Developmental Aspects Of Cannabinoids The cannabinoid system in development

Initial reports studying the first weeks of postnatal life in the rat described a gradual increase in brain CBX receptor mRNA (McLaughlin and Abood, 1993) and in the density of CB1 receptors (Belue et al., 1995; Rodriguez de Fonseca et al., 1993). In later studies, investigating the gestational period, CB1 receptor mRNA was detected from gestational day 11 in the rat (Buckley et al., 1998). Additional studies have uncovered more complex developmental patterns. Thus, whereas the highest levels of mRNA expression of the CB1 receptor are seen at adulthood in regions such as the caudate-putamen and cerebellum, other areas such as cerebral cortex and hippocampus display the highest mRNA CB1 receptor levels between gestational day 21 and postnatal day 5 (i.e., during the last trimester of pregnancy and the first week of life), with the first postnatal day expressing peak levels (Berrendero et al, 1998a; 1999).

Moreover, atypical patterns (i.e., different from those in adult) of CB1 receptor densities were observed: a transient presence of CB1 receptors was detected in white matter regions including the corpus callosum and anterior commisure (connecting neuronal pathways between the left and right hemispheres) between gestational day 21 and postnatal day 5, suggesting a role for endocannabinoids in brain development (Romero et al., 1997; Fernandez-Ruiz et al., 2000).

On the other hand, cannabinoid receptor binding in the areas with the densest CB 1 receptor presence in adults (caudate-putamen, cerebral cortex, hippocampus and cerebellum) appears to follow a more classical developmental course, increasing progressively from gestational day 14 throughout the postnatal period until adult levels are reached (Berrendero et al., 1998a; 1999; Fernandez-Ruiz et al., 2000).

These latter data are compatible with the observation in mice that motor depression in an open field and hypoalgesia in response to administration of anandamide or A9-THC are not fully developed until adulthood (Fride and Mechoulam, 1996a). Interestingly, A8-THC at relatively high doses (18mg/m2) prevented vomiting caused by anti-cancer chemotherapy in young children, without producing undesirable cannabimimetic CNS effects (Abrahamov et al., 1995). At such doses one would normally expect very significant cannabimimetic effects, as seen in adults. A tentative explanation based on the data from animals studies (Fride and Mechoulam, 1996a), was offered: on one hand, in the developing organism, the cannabinoid receptor system is not fully developed (hence the lack of cannabimi-metic effects). On the other hand, the antiemetic effects are not transmitted through the cannabinoid receptors. The existence of nonspecific effects caused by cannabinoids has been shown previously (Felder et al., 1992; Martin, 1986) and non cannabimimetic cannabinoids with antiemetic properties are indeed known (Feigenbaum et al., 1989). As the vomiting center in the brain, including the chemoreceptor trigger zone in the area postrema, is relatively poor in cannabinoid receptors (Herkenham et al., 1990; Herkenham, 1995; Mailleux and Vanderhaeghen, 1992b), it seems plausible that the antiemetic effects are not receptor mediated, or, at least, are not mediated through the cannabinoid receptor.

Although this clinical success can be explained based on the animal data described above (Fride and Mechoulam, 1996a; Fernandez-Ruiz et al., 2000), the absence of psychoactive cannabinoid effects in juvenile animals and humans, will have to be reconciled with CBX receptor density assessments made post mortem from human fetal (last trimester) and neonatal brains. These data, although derived from a very limited sample, demonstrated densities in the fetal/neonatal brains, generally higher than (Glass et al., 1997) or similar to (Mailleux and Vanderhaeghen, 1992b) those in adult brains.

Aging

At the other end of the life cycle, a loss of cannabinoid receptors and receptor function were found in the basal ganglia of aging rats (>two years old) (Mailleux and Vanderhaeghen, 1992a; Romero et al., 1998). Since these structures play a pivotal role in motor function (see Sanudo-Pena and Fride, this book), this loss of cannabinoid receptors may explain some of the motor impairments frequently seen in advancing age (Mailleux and Vanderhaeghen, 1992a; Romero et al., 1998).

When additional CBX receptor-rich brain regions were investigated in senescent rats, decreases in receptor binding were found in the cerebellum, cerebral cortex and hypothalamus. No changes in CBX receptor binding in limbic areas and in the brainstem were detected. On the other hand, increases in CBX receptor mRNA were observed in the brainstem (Berrendero et al., 1998b).

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