Interactions Between Cannabinoids And Dopamine At The Hypothalamic Level

Dopamine is also an important regulatory neurotransmitter in the neuroendocrine hypothalamus, where it belongs to the group of different hypothalamic factors that, released in the median eminence to the portal-hypophysial blood supply, are able to reach the anterior pituitary to control the synthesis and release of anterior pituitary hormones, mainly prolactin (for a review, see Ben-Jonathan and Hnasko, 2001). Therefore, it represents a target neurotransmitter for those compounds, either endogenous or exogenous, that interfere with anterior pituitary hormones. This is the case with cannabinoids, which are able to decrease prolactin and gonadotrophin secretion while increasing corticotrophin release in laboratory animals (Rettori et al., 1988; Romero et al., 1994; Wenger et al., 1994; Weidenfeld et al., 1994; Fernández-Ruiz et al., 1997; de Miguel et al., 1998) and also in humans (for a review, see Brown and Dobs, 2002).

Function of the Endocannabinoid System in the Neuroendocrine Hypothalamus

As mentioned in the preceding text, classic cannabinoids, such as A9-THC, and also endogenous cannabinoids, such as anandamide, decreased the release of most of anterior pituitary hormones, including prolactin (Rettori et al., 1988; Romero et al., 1994; Wenger et al., 1994; Fernández-Ruiz et al., 1997; de Miguel et al., 1998; for reviews, see Murphy et al., 1998; Wenger and Moldrich, 2002), luteinizing hormone (Murphy et al., 1990, 1994; Fernández-Ruiz et al., 1997; de Miguel et al., 1998; for reviews, see Murphy et al., 1998; Wenger and Moldrich, 2002), growth hormone (Rettori et al., 1988; for reviews, see Murphy et al., 1998; Wenger and Moldrich, 2002), thyrotropin (Hillard et al., 1984; for a review, see Murphy et al., 1998), and, to a lesser extent, follicle-stimulating hormone (Fernández-Ruiz et al., 1997; de Miguel et al., 1998; for a review, see Murphy et al., 1998; Wenger and Moldrich, 2002), with only the exception of corticotrophin, which was stimulated by cannabinoids (Weidenfeld et al., 1994; for a review, see Murphy et al., 1998). This occurred mainly in male animals, the effects in females being slightly different and depending on the ovarian cycle (Bonnin et al., 1993; Rodríguez de Fonseca et al., 1994; Scorticati et al., 2003). Numerous data have demonstrated that these effects likely originate through the capability of cannabinoids to interfere with hypothalamic factors controlling anterior pituitary hormones, among them the tubero-infundibular dopaminergic system but also other neurotransmitters (Rodríguez de Fonseca et al., 1992; Bonnin et al., 1993; Murphy et al., 1994; de Miguel et al., 1998; for reviews, see Murphy et al., 1998; Wenger and Moldrich, 2002). These effects are produced through the activation of CB1 receptors, as revealed by experiments with selective antagonists for this receptor subtype (Fernández-Ruiz et al., 1997; de Miguel et al., 1998). These receptors are present in several hypothalamic nuclei, in particular in the ventromedial hypothalamic nucleus (Herkenham, Lynn, Little, et al., 1991; Fernández-Ruiz et al., 1997; Romero, Wenger, et al., 1998). However, a direct action of cannabinoids on anterior pituitary cells seems to be also possible. This is based on the demonstration of endocannabinoid synthesis (González, Manzanares, et al., 1999) and the presence of CB1 receptor binding (Lynn and Herkenham, 1994), gene expression (González, Manzanares, et al., 1999), and immunoreactivity (Wenger, Fernandez-Ruiz, et al., 1999; González et al., 2000) in the anterior pituitary gland. The immunoreactivity for the CB1 receptor is located in prolactin- and luteinizing-hormone-containing cells (Wenger, Fernandez-Ruiz, et al., 1999; González et al., 2000). In addition, in vitro experiments have revealed that cannabinoid agonists were able to exert direct effects on the release of different anterior pituitary hormones from cultured cells or pituitary explants (Murphy et al., 1991; Rodríguez de Fonseca et al., 1999). In any case, independently of the mechanisms used by cannabinoids to alter anterior pituitary hormone secretion, direct effects, and modulation of hypothalamic influences to the anterior pituitary, it appears well demonstrated that these compounds are able to control the circulating levels of these hormones and then to affect the activity of different peripheral glands.

Involvement of Dopamine in Neuroendocrine Effects of Cannabinoids

In a similar way as with basal ganglia, the involvement of dopamine in the neuroendocrine effects of cannabinoid agonists is indirect, as it does not appear that CBj receptors identified in the medial basal hypothalamus are located in tuberoinfundibular dopaminergic neurons. In fact, the phenotype of neurons containing CB1 receptors in this region has remained elusive. It is known that (1) these neurons are intrinsic to the hypothalamus because the deafferentation of this structure does not accompany any decrease in the density of CB1 receptors (Romero, Wenger, et al., 1998); (2) CB1 receptor density is scarce but detectable in the arcuate nucleus (Fernández-Ruiz et al., 1997) and it is also present in other nondopaminergic structures of the hypothalamus, such as the paraventricular and periventricular nuclei, and the medial preoptic area (Fernández-Ruiz et al., 1997); and (3) the cell bodies of these neurons seem to be exclusively located in the ventromedial hypothalamus nucleus, as this structure, though exhibiting scarce specific binding for CB1 receptors (Herkenham, Lynn, Little, et al., 1991), excels by a significant amount of mRNA transcripts for this receptor that are not present in other hypothalamic structures (Mailleux and Vanderhaeghen, 1992). Tuberoinfundibular dopaminergic neurons would adjust the two first conditions but not the last one; therefore, it is little probable that they contain CB1 receptors. These receptors might be better located in GABAergic neurons (de Miguel et al., 1998) or, alternatively or complementary, in opioidergic neurons (Drolet et al., 2001), which are also intrinsic to the hypothalamus. Opioidergic neurons are located in the ventromedial hypothalamus nucleus (Drolet et al., 2001), correlating with the presence of CB1 receptor-mRNA (Mailleux and Vanderhaeghen, 1992). In addition, cannabinoids are able to modify the gene expression for opioid peptides in the hypothalamus (Corchero et al., 1999), which would support the option of location of CB1 receptors in opioidergic neurons. However, no double-labeling studies have been performed yet in order to clarify this question. In any case, it appears clear that the hypothalamic neurons containing CB1 receptors would be intimately connected with dopaminergic ones, as the activation of these receptors have been reported to significantly activate hypothalamic dopamine inputs, as reflected by an increase in tyrosine hydroxylase activity (Romero et al., 1994), the contents of dopamine and metabolites (Rodríguez de Fonseca et al., 1992; Bonnin et al., 1993; Fernández-Ruiz et al., 1997; Arévalo et al., 2001), and dopamine turnover (Rodríguez de Fonseca et al., 1992; Scorticati et al., 2003). Therefore, it can be concluded that the effects of cannabinoids on prolactin secretion were mediated by an activation of intrahypothalamic dopaminergic neurons, although the effects were not directly exerted on these neurons (Fernández-Ruiz et al., 1997) and involved alterations in other hypothalamic neurotransmitters (de Miguel et al., 1998; Corchero et al., 1999; Scorticati et al., 2003).

Therapeutic Implications of Cannabinoid-Dopamine Interactions in the Hypothalamus

This is probably another interesting aspect of the cannabinoid-dopamine interaction, because dysfunctions in the activity of dopaminergic neurons in the medial basal hypothalamus, among other causes, have been involved in the development of several types of pituitary disorders, including the development of prolactin-secreting adenomas (for a review, see Colao et al., 2002). In this sense, Di Marzo and co-workers (Pagotto et al., 2001) and our group (González et al., 2000) have recently reported the occurrence of changes in hypothalamic-pituitary endocannabinoid activity associated with the development of pituitary tumors. Unfortunately, there are no relevant pharmacological data yet supporting the observation that the interactions between cannabinoids and dopamine at the hypothalamic-pituitary level might have therapeutic applications. However, based on the effects of cannabinoids on dopamine, it should be expected that cannabinoid agonists might be useful to attenuate the dopaminergic deficiency accompanying the hyperprolactinemic disorders (see Colao et al., 2002, for a review). This hypothesis will have to be explored in the future.

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