ParaSynaptic Brain on Drugs

[drew hempel]

I had this debate on GNN a few years ago about the ability of hormones to turn into neurotransmitters. My souce was a book called Mapping the New Millenium but college students in the medical field refused to believe me. A few days ago I happened upon the book again (the same copy sold through various intermediators, for drug money, back to the used bookstore). haha.

the key word is PARASYNAPTIC -- a term coined in 1983 that severely challenges the "one-to-one correspondance" model of synapse brain function.

Check it! SOURCE: BRAIN BULLETIN RESEARCH

Extrasynaptic receptors and parasynaptic communication in the brain

Miles Herkenham, , a

a Section on Functional Neuroanatomy, National Institute of Mental Health, Bethesda, MD, USA

Received 14 May 1999; accepted 16 May 1999. Available online 14 December 1999.


Article Outline
• Background
• Highlight
• Significance
• Future directions
• References


Background
Synaptic transmission, by classical electrophysiological definition, is a rapid, short-latency event in which the postsynaptic action potentials reflect the presynaptic firing frequency. Such fidelity requires close apposition of presynaptic neurotransmitter and postsynaptic receptor molecules. In the 1950s, electron microscopy provided the requisite anatomical entity—the junctional contact—that became the physical embodiment of the synapse. The nicotinic cholinergic synapse at the neuromuscular junction fits both the electrophysiological and anatomical criteria for synaptic contact. From this model, a set of rigid criteria for intercellular transmission in the brain was generated. However, the discoveries of monoamines, peptides, hormones, growth factors and other neuroactive substances, their respective receptors and their modes of action severely strained the ability of investigators to satisfy criteria for synaptic transmission.

Highlight
In 1984, F. O. Schmitt [8] catalogued the growing list of “informational substances” and introduced the term “parasynaptic” to describe the action of released molecules that diffuse in the extracellular fluid (which comprises 20% of the brain volume) to reach distant high-affinity, highly selective receptors. Light-microscopic studies showed a “mismatch” between the locations of release sites (mapped by immunohistochemistry) and the locations of the corresponding high-affinity receptors (mapped by in vitro autoradiography) [5], providing anatomical support for the phenomenon. Electron microscopic studies showed that most plasmalemma receptors are extrasynaptically located, as reported in the collected works of Alain Beaudet, Virginia Pickel, Peter Somogyi, Bertrand Bloch, and others (see citations in [2]). Agnati and colleagues [1] introduced the term “volume transmission,” contrasted with “wiring transmission,” to emphasize the mechanistic and functional characteristics of parasynaptic communication and to broaden its scope by including nonneuronal and nonreceptor-mediated events. Much debate has ensured as to how far released molecules can diffuse before inactivation mechanisms stop the signal (for recent review see [6]).

Significance
Exogenously applied drugs operate in the parasynaptic mode and therefore define its scope (drugs distribute in the extracellular fluid and bind preferentially to extrasynaptic receptors simply because these receptors vastly outnumber receptors confined to postsynaptic locations). The extent to which the brain’s informational substances mimic the actions of drugs is a question deserving study. Signaling events might be occurring parasynaptically if they (1) manifest long latency, (2) are modulatory, (3) are “presynaptic,” or (4) seem to be holistic. However, care must be taken to provide hard scientific evidence before making conclusions.

Future directions
Neurotransmitters can actually drive receptors away from postsynaptic locations. A well-documented form is agonist-induced receptor internalization. The larger issue of receptor trafficking will afford insights into the dynamic interplay between endogenous ligands and their receptors. For example, availability of released transmitter appears to negatively correlate with receptor levels on the cell surface [4]. Transmitter levels and neural activity can also influence synaptic versus extrasynaptic receptor clustering. For the glutamate/NMDA receptor system in hippocampal cultures, antagonist-induced blockade of neural activity causes NMDA receptors to coalesce at synaptic sites; conversely, elevated activity drives the receptors to extrasynaptic locations [7]. This dramatic example is the opposite of what activity does at the neuromuscular junction, where receptor blockade promotes extrasynaptic receptor formation. The principles governing receptor targeting in the brain are only now being elaborated [3]. Once these principles are established, a future goal will be to define the functions of extrasynaptic receptors other than as drug targets.


References
1. L.F. Agnati, M. Zoli, I. Strömberg and K. Fuxe, Intercellular communication in the brain: Wiring versus volume transmission. Neuroscience 69 (1995), pp. 711–726. SummaryPlus | Full Text + Links | PDF (1577 K)

2. I. Caillé, B. Dumartin and B. Bloch, Ultrastructural localization of D1 dopamine receptor immunoreactivity in rat striatonigral neurons and its relation with dopaminergic innervation. Brain Res. 730 (1996), pp. 17–31. SummaryPlus | Full Text + Links | PDF (3545 K)

3. A.M. Craig, Activity and synaptic receptor targeting: The long view. Neuron 21 (1998), pp. 459–462. SummaryPlus | Full Text + Links | PDF (57 K)

4. P. Dournaud, H. Boudin, A. Schonbrunn, G.S. Tannenbaum and A. Beaudet, Interrelationships between somatostatin sst2A receptors and somatostatin-containing axons in rat brain: Evidence for regulation of cell surface receptors by endogenous somatostatin. J. Neurosci. 18 (1998), pp. 1056–1071.

5. M. Herkenham, Mismatches between neurotransmitter and receptor localizations in brain: Observations and implications. Neuroscience 23 (1987), pp. 1–38. Abstract

6. C. Nicholson, Signals that go with the flow. Trends Neurosci. 22 (1999), pp. 143–145. SummaryPlus | Full Text + Links | PDF (122 K)

7. A. Rao and A.M. Craig, Activity regulates the synaptic localization of the NMDA receptor in hippocampal neurons. Neuron 19 (1997), pp. 801–812. SummaryPlus | Full Text + Links | PDF (443 K)

8. F.O. Schmitt, Molecular regulators of brain function: A new view. Neuroscience 13 (1984), pp. 991–1001. Abstract


Address for correspondence: Prof. Miles A. Herkenham, Section on Functional Neuroanatomy, National Institute of Mental Health, Bldg. 36, Rm. 2D-15, 36 Convent Dr., MSC 4070, Bethesda, MD 20892, USA. Fax: 301-402-2200; email: milesh@codon.nih.gov