NEUROBIOLOGY: ON MARIJUANA CANNABINOIDS
The drug "marijuana" is derived from the hemp plant Cannabis
sativa. The parts of the plant vary in potency, the resinous
exudate of the flowering tops of the female plant the most
potent, providing "hashish" and "charas". Next in potency are the
dried leaves and flowering shoots of the female plant (providing
"bhang"), and the resinous mass from small leaves of
inflorescence (providing "ganja"). The drug is usually inhaled by
smoking, with marijuana "joints" containing approximately 500
milligrams of marijuana, which in turn contains approximately 5
to 15 milligrams of tetrahydrocannabinol (THC).
With moderate dosage, marijuana produces mild euphoria
followed by sleepiness. In the acute state, the user has an
altered time perception, less inhibited emotions, psychomotor
problems, and impaired immediate memory. High doses produce
transient effects resembling psychosis. The drug frequently
aggravates existing mental illness, adversely affects motor
performance, and slows the learning process in children. Studies
of long-term effects have conclusively demonstrated abnormalities
in the lungs, laryngitis, rhinitis, and chronic obstructive
pulmonary disease. Chronic usage has resulted in depression of
plasma testosterone levels and reduced sperm counts. Abnormal
menstruation and failure to ovulate have occurred in some female
users. Sudden withdrawal produces insomnia, nausea, muscle pain
(myalgia), and irritability. In general, marijuana is a potent
psychoactive drug acting on the central nervous system and
producing both acute and chronic neurophysiological effects.
The most important neuroactive chemical ingredients in
marijuana are the lipophilic cannabinoids, especially delta-9-
tetrahydrocannabinol. Cannabinoids are believed to act at several
specific cannabinoid receptors in the brain. When a human inhales
or ingests marijuana, the liver transforms it into a number of
metabolites, the most important of which is 11-hydroxy-delta-9-
tetrahydrocannabinol, which has effects identical to those of the
parent compound. 11-hydroxy-delta-9-THC is in turn converted to
more polar and inactive metabolites which are excreted in urine.
Since certain cannabinoids are already present in the
nervous system without input of any drug, cannabinoids need to be
categorized as "exogenous" (from outside) versus "endogenous"
(from inside).
In this context, the term "G-proteins" refers to a family of
signal-coupling proteins that act as intermediaries between
activated cell receptors and effectors, for example, the
transduction of hormonal signals from the cell surface to the
cell interior. The G-protein is apparently embedded in the cell
membrane with parts exposed on the outside surface and inside
surface. The outside moiety is activated by the "first messenger"
(e.g., a hormone), and the inside moiety activates a "second
messenger", the G-protein thus acting as a trans-membrane signal
transducer.
"Neurotransmitters" are chemical substances released at the
terminals of nerve axons in response to the propagation of an
impulse to the end of that axon. The neurotransmitter substance
diffuses into the synapse, the junction between the presynaptic
nerve ending and the postsynaptic neuron, and at the membrane of
the postsynaptic neuron the transmitter substance interacts with
a receptor. Depending on the type of receptor, the result may be
an excitatory or an inhibitory effect on the postsynaptic nerve
cell.
"GABA" is gamma-amino butyric acid, a neurotransmitter
substance. The term "GABA receptor" refers to any of several
membrane proteins that bind GABA and mediate its effects as an
inhibitory neurotransmitter.
In this context, the term "depolarization" refers to a
reduction in the potential difference across the cell membrane.
The neuron action potential involves not only a transient
depolarization of the membrane but also a transient reversal of
polarity of the potential difference, the potential difference
across the neuron membrane during an action potential changing
from approximately -60 millivolts (inside negative) to
approximately +40 millivolts.
The "hippocampus" is a brain cortex structure in the medial
part of the temporal lobe. In humans, among other functions, the
hippocampus is apparently involved in short-term memory. Analysis
of the neurological correlates of learning behavior in the rat
indicates that the hippocampus is also involved in memory in that
species. Nerve cells in rat brain slices remain active in vitro
in appropriate solutions for up to 24 hours, and such slices are
convenient tissues for experiments. "Hippocampal pyramidal
neurons" are a specific type of nerve cell in the hippocampus.
The term "retrograde signaling" refers to neural information
transmission in a direction opposite to the primary signal
direction. In this context, the term refers to signaling from
postsynaptic neuron to presynaptic neuron. In general, retrograde
signaling in neural systems is usually part of a negative
feedback process.
In general, an "interneuron" is any neuron that branches
locally to innervate other neurons.
In general, in this context, an "agonist" is any substance
that binds to and activates a receptor.
... ... R.I. Wilson and R.A. Nicoll (University of California San
Francisco, US) report a study of the action of endogenous
cannabinoids, the authors making the following points:
1) The authors point out that marijuana affects brain
function primarily by activating the G-protein-coupled
cannabinoid receptor-1 (CB1), which is genetically expressed
throughout the brain at high levels. Two endogenous lipids,
anandamide and 2-arachidonylglycerol (2-AG), have been identified
as cannabinoid receptor-1 ligands, and depolarized hippocampal
neurons have been shown to rapidly release both anandamide and 2-
AG in a calcium-dependent manner. In the hippocampus, cannabinoid
receptor-1 is expressed mainly by GABA-mediated inhibitory
interneurons, where cannabinoid receptor-1 apparently clusters on
axon terminals of such interneurons. A synthetic cannabinoid
receptor-1 agonist has been demonstrated to depress GABA release
from hippocampal slices, which suggests that the function of
endogenous cannabinoids released by depolarized hippocampal
neurons might be to reduce GABA release (down-regulate GABA
release).
2) The authors report that their experiments indicate that
the transient suppression of GABA-mediated transmission that
follows depolarization of hippocampal pyramidal neurons is
mediated by retrograde signaling through release of endogenous
cannabinoids. Signaling by the endocannabinoid system thus
represents a mechanism by which neurons can communicate backwards
across synapses to modulate their inputs. The authors suggest
this study represents the first identification of a physiological
process mediated by endogenous brain cannabinoids. Exogenous
cannabinoids such as marijuana may destroy the information
contained in endogenous cannabinoid feedback loops and thus
promote a more random pattern of synaptic modification.
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R.I. Wilson and R.A. Nicoll: Endogenous cannabinoids mediate
retrograde signalling at hippocampal synapses.
(Nature 29 Mar 01 410:588)
QY: Roger A. Nicoll:
[email protected]
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Summary by SCIENCE-WEEK http://scienceweek.com 20Jul01
For more information: http://scienceweek.com/swfr.htm
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Related Background:
ON THE MECHANISM OF PAIN MODULATION BY CANNABINOIDS
In general, the clinical entity "hyperalgesia" (sometimes known
as "hyperalgia") is a heightened sensitivity to painful stimuli.
Cannabinoids are derivatives or preparations from the plant
Cannabis sativa (the marijuana plant), a group of a dozen
compounds chemically related to cannabinol, including delta-9-
tetrahydrocannabinol (THC), and the cannabinoid receptor is the
binding site for the psychoactive component of marijuana, as well
as for anandamide, the endogenous physiological ligand. Anand-
amide is known to modulate the pain pathway, but the mechanisms
are not clear. ... ... Richardson et al (3 authors at Univ. of
Minnesota Minneapolis, US) now report studies in animal models
that indicate that hyperalgesia may be linked to a faulty
cannabinoid system in the spinal cord. The authors suggest that
endogenous cannabinoids attenuate pain by preventing the release
of glutamate from presynaptic terminals of neurons that transmit
pain messages to the spinal cord.
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QY: Jenelle D. Richardson, Harvard Univ. Medical School, Dept.
Neurobiology 617-432-1550.
(Chem. & Eng. News 19 Jan 98) (Science-Week 30 Jan 98)
For more information: http://scienceweek.com/swfr.htm