Klein, A B2; Ultved, Lene1; Adamsen, D3; Santini, M A1; Tobeña, A4; Fernandez-Teruel, A4; Flores, Pia5; Moreno, M6; Cardona, D6; Knudsen, G M1; Aznar, S7; Mikkelsen, J D1
1 Neurologisk Klinik, Neurocentret, Rigshospitalet, The Capital Region of Denmark2 Klinik for Klinisk Fysiologi, Nuklearmedicin og PET, Diagnostisk Center, Rigshospitalet, The Capital Region of Denmark3 University of Copenhagen4 Departamento de Psiquiatría y Medicina Legal, Instituto de Neurociencias, Universidad Autónoma de Barcelona, Barcelona, Spain.5 Institut for Marketing og Organisation6 Departmento de Neurociencias y Ciencias de la Salud, Universidad de Almería, Almería, Spain.7 Neurologisk Afdeling N BFH, Bispebjerg and Frederiksberg Hospital, The Capital Region of Denmark
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-HT(2A) and 5-HT(1A) receptor binding using highly specific radioligands ((3)H-escitalopram, (3)H-MDL100907 and (3)H-WAY100635) and mGlu2/3 receptor binding ((3)H-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-HT(2A), 5-HT(1A) 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.