Persistent α 1 - adrenergic receptor function in the nucleus locus coeruleus causes 1 hyperexcitability in AD / HD model rats 2 3

21 Spontaneous hypertensive rats (SHR) are widely used as a model of attention deficit 22 hyperactivity disorder (ADHD) as their ADHD-like behaviors are restored by 23 methylphenidate (MPH). However, a postnatal neural development in SHR is unknown. 24 We performed whole cell patch clamp recordings from locus coeruleus (LC) neurons in 25 neonatal (P 3–5), juvenile (P 21–28) and adult (P 49–56) SHR and age-matched Wistar 26 rats to evaluate α1and α2-adrenergic receptor (ARs) activities at each developmental 27 period. LC neurons in neonatal Wistar rats and SHR showed no difference in resting 28 membrane potential (RMP) and spontaneous firing rate (SFR), while juvenile and adult 29 SHR LC neurons showed depolarized RMP and faster SFR than in Wistar rats. Blockade 30 of α1-AR activity by prazosin hyperpolarized the membrane and abolished spontaneous 31 firings in all developmental periods in SHR LC neurons, but not in juvenile and adult 32 Wistar rats. α1-AR stimulation by phenylephrine (PE) evoked an inward current in 33 juvenile LC neurons in SHR, but not in juvenile Wistar rats. This PE-induced inward 34 current was abolished by non-selective cation channel blockers. By contrast, α2-AR 35 stimulation-induced outward currents in the presence of an α1-AR antagonist were 36 equivalent in SHR and Wistar LC neurons. These data suggest that Wistar LC neurons 37 lose α1-AR function during development, whereas α1-ARs remain functional in SHR LC 38 neurons. Thus, persistent intrinsic activity of α1-ARs may be a neural mechanism 39 contributing to developmental disorders in juvenile SHRs. 40 41