652 J.A. Ramos et al.
3.5
Endogenous Cannabinoid System
When adult male, but not female, rats perinatally exposed to∆^9 -THC were sub-
jected to a challenge with this cannabinoid, they showed marked tolerance in the
open-field response and in the neurochemical events underlying motor activity
(Fernández-Ruiz et al. 1994). However, there were no corresponding changes in
CB 1 receptor binding or mRNA expression in the basal ganglia or in other regions
that contain large populations of these receptors, such as the hippocampus, ante-
rior limbic structures, and cerebellum (García-Gil et al. 1999). Only in the arcuate
nucleus was a change observed in cannabinoid receptor binding levels (an increase
of 42.2% in∆^9 -THC-exposed males). This nucleus is only sparsely populated with
cannabinoid receptors (Herkenham et al. 1991). Even so, CB 1 receptors seem to
play an important role in the modulation of neuroendocrine function. Thus, the
administration of cannabinoids has marked effects on this regulation, located in
the arcuate nucleus and also in other hypothalamic structures (Fernández-Ruiz et
al. 1997).
4
Cannabinoids and Gene Expression
of Neural Adhesion Molecules During Brain Development
The ability of plant-derived cannabinoids to affect development does not depend
only on their neuromodulatory activity. Recently it has been observed that expo-
sure to∆^9 -THC during critical periods of brain development is associated with an
increase in L1 gene expression (Gómez et al. 2003). The protein L1 is a member of
the immunoglobulin superfamily and, together with other proteins that can me-
diate cell–cell and cell–matrix interactions, is involved in various developmental
events(Panickeretal.2003).Itplaysanimportantroleinvariousprocessesthattake
place during brain development, including cell proliferation and migration, neu-
ritic elongation and guidance, synaptogenesis, and myelogenesis (Burden-Galley
et al. 1997).
Exposure to∆^9 -THC increased L1 gene expression in most of the white matter
regions analyzed, in particular, transverse commissural tracts, such as the fimbria,
the stria terminalis, the stria medullaris, and the corpus callosum (Gómez et al.
2003). It has been reported that CB 1 receptors are present in all these tracts at this
fetal age (Berrendero et al. 1998).∆^9 -THC-induced increases in L1-mRNA levels
reached statistical significance in males but not in females, yet another example
of sexual dimorphism (Gómez et al. 2003). As already discussed, it is likely that
this sexual dimorphism stems from male–female differences in the hormonal
environment,inparticularwhenthebrainisundergoingsexualdifferentiation,and
notfrommale–femaledifferencesinthedistributionand/ordensityofcannabinoid
CB 1 receptors, for which there is no evidence at least in the perinatal period
(Fernández-Ruiz et al. 2000).