Dopamine is a key neurotransmitter in the basal ganglia circuitry. This can be asserted from both physiological (Pollack, 2001) and therapeutic (Hornykiewicz, 1998) points of view. So, the activation of dopamine transmission in this circuitry is generally associated with an increase of movement, whereas the inhibition is followed by hypokinesia (Brooks, 2001). In fact, the basal ganglia disorder with the highest prevalence in the human population, Parkinson's disease, is a consequence of the progressive degeneration of nigrostriatal dopaminergic neurons, resulting in slowing of movement (bradykinesia), rigidity, and tremor (Dawson and Dawson, 2003). Cannabinoids are hypokinetic substances, thus producing motor depression and even catalepsy (see Romero et al., 2002; Fernandez-Ruiz et al., 2002), and it has been largely speculated that this hypokinetic effect of cannabinoids might be produced by reducing dopaminergic activity. This assumption is correct, but the role of CB1 receptors, which are not located on dopaminergic neurons (Herkenham, Lynn, de Costa, et al., 1991), has not been completely elucidated in regard to this effect. Meanwhile, the recent relationship of TRPV1 receptors with endocannabinoids (Zygmunt et al., 1999; Smart et al., 2000), as well as the location of these receptors on dopaminergic neurons (Mezey et al., 2000), have opened interesting novel aspects to discuss about the role of the endocannabinoid signaling in the basal ganglia (de Lago, de Miguel, et al., 2004), from both basic and clinical perspectives, aspects that will be addressed later in this text.
Function of the Endocannabinoid System in the Basal Ganglia
The abundant presence of CB1 receptors and their endogenous ligands in brain regions related to the control of movement, such as the caudate-putamen, the globus pallidus, the substantia nigra, and the cerebellum (Herkenham, Lynn, Little, et al., 1991; Mailleux and Vanderhaeghen, 1992;
Tsou, Brown, et al., 1998; Bisogno et al., 1999), suggests that the endocannabinoid system is strongly related to the control of movement (for reviews, see Consroe, 1998; Sañudo-Peña et al., 1999; Fernández-Ruiz et al., 2002; Romero et al., 2002). Plant-derived, synthetic, or endogenous cannabinoid agonists produce dose-dependent motor inhibition in both humans and laboratory animals (see Fernández-Ruiz et al., 2002, for a review). Thus, low doses reduce spontaneous activity, whereas high doses may even produce catalepsy (Consroe, 1998; Sañudo-Peña et al., 1999; Fernández-Ruiz et al., 2002; Romero et al., 2002). Similar results were obtained by administering inhibitors of endocannabinoid inactivation, the so-called indirect cannabinoid agonists (González, Romero, et al., 1999; Beltramo et al., 2000; Lastres-Becker, Hansen, et al., 2002; de Lago et al., 2002 and de Lago, Ligresti, et al., 2004). By contrast, the administration of SR141716, a selective antagonist of CBj receptors, reversed these hypokinetic effects and even produced by itself a certain degree of hyperlocomotion due to its function as inverse agonist (Compton et al., 1996). Another piece of evidence supporting the involvement of the CB1 receptor in the control of movement derives from the observation of motor anomalies in mice lacking the CB1 receptor gene (Ledent et al., 1999; Zimmer et al., 1999), despite certain conflicting observations between the two models of knockout mice developed.
Involvement of Dopamine in Motor Effects of Cannabinoids
The motor effects of cannabinoid-based compounds have an explanation in the capability of these substances to influence the activity of several neurotransmitters acting at the basal ganglia circuitry. Striatal projection GABAergic neurons and subthalamonigral glutamatergic neurons, both containing CBj receptors (Herkenham, Lynn, de Costa, et al., 1991; Mailleux and Vanderhaeghen, 1992; Tsou, Brown, et al., 1998), are the major neurochemical substrates for the action of cannabinoids. Cannabinoids block GABA reuptake, thus potentiating GABA action (Maneuf et al., 1996; Romero, de Miguel, et al., 1998), or inhibit glutamate release (Szabo et al., 2000). CB1 receptors located in GABAergic and glutamatergic neurons in the cerebellum have also been involved in motor effects of cannabinoids, in particular, with their effects on posture and balance, but the neurochemical basis for these effects has been poorly explored (see Iversen, 2003, for a review).
Dopamine transmission is also affected by cannabinoids in the basal ganglia circuitry. This can be concluded a priori from pharmacological studies reporting that cannabinoids potentiated reserpine-induced hypokinesia (Moss et al., 1981), mimicking dopaminergic antagonist-induced catalepsy (Anderson et al., 1996), while reducing amphetamine-induced hyperactivity (Gorriti et al., 1999). Despite the lack of selectivity of these two drugs, it appears obvious that both reserpine and amphetamine behaved in the basal ganglia circuitry mainly as dopamine-acting drugs, cannabinoids being able to influence the magnitude of these effects. Neurochemical studies also support the notion that cannabinoids are able to reduce the activity of nigrostriatal dopaminergic neurons (Romero, Garcia, et al., 1995 and Romero, de Miguel, et al., 1995; Cadogan et al., 1997; see Romero et al., 2002; van der Stelt and Di Marzo, 2003, for reviews), although some studies have shown increases rather than decreases (Sakurai-Yamashita et al., 1989; see Romero et al., 2002; van der Stelt and Di Marzo, 2003, for reviews).
In our laboratory, we found that anandamide reduced the activity of tyrosine hydroxylase in the caudate-putamen and the substantia nigra (Romero, Garcia, et al., 1995 and Romero, de Miguel, et al., 1995), where this enzyme is only located on dopamine-containing neurons, an effect that is compatible with the hypokinesia caused by anandamide and by other cannabinoid agonists (Romero, de Miguel, et al., 1995). However, the effects of anandamide on tyrosine hydroxylase activity were small and transient (Romero, Garcia, et al., 1995 and Romero, de Miguel, et al., 1995), possibly because CB1 receptors are not located on nigrostriatal dopaminergic neurons (Herkenham, Lynn, de Costa, et al., 1991). In concordance with this idea, cannabinoid agonists and antagonists failed to inhibit electrically evoked dopamine release in the striatum (Szabo et al., 1999), although the matter is not clarified because other studies proved opposite effects (increases vs. decreases) of cannabinoids on striatal dopamine release in vitro (see van der Stelt and Di Marzo, 2003, for details). The lack of CBj receptors in nigrostriatal dopaminergic neurons would support the observation that the changes in the activity of these neurons caused by cannabinoids in vivo were originated by previous changes in GABAergic influences reaching the substantia nigra (Maneuf et al., 1996; Romero et al.,
1998). As mentioned in the preceding text, striatal GABAergic projection neurons do contain CB1 receptors (Herkenham, Lynn, de Costa, et al., 1991) and their activation stimulates GABA transmission (Maneuf et al., 1996; Romero, de Miguel, et al., 1998), which would result in a greater inhibition of nigral dopamine neurons.
However, several recent discoveries have provided new elements to reevaluate the idea that endocannabinoid effects on dopamine transmission in the basal ganglia are indirect. It has been demonstrated that anandamide and some analogs but not classic cannabinoids are also able to behave as full agonists for the vanilloid TRPV1 receptors (Zygmunt et al., 1999; Smart et al., 2000). These receptors are molecular integrators of nociceptive stimuli, abundant on sensory neurons, but they have also been located in the basal ganglia circuitry, possibly on nigrostriatal dopaminergic neurons (Mezey et al., 2000), thus representing another target for the action of anandamide in the basal ganglia. We have recently reported that: (1) the activation of vanilloid-like receptors with their classic agonist, capsaicin, or with other potential ligands produced hypokinesia in rats (Di Marzo et al., 2001) and (2) the antihyperkinetic activity of several cannabinoid-based compounds, such as AM404, in rat models of hyperkinetic disorders, such as Huntington's disease, is dependent on their capability to activate vanilloid-like receptors rather than CBj receptors (Lastres-Becker, Hansen, et al., 2002 and Lastres-Becker, de Miguel, De Petrocellis, et al., 2003), despite earlier evidence that suggested a major role of CB1 receptors in the AM404 effects (Beltramo et al., 2000). More recently, we have also observed that the hypokinetic and dopamine-lowering effects of anandamide were reversed by capsazapine, an antagonist of vanilloid-like receptors. This effect has also been confirmed in vitro using perifused striatal fragments (de Lago, de Miguel, et al., 2004). Classic cannabinoids, such as A9-tetrahydrocannabinol (A9-THC), which do not bind to vanilloid-like receptors, are not able to produce the same effect. This is in concordance with the observation that anandamide reduced dopamine release from striatal slices (Cadogan et al., 1997), although the authors also found a dopamine-lowering effect after application of a classic cannab-inoid such as CP55940 (Cadogan et al., 1997).
Extending the above findings that mainly indicate the occurrence of a regulation by cannabinoids of dopaminergic activity in the basal ganglia, there are also proposals of a bidirectional regulation. Thus, in striatal GABAergic projection neurons, CB1 receptors colocalize with D1 (striatonigral pathway) or with D2 (striatopallidal pathway) receptors (Hermann et al., 2002), which allow additional postsynaptic interactions between endocannabinoids and dopamine at the level of G-protein and adenylyl cyclase signal transduction (Giuffrida et al., 1999; Meschler, Conley, et al., 2000 and Meschler, Clarkson, et al., 2000; Meschler and Howlett, 2001). In addition, there is also evidence of a regulation by dopaminergic D2 receptors of anandamide production in the striatum (Giuffrida et al.,
1999), which was interpreted by the authors as indicative of a role for the endocannabinoid system as an inhibitory feedback mechanism counteracting dopamine-induced facilitation of psychomotor activity (Giuffrida et al., 1999). This observation agrees with the results reported by Mailleux and Vanderhaeghen (1993) that endocannabinoid signaling in the basal ganglia is under a negative control exerted by dopamine, which might be relevant for Parkinson's disease (see the following text). The authors found that chronic administration with dopaminergic antagonists or the lesion of nigros-triatal dopaminergic neurons with 6-hydroxydopamine upregulated CB1 receptors (Mailleux and Vanderhaeghen, 1993). Similar observations were obtained in 6-hydroxydopamine-lesioned rats by our group (Romero et al., 2000) and others (Herkenham, Lynn, de Costa, et al., 1991; Gubellini et al., 2002). These observations were extended to other models of dopamine deficiency, such as MPTP-treated marmosets (Lastres-Becker, Cebeira, et al., 2001) and reserpine-treated rats (Di Marzo et al.,
2000). Interestingly, dopaminergic replacement with L-dopa in these models reversed endocannabinoid overactivity (Lastres-Becker, Cebeira, et al., 2001; Macarrone et al., 2003).
Therapeutic Implications of Cannabinoid-Dopamine Interactions in the Basal Ganglia
Based on these observations that strongly support endocannabinoids modulating the activity of dopamine and other neurotransmitters at the basal ganglia by acting at CB1 or TRPV1 receptors, it has been postulated that the pharmacological management of the endocannabinoid system, which might result in normalizing dopamine transmission, could be useful to alleviate motor symptoms in various basal ganglia disorders characterized by either dopaminergic degeneration or malfunctioning (for reviews, see Consroe, 1998; Sanudo-Pena et al., 1999; Fernandez-Ruiz et al., 2002; Romero et al., 2002, van der Stelt and Di Marzo, 2003). Most studies are preclinical and have provided the first experimental evidences using animal models (for a review, see Fernandez-Ruiz et al., 2002). However, in some cases, there are also some clinical trials presently in progress or already finalized (Sieradzan et al., 2001; Fox, Kellett, et al., 2002; Muller-Vahl et al., 2002, 2003; Zajicek et al., 2003).
Hyperkinetic Disorders: Huntington's Disease
Direct or indirect (inhibitors of endocannabinoid inactivation) agonists of CB1 receptors have been proposed as having therapeutic value in hyperkinetic disorders, such as Huntington's chorea (Lastres-Becker, Hansen, et al., 2002 and Lastres-Becker, de Miguel, De Petrocellis, et al., 2003; for a review, see Lastres-Becker, De Miguel, Fernandez-Ruiz, et al., 2003) or Gilles de la Tourette's syndrome (Muller-Vahl et al., 1998, 2002, 2003; for a review, see Muller-Vahl, 2003). In the latter, cannabinoid agonists have been demonstrated to reduce tics and improve behavioral problems in patients (for a review, see Muller-Vahl, 2003), but there are no data on the status of the endocannabinoid signaling in patients or in animal models of this disease. Additionally, there is no information on the neurochemical substrates underlying the beneficial effects of cannabinoids. By contrast, in Huntington's disease, analysis of postmortem brains revealed a marked loss of CB1 receptor binding in the substantia nigra, in the lateral part of the globus pallidus and, to a lesser extent, in the putamen (Glass et al., 1993, 2000; Richfield and Herkenham, 1994). A priori, this loss might be a mere side-effect caused by the degeneration of striatal medium-spiny GABAergic neurons that contain CB1 receptors. However, studies in patients affected by Huntington's disease at different stages of the disease have revealed that the loss of CB1 receptors occurs earlier than the loss of other neurotrans-mitter receptors, even in presymptomatic phases of this disease, before the appearance of major Huntington's disease symptomatology and when the cell death is minimal (grades 0 and 1) (Glass et al., 2000). This has also been found in different models of transgenic mice that express mutated forms of huntingtin, as in the human pathology (Denovan-Wright and Robertson, 2000; Lastres-Becker, Berrendero, et al., 2002). It is remarkable that these changes always occurred in the absence of the cell death, paralleling the data observed in the early grades of the human disease (Glass et al., 2000) when cell loss is minimal. All these observations, collectively, have supported the opinion that CB1 receptor losses might be involved in the pathogenesis of Huntington's disease.
Huntington's chorea may also be generated in rats after local or systemic injection of 3-nitropro-pionic acid, a toxin that selectively destroys striatal projection neurons. These animals also exhibited a marked loss of CB1 receptors and their endogenous ligands in the basal ganglia (Page et al., 2000; Lastres-Becker, Fezza, et al., 2001 and Lastres-Becker, Hansen, et al., 2002), compatible with the notion that endocannabinoid transmission in the basal ganglia becomes hypofunctional in Huntington's disease, which contributes to some extent to the hyperkinesia typical of this disease. In this case, the changes might be mere side effects caused by the strong death of striatal medium-spiny GABAergic neurons originated by the neurotoxin, a situation comparable to the pattern of cell loss that occurs in symptomatic stages of the human disease (grades 2 to 4). This GABA reduction is accompanied by a profound dopamine deficit in the basal ganglia (Lastres-Becker, Hansen, et al., 2002).
Despite the evidence of a decreased endocannabinoid transmission in the basal ganglia in Huntington's disease and the suggestion that CB1 receptor activation might play an instrumental role in this disease (Lastres-Becker, Bizat, et al., 2003), the administration of cannabinoid agonists in humans increased choreic movements in Huntington's disease (Müller-Vahl et al., 1998, 1999; Consroe, 1998). It is possible that this is related to the fact that only those cannabinoid-based compounds having an additional profile as TRPV1 receptor agonists were really effective in animal models of this disease (Lastres-Becker, de Miguel, De Petrocellis, et al., 2003), thus stressing a relevant role for TRPV1 rather than CBj receptors in this disease. This was the case of AM404, an inhibitor of the endocannabinoid transporter (Beltramo et al., 1997) that also exhibits affinity for the TRPV1 receptor (Zygmunt, Chuang, et al., 2000). This compound, in contrast with other transporter inhibitors devoid of TRPV1 receptor affinity, behaved as antihyperkinetic in Hunting-ton's disease animals (Lastres-Becker, Hansen, et al., 2002 and Lastres-Becker, de Miguel, De Petrocellis, et al., 2003), and this effect was presumably produced by the activation of TRPV1 receptors that originates a normalization of neurochemical deficits, including a rise in GABA and dopamine activities in the basal ganglia (Lastres-Becker, Hansen, et al., 2002 and Lastres-Becker, de Miguel, De Petrocellis, et al., 2003). These effects did not occur in normal rats (Lastres-Becker, Hansen, et al., 2002 and Lastres-Becker, de Miguel, De Petrocellis, et al., 2003).
Hypokinetic Disorders: Parkinson's Disease
Cannabinoid-based compounds might also be useful in other basal ganglia disorders more directly related to a disturbance of dopaminergic transmission. This is the case of the dopamine deficiency typical of Parkinson's disease. In this disorder, CB1 receptor agonists or antagonists have both been proposed to be of therapeutic value, alone or as coadjuvants, to alleviate different motor symptoms characteristic of this disease (Brotchie, 2000; Romero et al., 2000; Di Marzo et al., 2000; Lastres-Becker, Cebeira, et al., 2001; Fox, Henry, et al., 2002). In particular, CBj receptor agonists have been proposed for: (1) the reduction of tremor associated with an overactivity of the subthalamic nucleus (Sañudo-Peña et al., 1999), (2) the reduction or delay of the dyskinetic states associated with long-term therapy of dopaminergic replacement with L-dopa (Sierazdan et al., 2001), and (3) the protection against dopaminergic cell death in the case of those compounds having antioxidant properties (Lastres-Becker et al., 2005). By contrast, the blockade of CB1 receptors with rimonabant (SR141716) or other selective antagonists has been proposed for its capability to reduce bradykinesia (Romero et al., 2000; Lastres-Becker, Cebeira, et al., 2001; Gubellini et al., 2002; Fernández-Espejo et al., 2004) and also L-dopa-induced dyskinesia (Brotchie, 2000, 2003). The evidence for the usefulness of CB1 receptor antagonists in this disease is based on studies reporting that dysfunctions of nigrostriatal dopaminergic neurons, such as those caused by reserpine (Di Marzo et al., 2000) or by dopaminergic antagonists (Mailleux and Vanderhaeghen, 1993), or the degeneration of these neurons caused by the local application of 6-hydroxydopamine (Mailleux and Vanderhaeghen, 1993; Romero et al., 2000; Gubellini et al., 2002; Fernández-Espejo et al., 2004) or MPTP (Lastres-Becker, Cebeira, et al., 2001) are associated with an increased endocannabinoid transmission in the basal ganglia (see preceding text). This suggests the occurrence of an unbalance between dopamine and endocannabinoids at the basal ganglia that supports the usefulness of CB1 receptor antagonists in this disease. In agreement with this, the classic dopaminergic replacement therapy with L-dopa reversed endocannabinoid anomalies (Lastres-Becker, Cebeira, et al., 2001; Maccarrone et al., 2003).
Despite this evidence, the first pharmacological studies that have examined the capability of rimonabant to reduce hypokinesia in animal models of Parkinson's disease have offered conflicting results (Di Marzo et al., 2000; Meschler et al., 2001). It is possible that the blockade of CB1 receptors might be effective only at very advanced phases of the disease. In this sense, recent evidence provided by Fernández-Espejo and co-workers (2004) is in favor of this option, which presents an additional advantage as it would allow an antiparkinsonism compound in a stage of the disease when the classic dopaminergic therapy has generally failed. In addition, one must also consider the implication of TRPV1 receptors, in view of their recently demonstrated role in regulating dopamine release from nigral neurons (de Lago, de Miguel, et al., 2004), as well as the evidence of neuroprotective effects ascribed to cannabinoid agonists in this (Lastres-Becker et al., 2005) and in other neurodegenerative diseases (for a review, see Grundy et al., 2001; Mechoulam et al., 2002; van der Stelt et al., 2002), effects that would not be directly related to the influence of the endocannabinoid signaling system on dopamine transmission.
There are other neurological diseases where the manipulation of endocannabinoid signaling has been proposed as therapeutically promising, and where these therapeutic effects might also be related to an influence on dopamine transmission (for a review, see Fernandez-Ruiz et al., 2002). These disorders are not directly related to basal ganglia degeneration but are associated with dysfunction in several neurotransmitters in this area, thus resulting in motor deterioration.
One relevant case is multiple sclerosis whose origin is immune but progresses with neurological deterioration mainly affecting the motor system (Pertwee, 2002; Baker and Pryce, 2003). Canna-binoid agonists have been proposed as clinically promising in this disease for the management of motor-related symptoms such as spasticity, tremor, ataxia, and others (for reviews, see Pertwee, 2002; Baker and Pryce, 2003). Thus, Baker et al. (2000) reported that plant-derived, synthetic, and endogenous cannabinoid agonists were able to reduce some signs (spasticity and tremor) in a mouse model of multiple sclerosis. They also demonstrated that these effects were mediated by cannabinoid CBj and, to a lesser extent, CB2 receptors (Baker et al., 2000). Using this mouse model, they have also described antispastic effects of compounds that are able to inhibit the process of termination of the biological action of endocannabinoids (Baker et al., 2001; Brooks et al., 2002; de Lago, Ligresti, et al., 2004). These data were concordant with the observation of increased contents of endocannabinoids in the brain and spinal cord of these animals (Baker et al., 2001). Using a rat model of multiple sclerosis, other authors (Lyman et al., 1989; Wirguin et al., 1994) have also demonstrated that a chronic administration of plant-derived cannabinoids may reduce or delay the incidence and severity of clinical signs in these rats.
This pharmacological evidence obtained in animal models has provided solid experimental support to previous anecdotal, uncontrolled, or preclinical data that suggested a beneficial effect for marijuana when smoked by multiple sclerosis patients to alleviate such symptoms as spasticity, dystonia, tremor, ataxia, and pain (for a review, see Consroe, 1998). In this line, a clinical trial has recently finalized in the U.K. using oral administration of placebo, cannabis extract, or A9-THC in a population of 667 patients with stable multiple sclerosis and muscle spasticity. The results of this trial have suggested that cannabinoids did not have a beneficial effect on spasticity in multiple sclerosis patients but increased the patient's perception of improvement of other signs including pain (Zajicek et al., 2003).
Despite the progress in the pharmacological evaluation of cannabinoid-based medicines in multiple sclerosis both in patients and animal models, there are no data on the possible changes in CBj and CB2 receptors in the postmortem brain of patients with multiple sclerosis, whereas only a few studies have examined the status of the endocannabinoid transmission in animal models of this disease (Baker et al., 2001; Berrendero et al., 2001). Thus, as mentioned above, Baker and co-workers reported an increase of endocannabinoid levels in the brain and the spinal cord in the mouse model of multiple sclerosis (Baker et al., 2001) that was interpreted by these authors as indicative of an endocannabinoid influence in the control of some symptoms of multiple sclerosis in an environment of existing neurological damage (see Baker and Pryce, 2003, for a review). In our laboratory, using the rat model of this disease, we reported a decrease of CB1 receptor binding and mRNA levels (Berrendero et al., 2001), although the decreases in CB1 receptors were mainly circumscribed to the basal ganglia (lateral and medial caudate-putamen) and to a lesser extent to cortical regions, which was related to the fact that motor deterioration is one of the most prominent neurological signs in these rats (Berrendero et al., 2001) and also in the human disease (for a review, see Baker and Pryce, 2003). We have also demonstrated that this decrease was accompanied by a reduction of endocannabinoid levels that may be recorded also in other brain structures (Cabranes et al., 2005). Based on this fact, we hypothesized that the changes in OB, receptors and their ligands in the basal ganglia might be associated with disturbances in several neurotransmitters, in particular in dopamine transmission, acting at this circuitry. If this were the case, the well-known effects of cannabinoid agonists on these neurotransmitters might underlie the improving effects of these compounds in motor symptoms of multiple sclerosis (see Fernandez-Ruiz et al., 2002, for a review). However, our hypothesis failed because we did not record any changes in dopamine, serotonin, GABA, or glutamate in the basal ganglia of EAE rats (Cabranes et al., 2005). So, there was no option for examining whether cannabinoid administration might influence these neurotransmitters in the rat model of multiple sclerosis. This also indicates that the endocannabinoid signaling in the basal ganglia has an important relevance in these rats, as the changes in receptors (Berrendero et al., 2001) and the changes in ligands (Cabranes et al., 2005) represent the only transmitter disturbance associated with motor deterioration in these animals. Assuming this particular relevance, it was expected that the pharmacological manipulation of this system might be beneficial in the rat model of multiple sclerosis, as previous studies revealed (Lyman et al., 1989; Wirguin et al., 1994). In this sense, we recently analyzed the effects of various inhibitors of endocannabinoid transport that were capable of elevating endocannabinoid levels and found that they were able to reduce the neurological decline typical of these rats, although we also documented a relevant involvement of TRPV1 receptors in these effects (Cabranes et al., 2005).
A second disorder is Alzheimer's disease, which, as with multiple sclerosis, is not a disorder of the basal ganglia, but where extrapyramidal signs, possibly caused by the degeneration of glutamate cortical afferents to the caudate-putamen, are frequently observed (for a review, see Kurlan et al., 2000). No data exist on the status of endocannabinoid transmission in the basal ganglia or in other brain regions in animal models of this disease. However, studies with postmortem brain regions of patients affected by this disease have revealed a significant loss of 03, receptors that seem to be notably circumscribed to the basal ganglia, in particular to the caudate nucleus, medial globus pallidus, and substantia nigra (Westlake et al., 1994). Brain regions other than the basal ganglia were less affected or did not exhibit any changes for the 03, receptor, except the hippocampus, which also showed significant reductions (Westlake et al., 1994). However, it is important to remark that the authors considered their results related more to increasing age rather than to an effect selectively associated with the pathology characteristic of Alzheimer's disease (Westlake et al., 1994). Also using postmortem tissue from Alzheimer's patients, Benito et al. (2003) recently reported a significant induction of CB2 receptors in activated microglia that surrounds the senile plaques, which would suggest both a role of this receptor subtype in a part of the pathogenesis in this disease and a potential therapeutic application of selective compounds targeting this receptor. The latter would be related to recent evidences concerning the possible utilization of cannabinoid-based compounds in Alzheimer's disease due to their potential as neuroprotectants (Milton, 2002; Iuvone et al., 2004), which adds to previous evidence of the symptomatic role of nabilone or other cannabinoid agonists in reducing anorexia and improving behavioral disturbances in Alzheimer's patients (Volicer et al., 1997).
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