Excitatory neurotransmission

Altered synaptic properties Numerous changes in the properties of inhibitory (GABAergic) and excitatory (glutamatergic) synapses have been reported. While the simple adage of an imbalance between inhibitory and excitatory neurotransmission in epilepsy is not generally applicable, some forms of inhibition are lost or impaired in epilepsy. Likewise, an increased function of glutamate receptors has been demonstrated in some brain areas. 

Purinergic System. Figure 2 Schematic of sympathetic cotransmission. ATP and NA released from small granular vesicles (SGV) act on P2X and a-i receptors on smooth muscle, respectively. ATP acting on inotropic P2X receptors evokes excitatory junction potentials (EJPs), increase in intracellular calcium ([Ca2+]j) and fast contraction while occupation of metabotropic ar-adrenoceptors leads to production of inositol triphosphate (IP3), increase in [Ca2+]j and slow contraction. Neuropeptide Y (NPY) stored in large granular vesicles (LGV) acts after release both as a prejunctional inhibitory modulator of release of ATP and NA and as a postjunctional modulatory potentiator of the actions of ATP and NA. Soluble nucleotidases are released from nerve varicosities, and are also present as ectonucleotidases. (Reproduced from Burnstock G (2007) Neurotransmission, neuromodulation cotransmission. In Squire LR (ed) New encyclopaedia of neuroscience. Elsevier, The Netherlands (In Press), with permission from Elsevier). 

Acamprosate. Acamprosate (calcium acetylhomotaurinate), an amino acid derivative, affects both GABA and excitatory amino acid (i.e., glutamate) neurotransmission (the latter effect most likely being the one that is important for its therapeutic effects in alcoholism). Initially evaluated in a singlecenter trial in France, acamprosate was shown to be twice as effective as placebo in reducing the rate at which alcoholic patients returned to drinking (Lhuin-tre et al. 1985). The safety and efficacy of the medication have been studied most widely in Europe, and three of these studies provided the basis for the recent approval of acamprosate by the FDA for clinical use in the United States. As with naltrexone, there exist a number of meta-analytic studies that provide consistent evidence of the efficacy of the medication in the treatment of alcohol dependence. 

There are few reports on the effects of nitrous oxide on dopaminergic neurotransmission. A study in mice showed that nitrous oxide inhalation produced a significant increase in locomotor activity that was antagonized in a dose-dependent fashion by the dopamine synthesis inhibitor a-methyl-/)-tyrosine (Hynes and Berkowitz 1983). Moreover, administration of the D2 antagonist haloperidol also reduced the locomotor activity induced by nitrous oxide (Hynes and Berkowitz 1983). These results suggest that excitatory effects induced by nitrous oxide may be also mediated by dopaminergic neurotransmission. However, other studies have reported that exposure to nitrous oxide resulted in decreased dopamine release by neurons in the striatum (Balon et al. 2002 Turle et al. 1998). 

Under normal conditions, a balance generally exists between excitatory and inhibitory neurotransmission. Changes in this balance can occur both peripherally and centrally resulting in exaggerated responses and sensitization such as that observed in inflammatory, neuropathic, or functional chronic pain. Pain... 

The AMPA receptors mediate the majority of fast excitatory neurotransmission in the mammalian brain. The rapid kinetics and the low Ca permeability make these receptors ideal for fast neurotransmission without sufficient changes in the intracellular calcium concentration to activate Ca2+-dependent processes. The NMDA receptors are co-localized with the AMPA receptors on many synapses, but the slow kinetics of the NMDA receptor minimize the receptor activation after a single presynaptic glutamate release where the neuron quickly repolarizes, resulting in Mg2+ block... 

The NMDA receptor is an ionotropic glutamate receptor involved in fast excitatory neurotransmission. It plays a key role in a variety of CNS functions, most notably long-term potentiation (LTP) and neuronal plasticity, and is regulated by several mechanisms. One such mechanism involves the amino acid glycine (1). 

Shifts in intracellular pH may be another mechanism by which intracellular PLA2 activity can be regulated. Glutamate-induced AA release in mouse cortical neuronal cultures is mediated in part by a membrane-associated PLA2 activity, which is upregulated in alkaline pH and is therefore sensitive to the shifts in pH induced by excitatory neurotransmission. 

Phospholipid molecules of membranes from neurons and glial cells store a wide variety of lipid messengers. Receptor-mediated events and changes in [Ca2+]i, such as occur during excitatory neurotransmission and activity-depen-dent synaptic plasticity, activate phospholipases that catalyze the release of bioactive moieties from phospholipids, which then participate in intra- and/or intercellular signaling pathways. 

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],... 

Seizure initiation is likely caused by an imbalance between excitatory (e.g., glutamate, calcium, sodium, substance P, and neurokinin B) neurotransmission and inhibitory (y-aminobutyric acid, adenosine, potassium, neuropeptide Y, opioid peptides, and galanin) neurotransmission. 

Ionotropic glutamate receptors mediate fast excitatory neurotransmission in practically all areas of the central nervous system (CNS). They are also critical for both the induction and expression of synaptic plasticity, and have been implicated in diverse pathological conditions, such as epilepsy, ischemic brain damage, anxiety, and addiction. There are three subtypes of ionotropic glutamate receptors that are named after their high-affinity agonists as a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), N-1nethyl-D-aspartate (NMDA), and kainate (KA) receptors (1). 

Mennerick, S. and Zorumski, C. F. (1994) Glial contributions to excitatory neurotransmission in cultured hippocampal cells. Nature 368, 59-62. 

So, methyixanthines cause a disinhibited release of excitatory amino acids. Caffeine also has a net disinhibitory effect on GABA neurotransmission (Kardos and Blandl 1994). It enhances GABA release in the spinal cord through nonbenzodiazepine mechanisms (Berti and Nistri 1983). 

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