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Perspectives |

Forty Years of Neurotransmitters A Personal Account

Solomon H. Snyder, MD
Arch Gen Psychiatry. 2002;59(11):983-994. doi:10.1001/archpsyc.59.11.983.
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All drugs in psychiatry act by influences on neurotransmitter systems. Hence, an appreciation of neurotransmitter disposition helps clarify our understanding of therapeutic actions as well as adverse effects of psychotropic drugs. Moreover, understanding the nuances of neurotransmitters facilitates efforts to develop novel agents. Currently available psychoactive drugs exert their effects through3 or 4 of the longest-known neurotransmitters. Over the past few decades, up to 100 novel neurotransmitter candidates have been identified, each of them as interesting as traditional biogenic amines. It is likely that totally new classes of therapeutic agents will emerge based on these transmitter molecules.

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Figure 1.

Nitric oxide (NO) and carbon monoxide(CO) signaling. Neuronal NO synthase (nNOS) is physically anchored to the N-methyl-D-aspartate (NMDA) receptor by the adaptor protein, PSD95. When the NMDA receptor is activated, calcium enters the cytosol, binds to calmodulin (CaM), and activates nNOS. Neuronal NO synthase uses oxygen and the reducing equivalents of NADPH (nicotinamide adenine dinucleotide phosphate) to catalyze the conversion of arginine to citrulline and NO. Nitric oxide can nitrosylate proteins directly by reacting with free cysteines. When the NMDA receptor is nitrosylated, NMDA-evoked currents are diminished, possibly providing negative feedback for NO production. Nitric oxide also activates soluble guanlyl cyclase, which converts guanosine triphosphate to cyclic guanosine monophosphate. Heme has a highly conjugated porphyrin ring with an iron atom chelated in the center and 3 different substituents on the outside (M = methyl, V = vinyl, P = propionate). Heme oxygenase-2 (HO2) is a 36-kd protein with a short hydrophobic C-terminus that anchors it to the endoplasmic reticulum(ER). Together with NADPH and cytochrome P450) reductase (CPR), it catalyzes a mixed oxidation-reduction reaction in which the α-meso bridge of heme is cleaved, releasing an iron atom and producing biliverdin and CO. Biliverdin is rapidly reduced to bilirubin by biliverdin reductase (BVR). Carbon monoxide, another freely diffusible gas, activates sGC.

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Figure 2.

D-serine is an endogenous ligand of the N-methyl-D-aspartate (NMDA) receptor. In astrocytes that ensheath synapses containing NMDA receptors, D-serine is synthesized from L-serine by serine racemase. When the presynaptic neuron releases glutamate, it acts not only on the postsynaptic neuron, but also on the surrounding astrocyte. Activation of the astrocyte's non-NMDA glutamate receptors releases D-serine, which binds to the NMDA receptor at a site distinct from the glutamate binding site.

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