CROSSTALK BETWEEN METABOTROPIC GLUTAMATE, OPIOID, AND ALPHA-2 ADRENORECEPTORS IN LOCUS COERULEUS NEURONS

Locus coeruleus (LC) are a major source of noradrenaline to the forebrain. These cells express several types of G protein coupled receptors that regulate excitability. This control is governed by opposing pathways: Gq-coupled Group I metabotropic glutamate receptors drive excitation via inward currents, whereas Gi-coupled receptors opioid and Alpha-AR) drive inhibition via outward currents. We examined interactions between two Gi-coupled receptors (opioid and alpha-2 adrenoreceptors) and Group I glutamate receptors in LC neuron excitability. ​Whole cell voltage clamp and current clamp recordings were conducted LC neurons in brainstem slices from male and female Wistar rats aged 6 to 8 days. Receptors were activated by applying selective agonists via perfusion in the bath or through local pressure application using a glass pipette. Brief (10-20 ms) pulses of the Group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) (0.1 mM), applied by a local perfusion pipette, generated an inward (excitatory) current of −27.1±12.1 pA (N=17). Activation of opioid receptors with morphine (0.005 mM) generated an outward (inhibitory) current of 69.6±20.3 pA (N=6), whereas activation of alpha-2 receptors with clonidine (0.001mM) generated an outward current of 51.4±16.9 pA (N=6). Both morphine and clonidine inhibited the inward current generated by DHPG by 17.8%±12.1 (N=11, p<0.001) and 27.7%±4.3 (N=5, p<0.05), respectively. We considered the possibility that these receptors share a common final pathway.These results reveal interactions between two types of G-protein Coupled Receptors with consequences for the regulation of the excitability of locus coeruleus neurons by glutamate, opioids, and (nor)adrenaline neurotransmitters.