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.
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.
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.
The functional alterations in the NAc core induced by NVHLs provide a link between the hippocampal damage and striatal DA hyperactivity in schizophrenia.
•Animal model of neurobiological processes related to the schizophrenia spectrum.•Roman High-Avoidance –RHA- rats display negative schizophrenia-like symptoms.•RHA rats show lowered social preference ...in the social interaction test.•Neonatal handling increase the levels of social behaviour in Roman rats.
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.
The Roman high- (RHA) and low-avoidance (RLA) outbred rat lines are selected for respectively rapid vs. poor acquisition of active avoidant behavior. Emotional reactivity appears to be the most ...prominent behavioral difference between the two lines, with RLA rats being more fearful/anxious than their RHA counterparts. Accordingly, here we show that shock-induced inhibition of drinking behavior in the Vogel's test is significantly more pronounced in RLA than RHA rats. Thus, unpunished drinking activity is similar in both lines (38.1 ± 0.9 and 36.4 ± 0.6 licking periods/3 min in RLA and RHA rats, respectively), whereas under punished conditions (0.05–1.00 mA electric shocks delivered through the drinking tube) a more robust decrease in drinking behavior is observed in RLA vs. RHA rats. Moreover, fear-related behaviors like freezing and self-grooming are more frequent in RLA than RHA rats throughout the test. Similar results are obtained with the inbred RHA-I and RLA-I rats, which have been selected and bred through brother/sister mating of the outbred lines. In keeping with the above findings, we also show that, compared with their RHA counterparts, the outbred RLA rats are similarly responsive to the anticonflict effect of diazepam but more responsive to the proconflict effect of pentylenetetrazole in the Vogel's test. Collectively, these results reveal another behavioral trait distinguishing RHA from RLA rats and add experimental support to the view that the Roman lines/strains are a valid genetic model for the study of the neural underpinnings of fear/anxiety- and stress-related behaviors.
•Drinking suppression by electric shocks is more pronounced in RLA vs. RHA rats.•This difference is not due to a lower nociceptive threshold of RLA vs. RHA rats.•Diazepam partially prevents drinking suppression to the same extent in both lines.•RLA rats are more sensitive than RHA rats to the proconflict effect of PTZ.
The selective breeding of Roman high‐ (RHA/Verh) and low‐avoidance (RLA/Verh) rats for rapid versus poor acquisition of active avoidant behaviour has produced two behavioural phenotypes with ...different performances in a variety of animal models of anxiety, in which RLA/Verh rats are consistently more fearful than RHA/Verh rats. In addition, these two lines display different functional properties of brain neurotransmitters like serotonin (5‐HT), known to be involved in the expression of anxiety‐ and depression‐related behaviours. Therefore, we used brain microdialysis and 3H‐citalopram binding autoradiography to characterize further the neurochemical properties of 5‐HTergic transmission in the two lines. No significant line‐related differences were detected in the basal 5‐HT output in the frontoparietal cortex (FPCx). In contrast, the increase in the cortical 5‐HT output elicited by the systemic administration or the local application, via reverse dialysis, of chlorimipramine and fluoxetine was more robust in RHA/Verh than in RLA/Verh rats. Moreover, the binding signal of 3H‐citalopram to 5‐HT re‐uptake sites was more intense in the FPCx of RHA/Verh rats than in their RLA/Verh counterparts. These findings suggest that the functional tone of the 5‐HTergic projection to the FPCx is stronger in the RHA/Verh line relative to the RLA/Verh line. It is proposed that RLA/Verh rats may be used as a model with heuristic value for studying the role of 5‐HTergic transmission in anxiety and in the anxiolytic effects of monoamine re‐uptake inhibitors.
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.
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.
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.
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.
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).
We show that repeated cocaine administration elicits augmented behavioural responses to both challenge doses of the same drug only in RHA rats.
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.
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