Excitation of area postrema neurons by transmitters, peptides, and cyclic nucleotides

Abstract

1. Multiple-barreled microelectrodes were used to record from neurons in the area postrema of anesthetized dogs and to test the responses of the neurons to a variety of substances in this structure, which is known to function as the chemoceptive trigger zone for emesis. 2. The neurons in area postrema were silent at rest but could be "found" by virtue of their response to ionophoretic glutamate. The glutamic response was brief and of short latency with high frequency of discharge. 3. Dog area postrema neurons were also excited by over 20 other substances, including acetylcholine, the biogenic amines, several peptides, and at least two hormones. Not all agents were excitatory, however. 4. The responses to all excitatory agents except glutamate were similar and unusual. All responses showed a relatively long latency (3-20 s), a long duration of excitation (30 s to many minutes), and a low discharge frequency (1-3 Hz). 5. There was a good correlation between substances that were excitatory on area postrema neurons and substances known to cause emesis. Because emesis due to intravenous application of these substances is known to be abolished in animals with ablation of the area postrema, it is very likely that recordings were from the neurons which trigger the response. 6. Because so many substances elicit the same type of response there is a possibility that all utilize a common second messenger. Neurons were not excited by ionophoresis of guanosine 3',5'-cyclic monophosphate (cGMP) but were excited by 8-bromo-adenosine 3',5'-cyclic monophosphate (cAMP) and by forskolin, an activator of adenylate cyclase. 7. Behavioral studies were performed looking for emetic responses in awake dogs following intravenous injection of apomorphine, insulin, angiotensin II, and leucine enkephalin. For each a threshold concentration could be determined, which would consistently evoke emesis. 8. Dogs pretreated with phosphodiesterase inhibitors (theophylline, 3-isobutyl-1-methylxanthine, or RO 1724) showed a shift in the threshold concentration of the above substances that triggered emesis, such that emesis was evoked by lower concentrations than in the control. 9. These results suggest that neurons of the dog area postrema trigger the emetic reflex in response to specific receptors for a great variety of transmitters, peptides, and hormones, and that these receptors act through a common second messenger, cAMP.

Synaptic Control of Motoneuronal Excitability

“…Spatial separation of cranial and especially spinal respiratory motoneurons from brain stem rhythm-generating networks has been exploited to establish the critical role of glutamate receptors in the transmission of excitatory inspiratory or expiratory drive (355,401,1026,1042 (190,278,724) reflexes. The precise pharmacology of motoneuronal glutamate receptors involved in these rhythmic behaviors remains to be established.…”

Peripheral Phosphodiesterase 4 Inhibition Produced by 4-[2-(3,4-Bis-difluoromethoxyphenyl)-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-phenyl]-ethyl]-3-methylpyridine-1-oxide (L-826,141) Prevents Experimental Autoimmune Encephalomyelitis

“…Rolipram possesses high affinity for its PDE4 binding sites in the brain, in particular the area postrema (Carpenter et al, 1988). In rodents, rolipram has previously been shown to increase Fos expression in the cerebral cortex (Svenningsson et al, 1995) caudate putamen, and nucleus accumbens (Thompson et al, 2004).…”

The human area postrema and other nuclei related to the emetic reflex express cAMP phosphodiesterases 4B and 4D

“…This effect is presumably related to the ability of PDE4 inhibitors to increase parietal cell 5 cAMP content, enhancing acid gastric secretion, an effect which correlates with the affinity for HARBS on PDE4 (Barnette et al, 1998). Other studies on the potentiation of apomorphine-induced emesis in dogs by RO20-1724 (Carpenter et al, 1988) suggest that nausea and vomiting are likely to be produced, at least in part, via the direct stimulation emetic centers in the brain. Consistent with these studies the administration of rolipram or quinoline compound PMPQ in rats, elevated the Fos-like immunoreactivity in brain regions potentially relevant to the emetic effects of PDE4 inhibition (Bureau et al, 2006).…”