Effects on Development 651proenkephalin-mRNA levels in rat fetuses at GD16 and GD18 in motor (caudate-
putamen and cerebellum), limbic (septum nuclei), and diencephalic (thalamus
and hypothalamus) structures (Pérez-Rosado et al. 2000). In this study, the varia-
tions observed after GD21 showed a marked sexual dimorphism with increases in
female fetuses and reductions in male fetuses in most of the brain regions analyzed
(Pérez-Rosado et al. 2000). Similar results were obtained for two other peptide pre-
cursors, proopiomelanocortin (POMC) and prodynorphin, whose levels of mRNA
transcripts also increased in female fetuses but were reduced in male fetuses in
several brain regions (Pérez-Rosado et al. 2002).
Thesealterationsinthedevelopmentofopioidergicneurotransmissionarelikely
to produce important long-lasting functional changes in these neurons in the adult
brain (Kumar et al. 1990; Vela et al. 1998; Corchero et al. 1998). Indeed, it has been
found that adult animals that had been perinatally exposed to cannabinoids exhibit
alterations in neuroendocrine control (Kumar et al. 1990), pain sensitivity (Vela et
al. 1995), and reward processes (Vela et al. 1998; González et al. 2003). Kumar et al.
(1990) reported an increase in both Met-enkephalin andβ-endorphin immunore-
activity in the hypothalamus of adult rats perinatally exposed to cannabinoids.
This effect could be related to changes in the synthesis and/or release of several
anterior pituitary hormones (Dalterio 1986; Murphy et al. 1990, 1995).
Vela et al. (1995) observed that adult animals perinatally exposed to cannabi-
noids exhibited higher tail-flick latencies at immature ages and were tolerant to the
analgesic effect of morphine when they became adults. These effects are sexually
dimorphic since both were evident in males but not in females. Animals that had
been perinatally exposed to∆^9 -THC also exhibited signs of opiate vulnerability
(Vela et al. 1995, 1998; Corchero et al. 1998; Rubio et al. 1998), although the response
was again sexually dimorphic. Thus, some somatic signs of withdrawal were ev-
ident in rats perinatally exposed to∆^9 -THC after the administration of a single
dose of naloxone at day 24 after birth, which coincided with the end of cannabi-
noid exposure (Vela et al. 1995). These withdrawal signs only appeared in males
(Vela et al. 1995). In contrast, adult females, but not males, self-administered mor-
phine more readily if they had been perinatally exposed to∆^9 -THC in a fixed-ratio
schedule (Vela et al. 1998). A possible explanation may be that, after treatment,
females, but not males exhibited higherμ-opioid receptor binding density in some
areas directly or indirectly related to drug reinforcement (Vela et al. 1998), and
that in some of these regions the expression of proenkephalin gene decreased in
females, but not in males (Corchero et al. 1998). In addition, following perinatal
exposure to∆^9 -THC, adult females, but not males, exhibited higher plasma levels
of stress hormones, an effect that has also been reported to be an indicator of opiate
vulnerability (Rubio et al. 1995). The results obtained using a fixed-ratio schedule
(Vela et al. 1998) contrast with those using a progressive ratio schedule, which
suggest that perinatal∆^9 -THC exposure does not affect the reinforcing efficacy of
morphine and food (González et al. 2003). According to these two schedules we
may conclude that when rats are forced to work harder for reward, the response to