Chapter 13 GABAA and GABAB receptors and the ionic mechanisms mediating their effects on locus coeruleus neurons

Abstract

Anatomical, neurochemical, and electrophysiological studies have provided evidence that gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the locus coeruleus (LC) nucleus. We have used intracellular recording to study the actions of GABA on putative noradrenergic neurons of the rat LC, in a brain slice preparation. GABA application in the bath, or more locally by micropressure ejection inhibited spontaneous firing and increased the conductance of LC neurons. In addition, GABA could hyperpolarize or depolarize LC neurons; the size of these responses depended on the Cl- gradient across the membrane. GABA responses were antagonized by bicuculline. These data indicate that the actions of GABA on LC neurons are primarily mediated by activation of GABAA receptors which increases the Cl- conductance. When GABA is applied to LC neurons after blockade of GABAA receptors with bicuculline, a residual action mediated by GABAB type receptors can be seen. Similar responses can be obtained with the GABAB-selective agonist baclofen. GABAB activation inhibits spontaneous firing and causes membrane hyperpolarization due to an increase in K+ conductance. Single-electrode voltage clamp experiments were used to study the voltage dependency of GABA responses in LC neurons. GABA-induced current showed outward rectification. The conductance increase caused by a given amount of GABA decreased with membrane hyperpolarization. The time constant of decay of the GABA current also decreased with membrane hyperpolarization. Due to the voltage dependency of GABA responses, GABA exerts a stronger inhibitory effect on LC neurons at depolarized potentials than at hyperpolarized potentials, which could serve as a negative feedback mechanism to control excitability of these neurons.