GABAA Receptors in the Pontine Reticular Formation of C57BL/6J Mouse Modulate Neurochemical, Electrographic,and Behavioral Phenotypes of Wakefulness.

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain and many drugs used to produce sleep, sedation, or general anesthesia enhance transmission at GABA-A receptors (GABA-ARs). The mechanisms underlying these effects remain unknown. The pontine reticular nucleus, oral part (PnO) plays an important role in generating cortical activation and rapid eye movement sleep (REM). GABAergic transmission causes brain-region specific effects on sleep and wakefulness, and in the PnO GABA promotes wakefulness. This dissertation research sought to elucidate the mechanisms by which GABAergic transmission in the PnO of C57BL/6J mouse modulates arousal states. Aim 1 tested the hypothesis that GABA-ARs in the PnO modulate two phenotypes of arousal – sleep/wake states and activity of the cortical electroencephalogram (EEG). PnO microinjection of the GABA-AR agonist muscimol caused a concentration-dependent, reversible increase in wakefulness and decrease in non-REM (NREM) and REM that was blocked by co-administration of the GABA-AR antagonist bicuculline. Muscimol also increased EEG delta power (0.5-4 Hz) during wakefulness and theta power (4-9 Hz) during REM. Microinjection of bicuculline alone caused a concentration dependent decrease in wakefulness and increase in NREM and REM. Cholinergic transmission in the PnO also contributes to arousal state control, and Aim 2 tested the hypothesis that GABAergic transmission in the PnO modulates acetylcholine (ACh) release in the PnO, breathing rate, and anesthesia recovery time. Microdialysis delivery of bicuculline to the PnO caused a concentration dependent increase in ACh release within the PnO, a decrease in respiratory rate, and an increase in anesthesia recovery time. These data are the first to characterize the effects of GABAergic transmission on arousal states in mouse PnO. The results from Aim 1 and 2 demonstrate that GABA-ARs in the PnO of C57BL/6J mouse modulate sleep/wake states, activity of the cortical EEG, release of ACh in the PnO, respiratory rate, and anesthesia recovery time. These results support the conclusion that GABA-ARs in mouse PnO promote wakefulness and suggest that increasing GABAergic transmission in the PnO may be one mechanism underlying the phenomenon of paradoxical behavioral activation by some benzodiazepines.Ph.D.PharmacologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/77749/1/rrflint_1.pd