648 J.A. Ramos et al.
3
Effects of Perinatal Exposure to Cannabinoids
on Several Neurotransmitters Systems
Endocannabinoids might act as epigenetic factors, through the activation of
cannabinoid receptors which emerge early in development. As to plant-derived
cannabinoids, by mimicking the effects of natural ligands of cannabinoid recep-
tors these would interfere with the sequence of events that results in the expression
of several genes involved in brain development and, in this way, modify the matu-
ration of several neurotransmitter systems (Fernández-Ruiz et al. 1992, 1994, 1996,
1999, 2000).
Also, it is possible that the usual pattern of expression of the endogenous
cannabinoid system could be altered by these cannabinoids during brain devel-
opment (Fernández-Ruiz et al. 1999, 2000). Thus, an acceleration or delay in the
expression of the genes implicated in the synthesis of endocannabinoids or their
receptors during a particular stage of development could well prevent the en-
docannabinoid system from functioning normally. Such abnormal functioning
might also result from an increase or a decrease in endocannabinoid or cannabi-
noid receptor concentrations or from a modification in the activity of cannabinoid
receptor signaling pathways. Such mechanisms may underlie reported behavioral
alterations in adult mice that had been perinatally exposed to anandamide (de-
creased open-field activity, catalepsy, hypothermia, hypoalgesia, and tolerance to
cannabinoid challenges) (Fride and Mechoulam 1996a,b), as well as the interrup-
tion of suckling behavior with subsequent inhibition of neonatal growth observed
in newborn mice in response to CB 1 receptor blockade (Fride et al. 2001).
To establish the effects of perinatal exposure to∆^9 -THC, studies were con-
ducted in rodents using doses that produce concentrations of this cannabinoid
in the body similar to those found in marijuana consumers. The effects observed
depended on when the drug treatment was initiated and on the dose used (Dalte-
rio 1986; Fernández-Ruiz et al. 1992, 1994, 1996). These studies demonstrated that
cannabinoids may behave as epigenetic factors, modifying normal development
of neurotransmission and, most likely, producing neurobehavioral disturbances.
Thus, adult animals perinatally exposed to cannabinoids exhibited long-term alter-
ations in male copulatory behavior (Dalterio 1980), open-field activity (Navarro et
al. 1994), learning ability (Dalterio 1986), stress response (Mokler et al. 1987), pain
sensitivity (Vela et al. 1995), social interaction and sexual motivation (Navarro et al.
1996), drug-seeking behavior (Vela et al. 1998), and neuroendocrine disturbances
(Dalterio and Barker 1979; Murphy et al. 1990, 1995), as well as other changes (for
review see Dalterio 1986; Fernández-Ruiz et al. 1992, 1994, 1996).
Most of these neurobehavioral effects presumably stemmed from changes in the
development of several neurotransmitter systems caused by exposure to cannabi-
noids during critical prenatal and early postnatal periods of brain development.
A large number of studies have demonstrated effects of cannabinoids on the mat-
uration of dopamine (DA) (Fernández-Ruiz et al. 1992, 1994, 1996; Walters and
Carr 1988; García-Gil et al. 1998), serotonin (5-HT) (Molina-Holgado et al. 1997),