Vestibular neurons in the rat contain imidazoleacetic acid‐ribotide, a putative neurotransmitter involved in blood pressure regulation

Abstract

A substantial body of research has led to the recognition that the vestibular system participates in blood pressure modulation during active movements and changes in posture, and that this modulation is effected at least partly by the caudal vestibular nuclei. The I-4 isomer of imidazoleacetic acid-ribotide (IAA-RP) is a putative neurotransmitter/modulator that is thought to be an endogenous regulator of general sympathetic drive, particularly systemic blood pressure. The present study employed immunofluorescence and light and electron microscopic immunocytochemistry to visualize IAA-RP in the vestibular nuclei of adult male rats. The results demonstrate IAA-RP immunolabeling of subpopulations of vestibular neurons in the descending nucleus and the caudal half of the medial nucleus, with scattered immunostained vestibular neurons also present more rostrally. On the basis of double immunofluorescence staining for IAA-RP and calbindin, many of these ribotide-immunoreactive neurons appear to be innervated by cerebellar Purkinje cell afferents. Ultrastructural observations in the caudal vestibular nuclei confirm the IAA-RP immunolocalization in cell bodies and dendritic processes, and in some myelinated axons and presynaptic boutons. The regional distribution of IAA-RP immunoreactivity corresponds to the location of vestibular neurons involved in autonomic functions. The presence of IAA-RP in those neurons suggests that they participate specifically in vestibulo-autonomic regulation of blood pressure. The localization of immunostain in processes and terminals suggests that vestibulo-autonomic activity is subject to local feedback control. Overall, the observations offer a chemoanatomic basis for understanding the vestibular side effects commonly experienced by patients treated with clonidine and other imidazoline-related drugs.

Imidazoleacetic acid-ribotide induces depression of synaptic responses in hippocampus through activation of imidazoline receptors

“…Subsequent immunocytochemical mapping studies localized IAA-RP in neurons of numerous other brain regions, suggesting that its putative modulatory role is not limited to the brainstem (Friedrich et al 2007). In fact, IAA-RP immunoreactivity is prominent in both CA3 and CA1 pyramidal cells, and high densities of I-R binding sites are present in the hippocampus (De Vos et al 1994;Piletz et al 2000;Ruggiero et al 1998).…”

“…Buffer was then removed, and sections were resuspended in rabbit anti-IAA-RP primary antiserum diluted in blocking buffer. The production, extensive characterization, and specificity of this antiserum have been published previously (Friedrich et al 2007;Martinelli et al 2007;Prell et al 2004). After overnight incubation at RT on an orbital rotator, sections were washed five times with PBS over a period of 8 h and then resuspended in blocking buffer (without NaN 3 ) containing 1-2 g/ml of anti-rabbit IgG conjugated to horseradish peroxidase (Jackson Immunoresearch).…”

“…IMIDAZOLE-4-ACETIC ACID-RIBOTIDE (IAA-RP) is an endogenous agonist at imidazoline receptors (I-Rs) and has been proposed to serve as a modulator of neural activity in various central nervous system (CNS) regions (Friedrich et al 2007;Martinelli et al 2007;Prell et al 2004). Several lines of evidence suggest that IAA-RP may have an important role in blood pressure regulation (Eglen et al 1998;Ernsberger et al 1993;Regunathan and Reis 1996) and may underlie the association between hypertension and diabetes (Bousquet et al 1984;Chan 1998;Morgan 1999).…”

“…In addition, IAA-RP undergoes depolarization-induced Ca 2ϩ -dependent release from synaptosomes, and microinjection of IAA-RP into the blood pressure regulatory region of the medullary reticular formation alters systemic blood pressure (Prell et al 2004). Moreover, intense IAA-RP immunoreactivity has been localized in cells in various regions of the CNS, including the hippocampal formation (Friedrich et al 2007;Martinelli et al 2007). …”

Responses of caudal vestibular nucleus neurons of conscious cats to rotations in vertical planes, before and after a bilateral vestibular neurectomy

“…The CVN also provide considerable inputs to the cerebellar nodulus and uvula (Epema et al 1985;Sato et al 1989;Thunnissen et al 1989;Barmack et al 1992). Furthermore, the CVN project to medullary regions that participate in regulation of blood pressure and breathing (Balaban and Beryozkin 1994;Yates et al 1995;Ruggiero et al 1996;Porter and Balaban 1997;Martinelli et al 2007), and lesions of the CVN abolish cardiovascular and respiratory responses to stimulation of vestibular afferents (Uchino et al 1970;Yates et al 1993;Kerman and Yates 1998).…”