Effects on Development 6472.2
Cannabinoid Ligands
Both endocannabinoids, AEA and 2-AG, are present in the whole brains of rat
fetuses at GD21 (Berrendero et al. 1999). The presence of these cannabinoids in
the brain in trace amounts limits how much can be learned about the distribution
of these compounds in the different regions of the developing brain and the extent
to which this parallels the distribution of the CB 1 receptors that are present at
that time. Even so, it has been possible to conclude from the results that have
been obtained that the ontogeny of these two endocannabinoids is not the same
(Berrendero et al. 1999).
High levels of 2-AG were measured at GD21. These levels peaked at postnatal
day (PND)1, with values approximately twofold higher than those found at other
ages. In contrast, AEA levels increased during the early postnatal period, reaching
their maximum in the adult brain (Berrendero et al. 1999). Cannabinoid receptor
binding and mRNA expression in certain brain areas also change with time during
development. Interestingly, in the caudate-putamen and cerebellum these changes
aresimilartothechangesthattakeplaceinAEAlevels,whereasinthehippocampus
andcerebralcortextheyresemblethechangesoccurringin2-AGlevels(Berrendero
et al. 1999).
The amount of 2-AG in the fetal and early postnatal brain is significantly higher
than that of AEA (Berrendero et al. 1999). It is possible that this might indicate
a more important role for 2-AG than AEA as an endogenous ligand for the CB 1
receptor in brain development. However, it must be remembered that 2-AG for-
mation in tissues may lead not only to the production of a cannabimimetic signal,
but also to the termination of a protein kinase C/diacylglycerol-mediated intra-
cellular signal or to the generation of arachidonic acid. Accordingly, the increase
of 2-AG observed at PND1 might be related to an increase in the formation of
diacylglycerol, which is an intermediate in the synthesis of 2-AG (Di Marzo 1998).
Diacylglycerol has been reported to be significantly involved in the metabolism of
phosphoglycerides and sphingolipids during the processes of neurite formation
and myelinogenesis, and hence in neural development (Araki and Wurtman 1997;
Sillence and Allan 1998).
The physiological significance of these differences between 2-AG and AEA is
still unknown, but could be related to regional differences in their distribution
and in their access to their receptors, and possibly to their having different roles
in brain development. In summary, there is good evidence that the endogenous
cannabinoid system plays a functional role in the early stages of brain development.
This role changes as the brain develops such that the way in which the endogenous
cannabinoid system modulates brain function during its development is not the
same as in the adult (i.e., control of movement, nociception, etc.).