Effects on Development 649γ-aminobutyric acid (GABA) (García-Gil et al. 1999b), and opioid peptide systems
(Kumar et al. 1990; Corchero et al. 1998; Vela et al. 1998).
3.1
Dopamine
The effects of∆^9 -THC on the development of specific brain dopaminergic path-
ways appear before the complete differentiation and maturation of dopaminergic
projections into their target areas, in particular during the final part of gestation
and first week after birth (Bonnin et al. 1996). The activity of tyrosine hydroxylase
(TH) represents the rate-limiting step in DA synthesis. This enzyme is present in
the growing axons before they make contact with their target neurons and seems
to play an important role, together with active receptors located on the target
neurons, in the formation of connections between neurons (Insel et al. 1995). In
rats, perinatal exposure to∆^9 -THChasbeenfoundtocauseamarkedriseinTH
gene expression in the brains of fetuses at GD14, in parallel with a pronounced
increase in the levels and activity of this enzyme (Bonnin et al. 1996). These re-
sults have been verified in vitro using cultured mesencephalic neurons from fetal
brains at GD14 (Hernández et al. 1997). Cultured cells obtained from fetuses that
had been exposed to∆^9 -THCdailyfromday5ofgestationexhibitedhigherTH
activity compared with cells obtained from vehicle-exposed fetuses (Hernández et
al. 2000).
These data suggest that interference of plant-derived cannabinoids with the
sequence of events in which the expression of TH gene is involved during brain
development might contribute to the abnormal pre- and postnatal development
of TH-containing neurons themselves and/or of the different neurons with which
they make contact (Walters and Carr 1988; Fernández-Ruiz et al. 1992, 1994, 1996).
Interruption of the exposure of pups to cannabinoids as a consequence of
weaning led to an apparent normalization of most of the dopaminergic indices
that had altered during development (Bonnin et al. 1996; Rodríguez de Fonseca
et al. 1991; Navarro et al. 1996). However, at adulthood, animals that had been
perinatally exposed to∆^9 -THC, although mostly having similar basal indices of
dopaminergic activity to those of controls (Navarro et al. 1996), exhibited an
abnormal ability to respond to a variety of drugs that affect key processes of
dopaminergic neurotransmission. Thus, the differences observed in the response
of∆^9 -THC-exposed animals to experimental challenges, using D 1 and D 2 antago-
nists,α-methyl-p-tyrosine combined with reserpine, amphetamine, or NSD1015,
support the existence of irreversible, although silent, changes in the adult function-
ality of dopaminergic neurons due to the early contact with∆^9 -THC (García-Gil et
al. 1996, 1999a,b).
A sexual dimorphism is evident in the sensitivity of maturing dopaminergic
neurons to∆^9 -THC exposure. This is already apparent at fetal ages (Bonnin et
al. 1996), but is particularly evident at early postnatal, immature, and adult ages
(Fernández-Ruiz et al. 1992, 1994, 1996; Navarro et al. 1996; García-Gil et al. 1998).
Usually, the changes are especially marked and constant in male offspring, whereas