Behavioral Biomarkers of Schizophrenia in High Drinker Rats: A Potential Endophenotype of Compulsive Neuropsychiatric Disorders

Abstract

Psychogenic polydipsia, which is compulsive, non-regulatory fluid consumption, is present in 6%–20% of chronic psychiatric patients and frequently associated with the schizophrenia diagnosis. In the present study, we investigated the relation between schizophrenia-like symptoms and biomarkers with a compulsive drinking behavior phenotype in rats. Rats that were selected for low drinking vs high drinking behavior following schedule-induced polydipsia (SIP) were assessed in a latent inhibition (LI) paradigm using tone and electrical foot shock and in a spatial reversal learning task to evaluate behavioral inflexibility. We also analyzed the myelin basic protein in different brain areas of high drinker (HD) and low drinker (LD) rats. The HD rats, which were characterized by a compulsive drinking behavior on SIP, had a reduced level of LI effect and increased behavioral inflexibility in the spatial reversal learning task in comparison to the LD group. Moreover, HD rats showed less myelination in the center of the corpus callosum, striatum, and amygdala in comparison to LD rats. These findings strengthen the validity of HD rats that were selected by SIP as a possible phenotype of compulsive neuropsychiatric disorders, as evidenced by the existence of behaviors and biological markers that are related to schizophrenia and obsessive-compulsive disorder, including a reduced LI effect, behavioral inflexibility and reduced brain myelination. Future studies could contribute to the elucidation of the mechanisms underlying the compulsive phenotype of HD rats and its relation to vulnerability to schizophrenia.

Excessive habit formation in schedule‐induced polydipsia: Microstructural analysis of licking among rat strains and involvement of the orbitofrontal cortex

“…67,68 Regarding the amygdalar region, a trend toward significance was found in the BLA, indicating hyperactivity in this region, in CD compared with LD rats. In support of this, previous SIP studies found hyperactivity in serotonergic and noradrenergic neurotransmission, 14 higher binding for D2 receptors 15 in the amygdala, and less myelination of the BLA 13 in HD compared with LD rats selected by the median split. Some studies elucidating the role of the amygdala in habit formation have found that intra-amygdalar infusions of dopamine or noradrenaline agonists are sufficient to bias behavior toward the use of habit-like strategies in a water-maze task.…”

“…Therefore, we cannot deduce that CD rats have an impulsive-hyperactive licking behavior like that seen in SHR rats.From all this we could conclude that the high intensity of licking is what probably best distinguished the SIP compulsive drinking, and points toward the relevance of introducing microstructural measures in studies of individual differences in SIP. We hypothesize that this excessive licking may be due to a lack of inhibition to exert control over habitual processes.In fact, previous studies that classified rats by their median water intake have shown that high-drinker rats displayed resistance to extinction in the 5-CSRT task14 and had increased lever pressing under a variable-interval 60-second schedule of reinforcement 13. These findings might indicate an increased habit formation in rats developing high-drinking rates.…”

“…Relative to their LD counterparts, HD WIST rats show behavioral inflexibility in a spatial reversal learning task 13 and a lack of inhibitory control in the 5-choice serial reaction time (5-CSRT) task, 14 which has been associated with changes in monoaminergic systems in the limbic-striatal circuitry. Relative to their LD counterparts, HD WIST rats show behavioral inflexibility in a spatial reversal learning task 13 and a lack of inhibitory control in the 5-choice serial reaction time (5-CSRT) task, 14 which has been associated with changes in monoaminergic systems in the limbic-striatal circuitry.…”

“…drinker (LD) phenotypes, according to a median split. Relative to their LD counterparts, HD WIST rats show behavioral inflexibility in a spatial reversal learning task 13 and a lack of inhibitory control in the 5-choice serial reaction time (5-CSRT) task, 14 which has been associated with changes in monoaminergic systems in the limbic-striatal circuitry. 12,14,15 Compared with WIST rats, Lister hooded (LH) rats do not acquire SIP drinking, 16 and show greater inhibitory control, as measured by the lowanticipatory responses in the 3-CSRT task and lower food hoarding behavior.…”

Increased Fear Memory and Glutamatergic Modulation in Compulsive Drinker Rats Selected by Schedule-Induced Polydipsia

“…In our laboratory, we have found consistent differences between these two populations in the inhibitory response deficit. Thus, HD rats selected by SIP have shown increased perseverative–compulsive responses under extinction conditions on the 5-Choice Serial Reaction Time task (5-CSRT; Moreno et al, 2012); impulsive decision making on the delay-discounting task (Cardona et al, 2011); less latent inhibition effect, considered as a behavioral model of schizophrenia, and augmented behavioral inflexibility in a spatial reversal learning task, characteristic in OCD patients (Navarro et al, 2017). Thus, HD and LD rats selected by SIP has shown consistent behavioral differences among different behavioral paradigms.…”