Persistent α1-adrenergic receptor function in the nucleus locus coeruleus causes hyperexcitability in AD/HD model rats

Abstract

Spontaneously hypertensive rats (SHR) are widely used as a model of attention deficit hyperactivity disorder (ADHD) as their ADHD-like behaviors are restored by methylphenidate. However, a postnatal neural development in SHR is unknown. We performed whole cell patch clamp recordings from locus coeruleus (LC) neurons in neonatal [postnatal day (P) 3-5], juvenile (P21-28), and adult (P 49-56) SHR and age-matched Wistar rats to evaluate α1- and α2-adrenergic receptor (ARs) activities at each developmental period. LC neurons in neonatal Wistar rats and SHR showed no difference in resting membrane potential and spontaneous firing rate, while juvenile and adult SHR LC neurons showed depolarized resting membrane potential and faster spontaneous firing rate than in Wistar rats. Blockade of α1-AR activity by prazosin hyperpolarized the membrane and abolished spontaneous firings in all developmental periods in SHR LC neurons, but not in juvenile and adult Wistar rats. α1-AR stimulation by phenylephrine evoked an inward current in juvenile LC neurons in SHR, but not in juvenile Wistar rats. This phenylephrine-induced inward current was abolished by nonselective cation channel blockers. By contrast, α2-AR stimulation-induced outward currents in the presence of an α1-AR antagonist were equivalent in SHR and Wistar LC neurons. These data suggest that Wistar LC neurons lose α1-AR function during development, whereas α1-ARs remain functional in SHR LC neurons. Thus persistent intrinsic activity of α1-ARs may be a neural mechanism contributing to developmental disorders in juvenile SHRs.