3. Umbruch 4.4..2005 - Online Pot

124 S.A. Varvel and A.H. Lichtman
nists impair memory, a cannabinoid inverse agonist would be expected to
enhance memory. On the other hand, SR-141716 was found to be 7000-fold
more selective as a CB 1 receptor antagonist than as an inverse agonist [72],
raising questions regarding the relevance of its inverse agonism in the whole
animal. Another plausible explanation is that SR-141716 may act at non-CB 1
sites of action, though it does not bind to CB 2, histamine, dopamine, opioid,
5-HT, adenosine, and several other receptors and ion channels [73, 74].
SR-141716 has been reported to antagonize WIN-55,212-mediated inhibition
of hippocampal excitatory transmission in CB 1 –/– mice, suggesting activity at
either an uncharacterized cannabinoid receptor or noncannabinoid site of
action [75]. Curiously, AM-251, a CB 1 receptor antagonist that is structurally
very similar to SR-141716, failed to block WIN-55,212-2-induced inhibition
of excitatory transmission [76].
In the case of CB 1 –/– mice, alternative interpretations related to the use of
knockout models must be considered. For example, potential confounding factors
include hitchhiking genes that are derived from the original cell line, epistasis
in which the effect of gene disruption is modified by the genetic background
in which it is placed, and pleiotropic effects in which other consequences
of gene disruption indirectly affect the behavior of interest [77].
Nonetheless, a similar phenotype between the CB 1 –/– mice and
SR-141716-treated wild-type mice in any given behavioral test would support
the notion that these processes are under tonic endocannabinoid tone.
Neuroanatomical locus of effects
The endocannabinoid system is heterogeneously distributed throughout the
central nervous system, reflecting the diversity of physiological processes in
which endocannabinoids have been implicated as playing a role. Several lines
of evidence suggest that the hippocampus, an area long implicated with learning
processes, plays a major role in the mediating both the effects of exogenous
cannabinoids on memory and endocannabinoid modulation of memory.
First, analysis of the distribution of CB 1 receptors shows that the hippocampus
contains a high density of CB 1 receptors, as has been demonstrated with
[ 3 H]CP-55,940 [78] and [ 3 H]SR-141716 [79] autoradiography, detection of
CB 1 mRNA expression [80], as well as with CB 1 receptor antibodies [81, 82].
The hippocampus has also been shown to contain relatively large amounts of
the endocannabinoids anandamide [83, 84] and 2-AG [84].
Immunocytochemical studies have revealed that FAAH, the enzyme responsible
for anandamide catabolism [85, 86] and monoglyceride lipase, an
enzyme that is believed to play a role in the hydrolysis of 2-AG [87, 88], are
significantly present within the hippocampus. Collectively, the high abundance
of CB 1 receptors, endogenous ligands, and enzymes associated with endocannabinoids
within the hippocampus strongly suggest that this system plays
a tonic role in physiological mechanisms of this brain area. Further support for