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

[drew hempel]

Here's the "spiritual" significance of Parasynaptic Holographic brain function:

Title: The psychosomatic network: Foundations of mind-body medicine
Author(s): Pert CB, Dreher HE, Ruff MR
Source: ALTERNATIVE THERAPIES IN HEALTH AND MEDICINE 4 (4): 30-41 JUL 1998
Document Type: Article
Language: English
Cited References: 88 Times Cited: 17
Abstract: Research in the 1980s uncovered ubiquitous neuropeptide-receptor distribution in brain structures associated with emotional processing, and throughout many organ systems. This finding supported neuropeptides as biochemical substrates of emotion, and the neuropeptide-receptor network as a parasynaptic system crossing traditional brain-body boundaries. The medical relevance of these findings was affirmed by psychoneuroimmunology research: neuropeptides help to regulate immunocyte trafficking, there is bidirectional communication between nervous and immune system components, immunocytes produce neuropeptides, and nerve cells produce immune-associated cytokines. In the past decade, the concept of a unified psychosomatic network has been strengthened by animal and human research demonstrating relationship between behavior and neuropeptide-mediated regulation of immune functions. Research on emotional expression or disclosure in healthy human subjects as well as in cancer and HIV-positive patients has shown significant positive correlations with clinically relevant immune functions and/or positive health outcomes. Psychosocial interventions emphasizing emotional expression or active coping have evidenced survival benefits in breast cancer and melanoma. These findings suggest that emotional expression generates balance in the neuropeptide-receptor network and a functional healing system. Emotional expression is also a marker for psychospiritual vitalization, and further research should evaluate links between energy-based models of health and neuropeptide-receptor-based models under the rubric of an informational paradigm.
KeyWords Plus: RECEPTOR-MEDIATED CHEMOTAXIS; STRUCTURED PSYCHIATRIC INTERVENTION; BRAIN OPIATE RECEPTORS; INDUCED HYPERGLYCEMIA; HUMAN-MONOCYTES; PHYSICAL ABUSE; PSYCHOSOCIAL FACTORS; HOMOSEXUAL IDENTITY; ENDOGENOUS OPIOIDS; MALIGNANT-MELANOMA
Addresses: Pert CB (reprint author), Georgetown Univ, Med Ctr, Dept Physiol & Biophys, Washington, DC 20007 USA
Georgetown Univ, Med Ctr, Dept Physiol & Biophys, Washington, DC 20007 USA

Publisher: INNOVISION COMMUNICATIONS, 101 COLUMBIA, ALISO VIEJO, CA 92656 USA
Subject Category: Integrative & Complementary Medicine
IDS Number: 166RP

ISSN: 1078-6791

[drew hempel]

Sure enough there's a new study that revolutionizes how the brain works. It turns out that the neurotransmitters are released in the "white matter" -- the cerebrum -- not just the "gray matter" -- the neocortex. There's no one-to-one correspondance so the brain is "chaotic" ---

http://anomalist.com for details -- wherein it states this will radically change how drugs are administered to the brain. Not sure what the hell they can do .... haha.