Glutamate brainstem

The neural structures involved in the promotion of the waking (W) state are located in the (1) brainstem [dorsal raphe nucleus (DRN), median raphe nucleus (MRN), locus coeruleus (LC), laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT), and medial-pontine reticular formation (mPRF)] (2) hypothalamus [tuberomammillary nucleus (TMN) and lateral hypothalamus (LH)[ (3) basal forebrain (BFB) (medial septal area, nucleus basalis of Meynert) and (4) midbrain ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) (Pace-Schott Hobson, 2002 Jones, 2003). The following neurotransmitters function to promote W (1) acetylcholine (ACh LDT/PPT, BFB) (2) noradrenaline (NA LC) (3) serotonin (5-HT DRN, MRN) (4) histamine (HA TMN) (5) glutamate (GLU mPRF, BFB, thalamus) (6) orexin (OX LH) and (7) dopamine (DA VTA, SNc) (Zoltoski et al, 1999 Monti, 2004). 

Some CNS stimulants have an effect on the same systems that are involved in wakefulness, including glutamate-, NE-, DA-, 5-HT-, histamine-, hypocretin- and ACh-containing neurons. This group includes molecules such as cocaine, amphetamine, and nicotine. The sleep-promoting systems are concentrated in the medial part of the brainstem, dorsal reticular substance of the medulla, anterior hypothalamus, and basal forebrain (Jones 2005). Other stimulants, such as caffeine and theophylline, block some sleep-inducing mechanisms. Modafinil is also a CNS stimulant with an unknown mechanism of action. 

Ammonia has deleterious effects on brain function by direct and indirect mechanisms. Concentrations of ammonia in the 1-2 mmol/1 range, equivalent to those reported in the brain in liver failure, impair postsynaptic inhibition in cerebral cortex and brainstem by a direct effect on Cl extrusion from the postsynaptic neuron. Millimolar concentrations of ammonia also inhibit excitatory neurotransmission. Synaptic transmission from Schaffer collaterals to CA1 hippocampal neurons is reversibly depressed by 1 mmol/1 ammonia, and the firing of CA1 neurons by iontophoretic application of glutamate is inhibited by 2 mmol/1 ammonia [10],... 

In the calyx of Held synapse in the auditory brainstem of rats the 5-HTib receptor inhibition of glutamate release was fully explained by inhibition of Ca2+ entry through voltage-dependent channels (Mizutani et al. 2006). In rat nucleus accumbens, in contrast, the analogous 5-HTib effect did not involve inhibition of Ca2+ channels (Muramatsu et al. 1998). In rat amygdala, the 5-HTia inhibition operated via a cyclic AMP pathway and apparently inhibition of Ca2+ entry an unexplained observation was the failure of pertussis toxin to abolish the 5-HTia inhibition (Cheng et al. 1998). 

Shigetomi E, Kato F (2004) Action potential-independent release of glutamate by Ca2+ entry through presynaptic P2X receptors elicits postsynaptic firing in the brainstem autonomic network. J Neurosci 24 3125-35... 

Kim SJ, Calejesan AA, Zhuo M (2002) Activation of brainstem metabotropic glutamate receptors inhibits spinal nociception in adult rats. Pharmacol Biochem Behav 73 429-437 Kirouac GJ, Li S, Mabrouk G (2004) GABAergic projection from the ventral tegmental area and substantia nigra to the periaqueductal gray region and the dorsal raphe nucleus. J Comp Neurol 469 170-184... 

Fig. 5. Drawing of the brainstem depicting neurons and pathways likely to use glutamate as a neurotransmitter. 1 = primary afferent inputs to the dorsal column nuclei (a), the solitary tract nucleus (b), and the cochlear nucleus (c) 2 = granule cell/parallel fibers in the dorsal cochlear nucleus 3 = calyces of Held in the medial nucleus of the trapezoid body 4 = cochlear nucleus inputs to the lateral superior olive 5 = input to the oculomotor nucleus from the ventral lateral vestibular nucleus 6 = input to the oculomotor nucleus from the abducens nucleus 7 = corticocollieular inputs 8 = spinal input to the periaqueductal gray 9 = inputs to the red nucleus and pontine nuclei from the cerebellar nuclei. For further details, see Section 3.3.

Fig. 7. Schematic drawing of a transverse section through the forebrain depicting pathways likely to use glutamate as a neurotransmitter. I = principal subcortical afferents to the thalamus from. somatosensory relay nuclei and the spinal cord (a), cerebellar nuclei (h). and retina (c) 2 = intrinsic neurons and retinal inputs to the hypothalamus 3 = thalamocortical inputs 4 = corticothalamic inputs 5 = cortical inputs to the basal ganglia and other areas in the brainstem and spinal cord 6 = associational and commi.ssural connections in the cerebral cortex. For further details, see Sections 3.5-3.9.

Caicedo A, Eybalin M (1999) Glutamate receptor phenotypes in the auditory brainstem and mid-brain of the developing rat. Eur J Neurosci / 7 51-74. 

Grundemar, L., Wahlestedt, C. Reis, DJ. (1991b) Neuropeptide Y acts at an atypical receptor to evoke cardiovascular depression and to inhibit glutamate responsiveness in the brainstem. J. Pharmacol. Exp. Ther. 258, 633-638. 

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