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Animal models with predictive and construct validity are necessary for developing novel and efficient therapeutics for psychiatric disorders. We have carried out a pharmacological characterization of the Roman high- (RHA-I) and low-avoidance (RLA-I) rat strains with different acutely administered propsychotic (DOI, MK-801) and antipsychotic drugs (haloperidol, clozapine), as well as apomorphine, on prepulse inhibition (PPI) of startle and locomotor activity (activity cages). RHA-I rats display a consistent deficit of PPI compared with RLA-I rats. The typical antipsychotic haloperidol (dopamine D2 receptor antagonist) reversed the PPI deficit characteristic of RHA-I rats (in particular at 65 and 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. 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.

The inbred Roman high- (RHA-I) and low-avoidance (RLA-I) rats, differing in dopaminergic activity and novelty/substance-seeking profiles, may be a suitable model to study the implication of the dopaminergic system in vulnerability to drug abuse. Differences in D3 receptor binding recently described between the two strains (Guitart-Masip M, Johansson B, Fernandez-Teruel A, Canete T, Tobena A, Terenius L, Gimenez-Llort L, Neuroscience 142:1231–1243, 2006b) may be important in shaping the aforementioned differences in novelty seeking. The aim of the present work was to study the effect of D3 receptor activation on novelty-induced locomotor activity in these two strains of rats. We administered saline and PD-128,907 (0.01 and 0.1 mg/kg), a putative D3 receptor agonist, to the Roman rats and studied the locomotor activity when animals were placed in a novel environment. Thereafter, by means of in situ hybridization, nerve growth factor inducible clone A (NGFI-A) mRNA was measured in the striatum and the Calleja islands of these animals. We found that RLA-I rats showed stronger locomotor inhibition than RHA-I rats after PD-128,907 administration. Moreover, RLA-I rats showed stronger reduction of NGFI-A mRNA in the Calleja islands than RHA-I rats. These results, together with previous findings, suggest that differences in D3 receptor expression in the Calleja islands may contribute to the divergent behavioral effect of PD-128,907 administration in the two strains of Roman rats.

Rationale: One of the major pathways for neurotransmitter signaling involves phosphoinositide-specific and G-protein-dependent phospholipase C-β (PLC-β), which stimulates the formation of inositol 1,4,5-trisphosphate and diacylglycerol. Serotonergic and muscarinic-cholinergic signals in the brain are largely mediated through the hydrolysis of phosphoinositides by PLC. Objectives: The aim of the experiments reported here was to explore the potential differences in neurotransmitter receptor coupling to PLC in Roman high-avoidance (RHA)/Verh and Roman low-avoidance (RLA)/Verh rats, by examining the changes in agonist (carbachol, 5-methyltryptamine)-stimulated phosphoinositide hydrolysis in hippocampal and cortical membranes derived from the two rat lines. Methods: To investigate changes in receptor and G-protein coupling to PLC in the brains of these two psychogenetically selected rat lines, which differ in their emotional profiles/learning abilities, we examined GTPγS-, agonist (carbachol, 5-methyltryptamine)-, and calcium-stimulated phosphoinositide hydrolysis in cortical and hippocampal membranes of RHA/Verh and RLA/Verh rats. Results: The results indicated that calcium-induced increase in PLC activity was larger in the cortex and hippocampus of RHA/Ver rats, as compared to their RLA/Verh counterparts. Conversely, GTPγS- and agonist-induced PLC activity was less pronounced in the hippocampus of RHA/Verh with respect to RLA/Verh rats. Western blot analysis showed no significant differences in the relative values of the G-proteins αq/11 and βγ subunits between both groups of rats in any brain region. However, the levels of PLC-β1, PLC-β3, and PLC-β4 were significantly lower in the hippocampus of RHA/Verh than in RLA/Verh rats. Conclusions: It is concluded that the hippocampus of RHA/Verh rats has severe deficiencies in PLC activity stimulated by guanine nucleotides and agonists, which are specifically related to a lower level of expression of the PLC-β type isozymes, a fact that may account for the differential behavioral phenotype observed in these psychogenetically selected rat lines.

Utilizing psychogenetically selected Roman high- and low-avoidance rats (RHA/Verh and RLA/Verh), the present experiments investigated the effects of prenatally administered vehicle and diazepam (1 and 3 mg/kg per day, SC) on the behavior and neurochemistry of adult, male offspring. Active, two-way avoidance behavior was analyzed in 96 rats, at 6 months of age, and swimming navigation in 68 others, at 11 months. Three weeks after testing, selected brain areas from the latter animals were immunoassayed for benzodiazepine (BZD)-like molecules. The 3 mg/kg dose of diazepam both decreased freezing behavior in the shuttle box and reduced the hippocampal content of BZD-like molecules in the RLA/Verh male rats. Swimming navigation (spatial learning), at which the RLA/Verh rats were more adept, was not specifically affected by prenatal diazepam in either rat line. The possibility exists that an increased hippocampal release of BZD-like substances may be necessary to alter shuttle box behavior in RLA/Verh rats.

The present study shows that postnatal "consistent" handling (CH) of rats had long-lasting improving effects on coping with an stressful task (i.e. two-way active avoidance), and that such effects were partially prevented by acute Ro 15-1788 (antagonist of benzodiazepine receptor-BZR; 5 mg/kg) administration. Long-lasting detrimental effects in the same task were also observed in rats which received postnatal "inconsistent" handling (INCH), effects that were slightly increased by acute Ro 15-1788 treatment. Finally, Ro 15-1788 tended to increase avoidance acquisition in non-handled (NH) animals. The observed effects of Ro 15-1788 could be partially attributed to a differential modulation of the process of avoidance acquisition depending on postnatal treatments producing different levels of emotionality.

The effect of infantile handling-stimulation and/or perinatal flumazenil (3.7 mg/kg/day) administration on exploratory and emotional-related behavior was investigated using Roman high- and low-avoidance (RHA/Verh and RLA/Verh) rats. Postnatal handling increased exploration in 30-day-old rats of both psychogenetically selected lines when they were exposed to a hexagonal tunnel maze including an illuminated central arena. Likewise, postnatal stimulation decreased emotional reactivity in both lines of rats, as expressed by increased entry into the central arena, decreased defecation and vocalization frequency, but these effects were more pronounced in the RLA/Verh line. There were interactions between perinatal flumazenil treatment and rat line, indicating that flumazenil enhanced entry into the maze central arena in handled-RLA/Verh rats, whereas a tendency toward the opposite effect was observed in drug-treated and handled-RHA/Verh animals. Thus, the present study emphasizes that the effects of environmental manipulations are partly dependent upon genetic factors, and that pharmacological effects also depend on both genetic and environmentally-induced predisposition.