Abstract
Purpose :
Glaucoma is a leading cause of blindness in adults. Elevations and fluctuations in intraocular pressure (IOP) are thought to be risk factors for development and progression of glaucoma. This research targets the hypothalamic suprachiasmatic nucleus (SCN) in an attempt to identify new pharmacological targets for regulating IOP. The SCN lies above the pituitary gland at the base of the brain. It makes direct neural connections to the retina and to other more caudal nuclei, such as the dorsomedial hypothalamic and perifornical areas, which our lab has identified as playing a potential role in IOP regulation. The SCN is the primary modulator of circadian rhythms and is well situated to modulate IOP diurnal rhythms, thus it is of significant interest.
Methods :
Male Sprague-Dawley rats (n=35) were placed under mild isoflurane anesthesia at midday. Using a stereotactic surgical approach, a 75 nL injectate of a chemical neurotransmitter agonist, antagonist, or control solution was delivered to the SCN while recording IOP, heart rate (HR), blood pressure (MAP), and intracranial pressure (ICP).
Results :
The net increase of IOP in response to the GABAA antagonist bicuculline methiodide (BMI) injected into the SCN was similar (+6.8 +/- 1.2 mm Hg, n=8) to previously reported responses by the dorsomedial hypothalamus (+7.1 +/- 1.9, n=9) or by the raphe pallidus (+7.4 +/- 1.4, n=8) to BMI injection. The IOP response of the SCN to the glutamate receptor agonist, NMDA, was low (+4.7 +/- 0.8 mm Hg, n=8), and the response to the glutamate receptor antagonist, MK 801, was also low (+5.0 +/- 0.5, n=5). However, IOP was markedly raised (+14.3 +/- 2.4 mm Hg, n=5) by injecting a standard PBS solution of 0.1M phosphate buffer with added 154 mM NaCl (579 mM calculated osmolarity), though there was an absence of corresponding increases in ICP, HR, or MAP. Further investigation using a 0.9% NaCl injectate (308 mM calculated osmolarity) did not show IOP stimulation (+4.0 +/- 1.1 mm Hg, n=4), nor did injection of an artificial CSF solution (311 mM calculated osmolarity) raise the IOP (+5.4 +/- 1.3, n=5).
Conclusions :
IOP regulation appears to be mediated by GABAergic and not glutamatergic neuronal pathways in the SCN, but neural conductivity associated with extracellular hyperosmolarity may play a significant role in SCN IOP regulatory activity.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.