Transmitter-Receptor Mismatches in Central Dopamine, Serotonin, and Neuropeptide Systems

Abstract

In the central nervous system (CNS), the existence of neurotransmitter-defined neurons, with projections showing a regional distribution distinctly separate from that of the corresponding receptors on target cells, represents a compelling argument in favor of volume transmission (VT). Such mismatches imply that the transmitter reaches its functional targets by diffusion into the extracellular space (ECS) (1–4), as initially postulated to be the case for cortical monoamines released from axon terminals (varicosities) often lacking synaptic membrane specializations (5; for review, see refs. 6 and 7). In the past 10 yr, it has been further realized that the VT modality may also apply to entirely synaptic neuronal systems, such as those using γ-aminobutyric acid and glutamate, in which spillover of transmitter beyond synaptic clefts has been described (8–10). This chapter focuses on recent immunofluorescence, confocal laser, and immunoelectron microscopic (IEM) observations, which illustrate the diversity of topological relationships between dopamine (DA)-, serotonin (5-hydroxytryptamine [5-HT])-, and neuropeptide (NP)-containing neurons and their receptors in various regions of the brain. The clinical relevance of some of these data is also emphasized (11). Noradrenaline and acetylcholine systems are not considered here, since they have been recently reviewed elsewhere (7,12,13). In each of these transmitter-defined systems, and presumably many others, the bulk of the data supports the view that VT plays a major role throughout the CNS.