and thymus weights), and neuroendocrine (corticosterone and prolactin reactivity, catecholamine enzyme activities) variables. Physiological characteristics and enzyme activities have a crucial role in sex dissociation. Avoidance behavior and prolactin reactivity to novel environment remained associated in segregating crosses despite gene rearrangement. They represented the most important variables to differentiate the Roman lines, perhaps sharing a common regulatory mechanism under genetic control.

Effects of training, early handling, and perinatal flumazenil on shuttle box acquisition in Roman low-avoidance rats: Toward overcoming a genetic deficit

The present series of studies investigated the effects of intensive training, postnatal handling-stimulation and/or perinatal flumazenil (Ro 15-1788, benzodiazepine receptor antagonist) on the acquisition of two-way active avoidance by Roman low-avoidance (RLA/Verh) rats. This rat line has been selectively bred for poor avoidance in the shuttle box, while their Roman high-avoidance counterparts (RHA/Verh) have been selectively bred for their extremely good performance in that task. In the first experiment, RLA/Verh rats submitted to a long and intensive training procedure (unlike those submitted to short training) were able to achieve a performance of 56% of avoidances per session. In the second experiment both postnatal handling and perinatal flumazenil treaments increased avoidance responding in another group of RLA/Verh rats tested at the age of 18 months. Finally, in the last experiment, the performance of a third stock of RLA/Verh rats of the same age which had received perinatal flumazenil did not differ, on the later phases of training, from that shown by RHA/Verh animals. The results are discussed in terms of the “warm up” phenomena which seems to be highly involved in the selection of RLA/Verh rats, as well as on the possibility that central benzodiazepine receptors could play a role in the genetic deficit shown by RLA/Verh rats, which apparently confers a greater emotivity.