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

Abstract

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-Irats, 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.

A Genetic Model of Impulsivity, Vulnerability to Drug Abuse and Schizophrenia-Relevant Symptoms With Translational Potential: The Roman High- vs. Low-Avoidance Rats

“…In line with these strain-related differences in LI, we have shown in a series of studies that RHA rats display clear and consistent deficits of PPI of the acoustic startle response compared with RLAs (Del Rio et al, 2014; Oliveras et al, 2015, 2016, 2017; Río-Alamos et al, 2015; Río-Álamos et al, 2017a,b, 2019; Tapias-Espinosa et al, 2018, 2019) and that PPI deficits predict spatial working memory impairments (Oliveras et al, 2015). Altogether, the above mentioned cognitive and attentional profiles of RHA vs. RLA rats suggest that the former may represent a model of schizophrenia-relevant features.…”

“…It is noteworthy that PPI of the acoustic startle is further impaired by the non-selective DA D1/D2 receptor agonist apomorphine and improved by the DA D2/D3 receptor antagonist haloperidol in RHAs but not RLA rats (Oliveras et al, 2017).…”

“…Accordingly, it has been shown that the dimeric mGlu2/5-HT2A receptor complex is critically involved in the pharmacologic effects of atypical antipsychotics; thus, clozapine does not decrease locomotion in rodents with a disruption of the dimeric mGlu2/5-HT2A receptor complex (González-Maeso et al, 2008; Kurita et al, 2012). Therefore, the alterations observed in this complex in RHA rats may at least partly account for some of the phenotypical schizophrenia-related traits observed in this strain and the almost complete lack of enhancing effect of clozapine on either the baseline or MK-801-impaired PPI performance (Oliveras et al, 2017).…”

Roman high and low avoidance rats differ in their response to chronic olanzapine treatment at the level of body weight regulation, glucose homeostasis, and cortico-mesolimbic gene expression

“…Interestingly, recent data (Oliveras et al, 2017) also shows a difference in responsiveness of the RHA and RLA strains to antipsychotic drug treatment. Oliveras et al (2017) revealed that only the RHA rats are responsive to the typical antipsychotic haloperidol (Drd2 antagonist) in reducing prepulse inhibition (PPI). The a-typical antipsychotic clozapine did not show any difference in efficiency to reduce PPI between the RHA and RLA strains.…”

Comparative Analysis of Dopaminergic and Cholinergic Mechanisms of Sensory and Sensorimotor Gating in Healthy Individuals and in Patients With Schizophrenia

“…The interaction of glutamatergic and dopaminergic systems in the prefrontal cortex plays a significant role in the mechanisms of attention and executive control (Aquila and Citrome, 2015 ; Storozheva et al, 2015 ). Of note, the results of the animal studies showed relatively independent pathways for the participation of glutamatergic and dopaminergic transmission in the mechanisms of PPI (Keith et al, 1991 ; Callahan et al, 2014 ; Oliveras et al, 2017 ). At the same time, the close interaction of dopaminergic and cholinergic activities on sensory and sensorimotor gating has been documented in several studies (De la Salle et al, 2013 ).…”