646 J.A. Ramos et al.
several effects such as induction of key genes, activation of energy metabolism,
arachidonic acid mobilization, and other responses potentially related to events of
neural development (for review see Ramos et al. 2002).
The levels of these receptors are substantially higher than those seen in the adult
rat brain (Berrendero et al. 1999). Moreover, in the fetal and early neonatal brain,
thereisanatypicaldistributionofCB 1 receptors compared to the adult brain,
particularly with regard to the location of receptor binding in white matter areas
(Romero et al. 1997) and mRNA expression in subventricular zones of the forebrain
(Berrendero et al. 1998, 1999), areas in which these receptors are scarce or unde-
tectable in the adult brain (Herkenham et al. 1991; Mailleux and Vanderhaeghen
1992b). This atypical location of CB 1 receptors is a transient phenomenon, since
during the course of late postnatal development these receptors progressively ac-
quire the classic pattern of distribution observed in the adult brain (Romero et al.
1997; Berrendero et al. 1998).
With regard to humans, data about the appearance and location of CB 1 receptors
in the developing brain are still very limited (Mailleux and Vanderhaeghen 1992a;
Glass et al. 1997; Biegon and Kerman 2001; Mato et al. 2003). There is a significant
population of cannabinoid receptors at week 19 of gestation that is functionally
coupled to signal transduction mechanisms. These receptors are present in the
same areas as in the adult human brain and seem to increase progressively in
number from early prenatal stages to adulthood (Mato et al. 2003).
As in animal models, high densities of cannabinoid receptors have also been
detected during human prenatal development in fiber-enriched areas that are
practically devoid of these receptors in the adult brain. This atypical distribution
of CB 1 receptors, which is similar to that observed in rats, has been interpreted,
for both species, as indicating a possible involvement of CB 1 receptors in specific
events relating to brain development during fetal and early postnatal periods. As
has been suggested for other neurotransmitter receptors (del Olmo and Pazos
2001), the early and transient presence of these receptors could indicate a specific
role for the endocannabinoid system in several developmental events, such as
metabolic support, cell proliferation and migration, axonal elongation, and later,
synaptogenesis and myelogenesis (for review see Fernández-Ruiz et al. 2000).
This hypothesis is supported by the demonstration of a role for CB 1 receptors
in neurite remodeling in vitro (Zhou and Song 2001). Support also comes from
the findings that endocannabinoids inhibit both cortical neuron differentiation to
mature neurons using in vitro cellular models and adult hippocampal neurogenesis
in vivo (Rueda et al. 2002). The endocannabinoids interfere with nerve growth
factor (NGF) signaling that is responsible for the activation of the differentiation
program by acting via CB 1 receptors to inhibit NGF-induced signaling events that
ultimately result in inhibition of neural generation (Rueda et al. 2002). Therefore,
inhibition of neurogenesis in adult hippocampus, triggered by cannabinoids either
during development or in the adult, might help to explain cannabinoid-related
disruption of cognitive processes such as learning and short-term memory.