5-HT2A and mGlu2 receptor binding levels are related to differences in impulsive behavior in the Roman Low- (RLA) and High- (RHA) avoidance rat strains

• Roman Low- and High-Avoidance (RLA and RHA) rats differ in 5-HT2AR binding.
• 5-HT2AR binding correlated with impulsivity in RHA rats.
• SERT binding was significantly higher in RHA rats compared to RLA rats.
• We found marked differences in mGluR2 protein levels between RLA and RHA rats.
• We found marked differences in mGluR2/3 binding between RLA and RHA rats.

The Roman Low- and High-Avoidance rat strains (RLA-I vs RHA-I) have been bidirectionally selected and bred according to their performance in the two-way active avoidance response in the shuttle-box test. Numerous studies have reported a pronounced divergence in emotionality between the two rat strains including differences in novelty seeking, anxiety, stress coping, and susceptibility to addictive substances. However, the underlying molecular mechanisms behind these divergent phenotypes are not known. Here, we determined impulsivity using the 5-choice serial reaction time task and levels of serotonin transporter (SERT), 5-HT2A and 5-HT1A receptor binding using highly specific radioligands (3H-escitalopram, 3H-MDL100907 and 3H-WAY100635) and mGlu2/3 receptor binding (3H-LY341495) using receptor autoradiography in fronto-cortical sections from RLA-I (n = 8) and RHA-I (n = 8) male rats. In the more impulsive RHA-I rats, 5-HT2A, 5-HT1A and SERT binding in the frontal cortex was significantly higher compared to RLA-I rats. In contrast, mGlu2/3 receptor binding was decreased by 40% in RHA-I rats compared to RLA-I rats. To differentiate between mGlu2 and mGlu3 receptor protein levels, these were further studied using western blotting, which showed non-detectable levels of mGlu2 receptor protein in RHA rats, while no differences were observed for mGlu3 receptor protein levels. Collectively, these data show general congenital differences in the serotonergic system and a pronounced difference in mGlu2 receptor protein levels. We suggest that the differences in the serotonergic system may mediate some of the phenotypic characteristics in this strain such as hyper-impulsivity and susceptibility to drug addiction.