Non‐synaptic receptors and transporters involved in brain functions and targets of drug treatment

Abstract

Beyond direct synaptic communication, neurons are able to talk to each other without making synapses. They are able to send chemical messages by means of diffusion to target cells via the extracellular space, provided that the target neurons are equipped with high-affinity receptors. While synaptic transmission is responsible for the 'what' of brain function, the 'how' of brain function (mood, attention, level of arousal, general excitability, etc.) is mainly controlled non-synaptically using the extracellular space as communication channel. It is principally the 'how' that can be modulated by medicine. In this paper, we discuss different forms of non-synaptic transmission, localized spillover of synaptic transmitters, local presynaptic modulation and tonic influence of ambient transmitter levels on the activity of vast neuronal populations. We consider different aspects of non-synaptic transmission, such as synaptic-extrasynaptic receptor trafficking, neuron-glia communication and retrograde signalling. We review structural and functional aspects of non-synaptic transmission, including (i) anatomical arrangement of non-synaptic release sites, receptors and transporters, (ii) intravesicular, intra-and extracellular concentrations of neurotransmitters, as well as the spatiotemporal pattern of transmitter diffusion. We propose that an effective general strategy for efficient pharmacological intervention could include the identification of specific non-synaptic targets and the subsequent development of selective pharmacological tools to influence them.

Are cyclooxygenase-2 and nitric oxide involved in the dyskinesia of Parkinson's disease induced byl-DOPA?

“…The dense dopaminergic nerve terminal plexus in the striatal cellular networks mainly operates via extrasynaptic/volume transmission [122]. Various subtypes of extrasynaptic dopamine receptors [123][124][125] are located in projection neurons and interneurons as well as on the afferent nerve terminal networks.…”

In Vivo Effects of Amphetamine Analogs Reveal Evidence for Serotonergic Inhibition of Mesolimbic Dopamine Transmission in the Rat

“…Monoamine transporter proteins play a fundamental role in limiting the extent of nonsynaptic volume transmission in the central nervous system (Rice and Cragg, 2008;Vizi et al, 2010). Amphetamine-type stimulants target these transporters by acting as substrates and triggering the efflux of monoamine transmitters, especially dopamine (DA) and norepinephrine (NE) (Rothman and Baumann, 2003;Fleckenstein et al, 2007).…”

Organization of the serotonergic innervation of the feeding (buccal) musculature during the maturation of the pond snailLymnaea stagnalis: A morphological and biochemical study

“…This indicates another form of regulation by 5-HT, the volume transmission. This type of nonsynaptic release of modulatory action (Vízi, 1984;Vízi et al, 2010) was also suggested in a number of peripheral organs of Helix (Benedeczky and Halasy, 1988;Elekes, 2000) and in arthropods (see Nässel, 2009). In conclusion, based on the ultrastructure of neuromuscular contacts of 5-HTLIR axon profiles, we suggest that these contacts are involved in nonsynaptic modulatory processes and may play a double role in regulating the developing buccal mass: 1) a localized effect of 5-HT on the muscle cells through the close but unspecialized contacts and 2) a slow volume transmission effect via the wide intercellular space.…”