Reduced Expression of the Htr2a, Grin1, and Bdnf Genes and Cognitive Inflexibility in a Model of High Compulsive Rats

Abstract

Compulsivity is a core symptom in different psychopathological disorders, characterized by excessive behaviors and behavioral inflexibility. In preclinical studies, the selection of high drinker (HD) versus low drinker (LD) rats by schedule-induced polydipsia (SIP) is a valid model of compulsivity. HD rats shows a compulsive phenotype with a reduction in serotonin 2A (5-HT2A) receptor binding levels in the frontal cortex (FC). However, is necessary further explore the cognitive components regarding inflexibility in the compulsive HD rats, as well as, the related brain gene expression. Here, first, we assessed spatial memory and cognitive inflexibility by Morris Water Maze (MWM), working and reference memory by Radial Arm Maze, and behavioral deficits in stimulus processing by novel object recognition test. Second, we analyed the genetic expression of 5HT2A, 5HT2C, glutamate NMDA receptors, and brain-derived neurotrophic factor (BDNF) in FC, hippocampus, and amygdala. HD rats confirmed a cognitive inflexibility profile in the reversal condition in MWM compared to LD rats, while no differences were observed in stimulus processing, spatial and working memory. Moreover, HD rats showed a reduced expression of the Htr2a, Grin1, and Bdnf genes in FC. Furthermore, there was a negative correlation between the relative expression of the Htr2a, Grin1 and Bdnf genes in FC and the level of compulsive water intake in HD rats on SIP. These data reveal that cognitive inflexibility may not be associated with memory or stimulus processing alterations, but may result from a regionspecific alteration on FC of the gene expression Htr2a, Grin1, and Bdnf in compulsive individuals.