Cannabinoid Control of Motor Function at the Basal Ganglia 485enables endocannabinoids to directly influence presynaptic events, such as synthe-
sis, release, or reuptake (see Fernández-Ruiz et al. 2002 for a review). In contrast,
dopaminergic neurons do not contain CB 1 receptors (Herkenham et al. 1991b).
However, these receptors are abundantly expressed in the caudate-putamen, which
is innervated by dopamine-releasing neurons (Herkenham et al. 1991a; Mailleux
and Vanderhaeghen 1992a; Tsou et al. 1998a), thus allowing an indirect interaction.
In addition, recent data showing that VR1 receptors present in the basal ganglia are
likely located in nigrostriatal dopaminergic neurons (Mezey et al. 2000) open up
the possibility that some cannabinoids may have a direct effect on dopaminergic
transmission (de Lago et al. 2004b).
1.2.1
γ-Aminobutyric Acid
The involvement of GABAergic transmission in motor effects of cannabinoids has
been documented in several studies (for a review see Fernández-Ruiz et al. 2002).
We reported that the blockade of GABAB, but not GABAA, receptors attenuated
most of the signs of motor inhibition caused by the administration of cannabinoid
agonists in rats (Romero et al. 1996b). This is consistent with results obtained by
Miller and Walker (1995, 1996) in a series of electrophysiological studies. These
indicated that cannabinoids can modulate GABA release in vivo in the globus pal-
lidus and substantia nigra. However, the effects were very modest. More recently,
neurochemical studies demonstrated that the administration of cannabinoids did
not affect GABA synthesis or release in the basal ganglia of naïve animals (Maneuf
et al. 1996; Romero et al. 1998a; Lastres-Becker et al. 2002a), although cannabi-
noids were effective in increasing both processes in animals with lesions of striatal
GABAergic neurons of the sort that occur in HD (Lastres-Becker et al. 2002a).
In addition, the stimulation of CB 1 receptors located on axonal terminals of stri-
atal GABAergic neurons resulted in an inhibition of GABA reuptake in globus
pallidus slices (Maneuf et al. 1996) or substantia nigra synaptosomes (Romero
et al. 1998a), and hence in the potentiation of GABAergic transmission. These
observations are concordant with the finding by Gueudet et al. (1995) that the
blockade of CB 1 receptors in striatal projection neurons with SR141716 reduced
inhibitory GABAergic tone, thereby allowing the firing of nigrostriatal dopamin-
ergic neurons. The authors concluded that endocannabinoid transmission might
increase the action of striatal GABAergic neurons in the substantia nigra, produc-
ing a decrease of the stimulation of nigral dopaminergic neurons (Gueudet et al.
1995). However, other studies have reported opposite effects. Thus, Tersigni and
Rosenberg (1996) reported an increase by cannabinoids in the activity of nigral
neurons without any alteration of GABAergic activity. Other authors have observed
inhibition rather than stimulation of GABAergic neurons by cannabinoid agonists
via a presynaptic action in the substantia nigra (Chan et al. 1998) or the striatum
(Szabo et al. 1998). Therefore, further studies will be required to elucidate the
complex interaction of cannabinoids with GABAergic transmission in the basal
ganglia.