Bladder distention activates noradrenergic locus coeruleus neurons by an excitatory amino acid mechanism

Abstract

The present study was designed to determine the neurotransmitter(s) involved in activation of noradrenergic locus coeruleus neurons by urinary bladder distention. The spontaneous discharge rate of single locus coeruleus neurons was recorded from halothane-anesthetized rats during the physiological challenge of bladder distention. Intrabladder saline infusion (0.5 ml) increased bladder pressure by 77 ± 9.7mmHg (n = 19) and this was associated with an increase in locus coeruleus discharge rate of 53 ± 4.8% (n = 29). Simultaneous recordings of cortical electroencephalographic activity demonstrated that electroencephalographic activation, characterized by a decreased amplitude and tendency to shift from low frequency activity to higher frequency activity, was also associated with bladder distention. The role of corticotropin-releasing factor and excitatory amino acid inputs to the locus coeruleus in activation by bladder distention was tested in rats pretreated with a corticotropin-releasing factor antagonist, or excitatory amino acid antagonists. Intracerebroventricular administration of the corticotropin-releasing factor antagonist did not alter locus coeruleus activation by bladder distention. In contrast, both locus coeruleus activation and electroencephalographic activation associated with bladder distention were prevented by intracerebroventricular administration of kynurenic acid. The same dose of kynurenic acid also prevented locus coeruleus activation by repeated sciatic nerve stimulation, as previously reported. Local administration of kynurenic acid into the locus coeruleus greatly attenuated, but did not completely prevent the increase in locus coeruleus discharge elicited by bladder distention. Finally, locus coeruleus activation by bladder distention appeared to be mediated by excitatory amino acid receptors of the non-N-methyl-d-aspartate subtype because this was prevented by 6-cyano-7-nitroquinoxaline-2,3-dione, but not by 2-amino-5-phosphono-pentanoic acid.

Taken together, these results implicate excitatory amino acid neurotransmission in locus coeruleus activation by bladder distention, and argue against a role for corticotropin-releasing factor. Additionally, these findings suggest that locus coeruleus activation may be important in arousal associated with bladder distention.