Neurobehavioral and neurodevelopmental profiles of a heuristic genetic model of differential schizophrenia- and addiction-relevant features: The RHA vs. RLA rats.

The Roman High- (RHA) and Low-(RLA) avoidance rat lines/strains were generated through bidirectional selective breeding for rapid (RHA) vs. extremely poor (RLA) two-way active avoidance acquisition. Compared with RLAs and other rat strains/stocks, RHAs are characterized by increased impulsivity, deficits in social behavior, novelty-induced hyper-locomotion, impaired attentional/cognitive abilities, vulnerability to psychostimulant sensitization and drug addiction. RHA rats also exhibit decreased function of the prefrontal cortex (PFC) and hippocampus, increased functional activity of the mesolimbic dopamine system and a dramatic deficit of central metabotropic glutamate-2 (mGlu2) receptors (due to a stop codon mutation at cysteine 407 in Grm2 -cys407*-), along with increased density of 5-HT2A receptors in the PFC, alterations of several synaptic markers and increased density of pyramidal "thin" (immature) dendrític spines in the PFC. These characteristics suggest an immature brain of RHA rats, and are reminiscent of schizophrenia features like hypofrontality and disruption of the excitation/inhibition cortical balance. RHA rats represent a promising heuristic model of neurodevelopmental schizophrenia-relevant features and comorbidity with drug addiction vulnerability.

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.

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.

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.

Effect of Acute Stress on the Expression of BDNF, trkB, and PSA-NCAM in the Hippocampus of the Roman Rats: A Genetic Model of Vulnerability/Resistance to Stress-Induced Depression.

The Roman High-Avoidance (RHA) and the Roman Low-Avoidance (RLA) rats, represent two psychogenetically-selected lines that are, respectively, resistant and prone to displaying depression-like behavior, induced by stressors. In the view of the key role played by the neurotrophic factors and neuronal plasticity, in the pathophysiology of depression, we aimed at assessing the effects of acute stress, i.e., forced swimming (FS), on the expression of brain-derived neurotrophic factor (BDNF), its trkB receptor, and the Polysialilated-Neural Cell Adhesion Molecule (PSA-NCAM), in the dorsal (dHC) and ventral (vHC) hippocampus of the RHA and the RLA rats, by means of western blot and immunohistochemical assays. A 15 min session of FS elicited different changes in the expression of BDNF in the dHC and the vHC. In RLA rats, an increment in the CA2 and CA3 subfields of the dHC, and a decrease in the CA1 and CA3 subfields and the dentate gyrus (DG) of the vHC, was observed. On the other hand, in the RHA rats, no significant changes in the BDNF levels was seen in the dHC and there was a decrease in the CA1, CA3, and DG of the vHC. Line-related changes were also observed in the expression of trkB and PSA-NCAM. The results are consistent with the hypothesis that the differences in the BDNF/trkB signaling and neuroplastic mechanisms are involved in the susceptibility of RLA rats and resistance of RHA rats to stress-induced depression.

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.

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

RATIONALE: Animal models with predictive and construct validity are necessary for developing novel and efficient therapeutics for psychiatric disorders. OBJECTIVES: 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). RESULTS: 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 70 dB 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 0.05 mg/kg, decreased PPI in RHA-I, but not RLA-I rats. The hallucinogen drug DOI (5-HT2A agonist; 0.1-1.0 mg/kg) disrupted PPI in RLA-I rats in a dose-dependent manner at the 70 dB prepulse intensity, while in RHA-I rats, only the 0.5 mg/kg dose impaired PPI at the 80 dB 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. CONCLUSIONS: 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.

Prepulse inhibition predicts spatial working memory performance in the inbred Roman high- and low-avoidance rats and in genetically heterogeneous NIH-HS rats: relevance for studying pre-attentive and cognitive anomalies in schizophrenia.

Animal models of schizophrenia-relevant symptoms are increasingly important for progress in our understanding of the neurobiological basis of the disorder and for discovering novel and more specific treatments. Prepulse inhibition (PPI) and working memory, which are impaired in schizophrenic patients, are among the symptoms/processes modeled in those animal analogs. We have evaluated whether a genetically-selected rat model, the Roman high-avoidance inbred strain (RHA-I), displays PPI deficits as compared with its Roman low-avoidance (RLA-I) counterpart and the genetically heterogeneous NIH-HS rat stock. We have investigated whether PPI deficits predict spatial working memory impairments (in the Morris water maze; MWM) in these three rat types (Experiment 1), as well as in a separate sample of NIH-HS rats stratified according to their extreme (High, Medium, Low) PPI scores (Experiment 2). The results from Experiment 1 show that RHA-I rats display PPI and spatial working memory deficits compared to both RLA-I and NIH-HS rats. Likewise, in Experiment 2, "Low-PPI" NIH-HS rats present significantly impaired working memory with respect to "Medium-PPI" and "High-PPI" NIH-HS subgroups. Further support to these results comes from correlational, factorial, and multiple regression analyses, which reveal that PPI is positively associated with spatial working memory performance. Conversely, cued learning in the MWM was not associated with PPI. Thus, using genetically-selected and genetically heterogeneous rats, the present study shows, for the first time, that PPI is a positive predictor of performance in a spatial working memory task. These results may have translational value for schizophrenia symptom research in humans, as they suggest that either by psychogenetic selection or by focusing on extreme PPI scores from a genetically heterogeneous rat stock, it is possible to detect a useful (perhaps "at risk") phenotype to study cognitive anomalies linked to schizophrenia.

Differential effects of cocaine on extracellular signal-regulated kinase phosphorylation in nuclei of the extended amygdala and prefrontal cortex of psychogenetically selected Roman high- and low-avoidance rats.

Roman high (RHA)- and low (RLA)-avoidance rats are selectively bred for rapid vs. poor acquisition of active avoidance, respectively, and differ markedly in emotional reactivity, coping style, and behavioral and neurochemical responses to morphine and psychostimulants. Accordingly, acute cocaine induces more robust increments in locomotion and dopamine output in the nucleus accumbens shell (AcbSh) of RHA than of RLA rats. Cocaine induces short- and long-term neuronal plasticity via activation of the extracellular signal-regulated kinase (ERK) pathway. This study compares the effects of acute cocaine on ERK phosphorylation (pERK) in limbic brain areas of Roman rats. In RHA but not RLA rats, cocaine (5 mg/kg) increased pERK in the infralimbic prefrontal cortex and AcbSh, two areas involved in its acute effects, but did not modify pERK in the prelimbic prefrontal cortex and Acb core, which mediate the chronic effects of cocaine. Moreover, cocaine failed to affect pERK immunolabeling in the bed nucleus of stria terminalis pars lateralis and central amygdala of either line but increased it in the basolateral amygdala of RLA rats. These results extend to pERK expression previous findings on the greater sensitivity to acute cocaine of RHA vs. RLA rats and confirm the notion that genetic factors influence the differential responses of the Roman lines to addictive drugs. Moreover, they support the view that the Roman lines are a useful tool to investigate the molecular underpinnings of individual vulnerability to drug addiction.

Effects of chronic antidepressant treatments in a putative genetic model of vulnerability (Roman low-avoidance rats) and resistance (Roman high-avoidance rats) to stress-induced depression.

INTRODUCTION: The Roman low- (RLA) and high-avoidance (RHA) rats were selectively bred for, respectively, poor versus rapid acquisition of active avoidance in a shuttle box and, under aversive conditions, display reactive (RLA) versus proactive (RHA) coping behaviors. In the forced swim test (FST), RLA rats exhibit a depression-like behavior characterized by greater immobility and fewer climbing counts when compared with their RHA counterparts. Furthermore, subacute treatments with clinically effective antidepressant drugs decrease immobility and increase climbing or swimming in RLA rats but do not modify the performance of RHA rats. OBJECTIVE AND METHODS: Because chronic treatment with antidepressants is usually required to produce clinical effects, the present study was designed to compare the behaviors of RLA and RHA rats in the FST after subacute (1 day) and chronic (15 days) administration of desipramine, fluoxetine, and chlorimipramine. RESULTS: In RLA rats, subacute treatments with low doses of desipramine, fluoxetine, and chlorimipramine (2.5-5 mg/kg) were ineffective whereas chronic treatments with the same doses of all three antidepressants decreased immobility and also increased climbing (desipramine) or swimming (fluoxetine). By contrast, neither subacute nor chronic treatments with these antidepressants induced significant changes in the behavior of RHA rats in the FST. CONCLUSIONS: RLA and RHA rats represent two divergent phenotypes, respectively susceptible and resistant to develop depression-like behavior under aversive environmental conditions that may be used to identify genetically determined neural substrates and mechanisms underlying vulnerability and resistance to stress-induced depression.

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.

INTRODUCTION: 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. OBJECTIVE AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 Roman high- and low-avoidance rat lines differ in the acquisition, maintenance, extinction, and reinstatement of intravenous cocaine self-administration.

The selective breeding of Roman high- (RHA) and low-avoidance (RLA) rats for, respectively, rapid vs extremely poor acquisition of avoidant behavior in a shuttlebox has produced two phenotypes that differ in temperament traits, in mesocortical/mesolimbic dopamine system function, and in the behavioral and neurochemical responses to the acute and repeated administration of psychostimulants and opiates. The phenotypic traits of the RHA line predict higher susceptibility, compared with RLA rats, to the reinforcing properties of addictive substances like cocaine. The present study was designed to compare the acquisition, maintenance, reinstatement of drug-seeking after long-term extinction, and reacquisition of intravenous cocaine self-administration (SA) behavior in the Roman lines. Compared with RLA rats, the rates of responding during cocaine SA acquisition were higher, extinction from cocaine SA was prolonged, and drug-induced reinstatement of cocaine-seeking behavior was more robust in RHA rats. Moreover, only RHA rats reacquired extinguished lever-pressing activity when a low reinforcing dose of cocaine was available. These findings are consistent with the view that subjects with genetically determined high responsiveness to the acute and chronic (ie, sensitizing) effects of psychostimulants, such as RHA rats, also display a higher propensity to self -administer cocaine. Further comparative studies in the Roman lines, using SA paradigms that distinguish mere drug-taking from the compulsive and uncontrolled drug use that characterizes addiction in humans, may eventually help to characterize the relationships among genotype, temperament traits, and neurobiological mechanisms involved in the individual vulnerability to cocaine addiction.

The psychogenetically selected Roman high- and low-avoidance rat lines: a model to study the individual vulnerability to drug addiction.

The Roman high- (RHA) and low-avoidance (RLA) rat lines were selected for, respectively, rapid vs poor acquisition of two-way active avoidance in the shuttle-box. Here, we review experimental evidence indicating that, compared with their RLA counterparts, RHA rats display a robust sensation/novelty seeking profile, a marked preference and intake of natural or drug rewards, and more pronounced behavioral and neurochemical responses to the acute administration of morphine and psychostimulants. Moreover, we show that (i) the repeated administration of morphine and cocaine elicits behavioral sensitization in RHA, but not RLA, rats, (ii) in sensitized RHA rats, acute morphine and cocaine cause a larger increment in dopamine output in the core, and an attenuated dopaminergic response in the shell of the nucleus accumbens, as compared with RHA rats repeatedly treated with saline, and (iii) such neurochemical changes are not observed in the mesoaccumbens dopaminergic system of the sensitization-resistant RLA line. Behavioral sensitization plays a key role in several cardinal features of addiction, including drug craving, compulsive drug seeking and propensity to relapse following detoxification. Comparative studies in the Roman lines may therefore represent a valid approach to evaluate the contribution of the genotype on the neural substrates of drug sensitization and addiction.

Neonatal ventral hippocampal lesions potentiate amphetamine-induced increments in dopamine efflux in the core, but not the shell, of the nucleus accumbens.

BACKGROUND: In rats, neonatal ventral hippocampal lesions (NVHLs) result in the postpubertal emergence of alterations reminiscent of several features of schizophrenia, including increased responsivity to the behavioral effects of amphetamine (AMPH). The precise nature of presynaptic aspects of accumbal dopamine (DA) function in these alterations is however uncertain: previous studies have found that the exacerbated responses to AMPH of NVHL rats are associated with either decreased or unchanged DA efflux in the nucleus accumbens (NAc) as compared with shams. Because these studies investigated DA output in the whole NAc, it was considered of interest to examine the impact of NVHLs on DA transmission in NAc subregions involved in distinct aspects of goal-directed behavior. METHODS: The effects of AMPH (.25 mg/kg, subcutaneous) on the accumbal DA efflux of adult rats were evaluated using brain microdialysis, and motor activity was recorded alongside dialysate sample collection. RESULTS: The enhanced behavioral responsivity to AMPH of NVHL rats is associated with potentiation of AMPH-induced DA output in the NAc core and a concomitant attenuation of DA overflow in the NAc shell. CONCLUSIONS: The functional alterations in the NAc core induced by NVHLs provide a link between the hippocampal damage and striatal DA hyperactivity in schizophrenia.

Behavioural effects of acute and repeated cocaine treatments: a comparative study in sensitisation-prone RHA rats and their sensitisation-resistant RLA counterparts.

RATIONALE: Dopamine (DA) transmission is critically involved in the motor effects of psychostimulants and opiates, as well as in the augmentation of these effects resulting from repeated drug administration-a process termed behavioural sensitisation. The latter is known to play a central role in the development and maintenance of drug addiction as well as in the high frequency of relapse observed in drug addicts following detoxification. The selective breeding of Roman high- (RHA) and low-avoidance (RLA) rats for extreme performances in the acquisition of avoidant behaviour has generated two phenotypes that differ in the functional properties of the mesocortical and mesolimbic DA systems and in their behavioural and neurochemical responses to the acute administration of psychostimulants and opiates. More recently, we showed that repeated morphine or amphetamine injections induce behavioural sensitisation in RHA, but not RLA, rats. OBJECTIVE: To further characterize the differences in the susceptibility to develop psychostimulant sensitisation between the Roman lines, we evaluated the behavioural effects of acute cocaine (5 and 10 mg kg(-1), i.p.) 1 day before and 8 days after repeated administration of saline (2 ml kg(-1), i.p.) or cocaine (10 mg kg(-1), i.p. for 14 consecutive days). RESULTS: We show that repeated cocaine administration elicits augmented behavioural responses to both challenge doses of the same drug only in RHA rats. CONCLUSIONS: The Roman lines represent a useful model to investigate how, and to what extent, the genetic make-up influences the neural substrates of individual vulnerability to addiction.

The psychogenetically selected Roman rat lines differ in the susceptibility to develop amphetamine sensitization.

The mesolimbic dopamine system is considered to play a pivotal role in the locomotor activation produced by psychostimulants and in the augmentation of this effect observed upon repeated drug administration, a process denominated behavioral sensitization. The selective breeding of Roman high- (RHA) and low-avoidance (RLA) rats, respectively, for rapid versus poor active avoidance acquisition has resulted in two phenotypes that differ in the functional properties of the mesolimbic dopamine system and in their behavioral and neurochemical responses to addictive drugs, including psychostimulants and opiates. Hence, the present study was designed to compare the ability of these lines to develop behavioral sensitization to psychostimulants. To this aim, the acute effects of amphetamine (0.125 or 0.25 mg/kg, s.c.) on locomotion were assessed in RHA and RLA rats prior to and subsequent to 10 daily doses of either amphetamine (1 mg/kg, s.c.) or saline (1 ml/kg, s.c.). In the RHA line, the locomotor activation produced by either challenge dose of amphetamine was more pronounced in rats that had been repeatedly treated with amphetamine versus the respective saline treated controls. In contrast, no significant change in locomotor activity was observed in RLA rats. Likewise, repeated amphetamine caused an increased frequency of sniffing, rearing, licking/gnawing, and grooming versus the control, repeated saline, group only in the RHA line. The results show that the repeated treatment regimen used in this study induced behavioral sensitization to amphetamine in RHA rats, but not in their RLA counterparts, and underscore the utility of these lines for studying the influence of neural substrates and genetic make up on the individual vulnerability to addiction.

A differential activation of dopamine output in the shell and core of the nucleus accumbens is associated with the motor responses to addictive drugs: a brain dialysis study in Roman high- and low-avoidance rats.

Addictive substances like morphine and psychostimulants induce a preferential increase in dopamine (DA) output in the nucleus accumbens (NAC), a major terminal field of the mesolimbic dopaminergic projection. Two subregions of the NAC, the dorsolateral core and the ventromedial shell, are thought to subserve different functions related to the reinforcing properties of natural and drug rewards. The selective breeding of Roman high- (RHA) and low-avoidance (RLA) rats, respectively, for rapid vs. extremely poor active avoidance acquisition in a shuttle-box has resulted in two phenotypes that differ in their behavioural and neurochemical responses to addictive drugs. We used brain dialysis to assess whether such differences in the responsiveness to drugs of abuse are related to differences in mesolimbic DA neuron function. In RHA rats, morphine, cocaine, and amphetamine caused a larger increase in DA efflux in the NAC shell vs. the NAC core, whereas the profile for the drug-induced increases in DA output was almost completely superimposable in the NAC shell and NAC core of RLA rats. Moreover, morphine, cocaine, and amphetamine caused a larger increment in basal DA output in the NAC shell of RHA rats vs. the NAC shell of RLA rats. These drugs also elicited a more robust increase in locomotion, rearing, sniffing, and grooming in RHA than in RLA rats. These results demonstrate that genetically determined differences in the functional properties of DA neurons projecting to the NAC shell may critically influence the behavioural response patterns to addictive drugs that distinguish the Roman lines.

Repeated morphine injections induce behavioural sensitization in Roman high- but not in Roman low-avoidance rats.

The selective breeding of Roman high- (RHA) and low-avoidance (RLA) rats for, respectively, rapid vs poor active avoidance acquisition has resulted in two phenotypes that differ in their behavioural and neurochemical responses to addictive drugs, including morphine. To compare the ability of these lines to develop behavioural sensitization to morphine, female RHA and RLA rats were treated twice daily with either saline or escalating doses of morphine (5, 10, and 20 mg/kg, s.c. on the 1st, 2nd, and 3rd day of treatment, respectively), and were challenged with morphine (0.5 or 2 mg/kg, s.c.) 1 day before and 3 weeks after repeated morphine administration. The locomotor activation produced by either challenge dose of morphine was more pronounced in RHA rats repeatedly treated with morphine vs the respective saline-treated controls, whereas no significant change in locomotor activity was observed in RLA rats. The results show that behavioral sensitization to morphine was induced in RHA but not in RLA rats.