The mechanism of noradrenergic α₁ excitatory modulation of pontine reticular formation neurons

The α₁ adrenergic receptor occurs in all major divisions of the CNS and is thought to play a role in all behaviors influenced by norepinephrine (NE). In the medial pontine reticular formation (mPRF), the proposed site of adrenergic enhancement of startle responses (Davis, 1984), α₁ agonists excite most neurons (Gerber et al., 1990). We here report that α₁ excitation results from a reduction of a voltage- and calcium-dependent potassium current, not previously recognized as ligand-modulated. The calcium sensitivity is suggested by its antagonism with Mg²⁺, Cd²⁺, Ba²⁺, low concentrations of tetraethylammonium, and charybdotoxin. The voltage sensitivity of this conductance falls within the membrane potential range critical to action potential generation. Based on this voltage sensitivity, the change in repetitive firing characteristics may be predicted according to a mathematical model of the mPRF neuronal electrophysiology. The predicted response to a 50% decrease in the phenylephrine (PE)-sensitive conductance is similar to the observed responses, with respect to both the current response under voltage-clamp conditions and alterations of the AHP and frequency/current curve. In contrast, modeling a reduction of a voltage- insensitive leak current predicts none of these changes. Thus, the noradrenergic reduction of this current depolarizes the membrane, increases the likelihood of an initial response to depolarizing input, and increases firing rate during sustained depolarization in a manner consistent with an NE role as an excitatory neuromodulator of the mPRF.