Publisher Summary This chapter presents a discussion on chemical neurotransmission and role of chemical neurotransmitters in the prefrontal cortex. It begins with an introduction to neurotransmitters and neurotransmitter receptors. Cells produce certain chemical substances called neurotransmitters and neuromodulators that, through specific receptors embedded in pre- and postsynaptic membranes, modify the electrical activity of other nerve cells. The most important classes of neurotransmitters thus far identified in the cerebral cortex include: amino acids (i.e. glutamate (Glu), aspartate, γ -aminobutyric acid [GABA]); the monoamines, including two catecholamines, dopamine (DA) and norepinephrine (NE), and an indoleamine, 5-hydroxytriptamine (5-HT) or serotonin; Acetylcholine (ACh); and neuropeptides (e.g., enkephalins, substance P, somatostatin, neurotensin). Among the six best-known transmitters in prefrontal transmitters include Glu, GABA, NE, DA, 5-HT, and Ach. GABA is the prime inhibitory neurotransmitter in the central nervous system. Glutamate is the prime excitatory neurotransmitter in the cortex. It serves not only the local prefrontal circuitry but also the excitatory connectivity of the prefrontal cortex with striatal, thalamic, and limbic structures. The three monoaminergic systems, with their cells of origin in the brainstem, innervate the prefrontal cortex by way of ascending fiber paths that bypass the thalamus: the noradrenergic system (its transmitter NE) from the nucleus coeruleus, the dopaminergic system (its transmitter DA) from the ventral tegmentum, and the serotonergic system (its transmitter, serotonin, 5-HT) from the nuclei of the raphe. In addition to the monoamines, the prefrontal cortex, like the rest of the neocortex, receives profuse afferents from the subcortical components of the cholinergic system. Also active in the prefrontal cortex are a number of neuropeptides (somatostatin, substance P, CCK, angiotensin, neurotensin, and others) that act there as neurotransmitters or neuromodulators.