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Endogenous cannabinoids and brain development
S.15. Cannabinoids: Receptors and treatment
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Several novel types of receptors for cannabinoids have been proposed (Pertwee and Ross, 2002). One of these is an SR141716Asensitive non-CB1, non-CB2-, non-vanilloid-receptor that may be present in mesenteric arteries. Ligands for this putative receptor include anandamide (agonist) and the non-psychotropic plant cannabinoid, cannabidiol (antagonist), but exclude 2-AG and established non-eicosanoid CB 1/CB2 receptor agonists. Other novel receptors to have been proposed are (i) SR141716A-insensitive non-CB1, non-CB2-, non-vanilloid-receptors that appear to be expressed in some brain areas of CB1 knockout mice and to be activated by R-(+)-WIN55212 and anandamide but not by THC or CP55940 and (ii) SR144528-sensitive non-CB2 caunabinoid receptors on which palmitoylethanolamide but not anandamide may act to relieve inflammatory pain ('CB2-1ike' receptors). There is also evidence from experiments with the mouse isolated vas deferens that submicromolar concentrations of cannabidiol attenuate the ability of R-(+)-WlN55212, anandamide and CP55940 in inhibit evoked transmitter release in this tissue (Thomas et al., 2002).
References [1] [2] [3] [4]
•
Pertwee, R.G. (2000) Exp. Opin. Invest. Drugs 9: 1553-1571. Pertwee, R.G. (2001) Prog. Neurobiol. 63:569~611. Pertwee, R.G. (2002) Pharmacol. Ther. In press. Pertwee, R.G. and Ross R.A. (2002) Prostaglandins Leukotrienes and Essential Fatty Acids. In press.
Endogenous cannabinoids and brain development
J. Feruandez-Ruiz 1, M. Hernandez 2, M. Gomez 1, J.A. Ramos 1.
1Universidad Complutense, Bioquimica y Biologia Molecular, Madrid, Spain; 2Universidad Complutense, Psicobiologia, Madrid, Spain New data strengthen the idea of a prominent role for endocannabinoids in the modulation of a wide variety of neurobiological functions. Among these, two functions, control of movement and antinociception, have attracted the maximal interest because of the possibility that cannabinoids and related compounds might be used with a therapeutic purpose. However, the functions of endocannabinoids in the brain, and also in the periphery, are large and involve, not only the adulthood, but also the period of prenatal and postnatal development, when endocaunabinoids have been reported to play a role in specific processes of brain development (see 1,2 for review). This finding is based on a three-fold evidence. The first evidence deals with the location of elements of the endocarmabinoid system, ligands and/or receptors, in the developing brain (3,4). Cannabinoid CB1 receptors emerge early during development and their pattem of ontogenic maturation differs from that reported for most of classic neurotransmitter receptors (1-3). The most intriguing fact is that these elements, particularly the receptors, are located transiently in atypical regions, where they are not located in the adult brain (3). For instance, CB1 receptor binding is highly concentrated in white matter areas during prenatal and early postnatal period, in particular in transverse or commissural fiber tracts, such as the corpus callosum, the anterior commissure, the stria terminalis and others (3). In addition, CB1 receptor mRNA is highly expressed in regions involved in neuronal and glial cell proliferation, such as the subventricular regions of the forebrain (3). All these observations are compatible with the suggestion that endocannabinoid
ligands and their receptors present in the developing stages might play a role in specific events of brain development as neuronal proliferation and migration, axonal elongation, synaptogenesis and/or myelinogenesis, which would be different to the roles assigned to this signaling system in the adult brain. In fact, the location of CB1 receptors, as well as the effects produced by their activation, in the regions where they are highly concentrated in adulthood, such as the basal ganglia or the regions involved in the control of nociception, is an event that occurs late in the brain development (see key refs in 2). A second evidence derives from numerous studies which have reported that the administration of plant-derived or synthetic caunabinoids, compounds that are able to activate cannabinoid CB1 receptors, during either gestational or neonatal periods affects the development of several neurotransmitters, particularly two of them, dopamine and opioid peptides (1,2). In vitro studies have also reported that, during prenatal development, CB1 receptors are present in neuronal cells, such as mesencephalic tyrosine hydroxylase (TH)-containing neurons, where they are not present in the adult brain (5). The activation of these receptors is accompanied by an increase of the expression of TH gene, which is a key gene for the development of dopaminergic neurons and also for the maturation of neurons expressing other neurotransmitters (5). As a result of these neurotransmitter disturbances elicited by the perinatal exposure to cannabinoids, when animals matured, they exhibited deterioration in a variety of functions, in which these neurotransmitters are involved, such as motor activity, pain sensitivity, drug-seeking behavior, social interaction, sexual behavior, learning ability, stress response and neuroendocrine regulation (see 1,2 for review). The last evidence is the suggested role for the endocannabinoid system in neuron-glia cell interaction, which is a crucial event during brain development. In vitro studies (4) have demonstrated that glial cells express cannabinoid receptors (CB1 subtype or others) and their activation seems to play a role in specific functions of these cells, which are particularly relevant during development, such as stimulation of energy metabolism or immediate early gene expression (see key refs in 2). An attractive possibility is that endocannabinoids might play a role in the expression of neuronglial cell adhesion molecules (NgCAM), which play a key role in specific processes of neuronal development as neuronal migration or axonal elongation, but there is no evidence, to this date, on this possibility. In summary, although further studies will be necessary, there is robust evidence to support that, from an early age, the endocannabinoid system has all the necessary elements to play a fimctional role in specific events related to brain development, which would be different to its classic functions in the adult brain. The exact processes in which endocannabinoids are involved are not fully known and discovering these processes remain the major challenge for the future.
References [1] [2] [3] [4] [5]
Fernfindez-Ruizet al., Life Sciences 65, 725-736 (1999) Fernfindez-Ruizet al., Trends in Neurosciences 23, 14-20 (2000) Berrendero et al., Development 125, 3179-3188 (1998) Berrendero et al., Synapse 33, 181-191 (1999) Hernfindez et al., Brain Research 857, 56-65 (2000)
$128
Several novel types of receptors for cannabinoids have been proposed (Pertwee and Ross, 2002). One of these is an SR141716Asensitive non-CB1, non-CB2-, non-vanilloid-receptor that may be present in mesenteric arteries. Ligands for this putative receptor include anandamide (agonist) and the non-psychotropic plant cannabinoid, cannabidiol (antagonist), but exclude 2-AG and established non-eicosanoid CB 1/CB2 receptor agonists. Other novel receptors to have been proposed are (i) SR141716A-insensitive non-CB1, non-CB2-, non-vanilloid-receptors that appear to be expressed in some brain areas of CB1 knockout mice and to be activated by R-(+)-WIN55212 and anandamide but not by THC or CP55940 and (ii) SR144528-sensitive non-CB2 caunabinoid receptors on which palmitoylethanolamide but not anandamide may act to relieve inflammatory pain ('CB2-1ike' receptors). There is also evidence from experiments with the mouse isolated vas deferens that submicromolar concentrations of cannabidiol attenuate the ability of R-(+)-WlN55212, anandamide and CP55940 in inhibit evoked transmitter release in this tissue (Thomas et al., 2002).
References [1] [2] [3] [4]
•
Pertwee, R.G. (2000) Exp. Opin. Invest. Drugs 9: 1553-1571. Pertwee, R.G. (2001) Prog. Neurobiol. 63:569~611. Pertwee, R.G. (2002) Pharmacol. Ther. In press. Pertwee, R.G. and Ross R.A. (2002) Prostaglandins Leukotrienes and Essential Fatty Acids. In press.
Endogenous cannabinoids and brain development
J. Feruandez-Ruiz 1, M. Hernandez 2, M. Gomez 1, J.A. Ramos 1.
1Universidad Complutense, Bioquimica y Biologia Molecular, Madrid, Spain; 2Universidad Complutense, Psicobiologia, Madrid, Spain New data strengthen the idea of a prominent role for endocannabinoids in the modulation of a wide variety of neurobiological functions. Among these, two functions, control of movement and antinociception, have attracted the maximal interest because of the possibility that cannabinoids and related compounds might be used with a therapeutic purpose. However, the functions of endocannabinoids in the brain, and also in the periphery, are large and involve, not only the adulthood, but also the period of prenatal and postnatal development, when endocaunabinoids have been reported to play a role in specific processes of brain development (see 1,2 for review). This finding is based on a three-fold evidence. The first evidence deals with the location of elements of the endocarmabinoid system, ligands and/or receptors, in the developing brain (3,4). Cannabinoid CB1 receptors emerge early during development and their pattem of ontogenic maturation differs from that reported for most of classic neurotransmitter receptors (1-3). The most intriguing fact is that these elements, particularly the receptors, are located transiently in atypical regions, where they are not located in the adult brain (3). For instance, CB1 receptor binding is highly concentrated in white matter areas during prenatal and early postnatal period, in particular in transverse or commissural fiber tracts, such as the corpus callosum, the anterior commissure, the stria terminalis and others (3). In addition, CB1 receptor mRNA is highly expressed in regions involved in neuronal and glial cell proliferation, such as the subventricular regions of the forebrain (3). All these observations are compatible with the suggestion that endocannabinoid
ligands and their receptors present in the developing stages might play a role in specific events of brain development as neuronal proliferation and migration, axonal elongation, synaptogenesis and/or myelinogenesis, which would be different to the roles assigned to this signaling system in the adult brain. In fact, the location of CB1 receptors, as well as the effects produced by their activation, in the regions where they are highly concentrated in adulthood, such as the basal ganglia or the regions involved in the control of nociception, is an event that occurs late in the brain development (see key refs in 2). A second evidence derives from numerous studies which have reported that the administration of plant-derived or synthetic caunabinoids, compounds that are able to activate cannabinoid CB1 receptors, during either gestational or neonatal periods affects the development of several neurotransmitters, particularly two of them, dopamine and opioid peptides (1,2). In vitro studies have also reported that, during prenatal development, CB1 receptors are present in neuronal cells, such as mesencephalic tyrosine hydroxylase (TH)-containing neurons, where they are not present in the adult brain (5). The activation of these receptors is accompanied by an increase of the expression of TH gene, which is a key gene for the development of dopaminergic neurons and also for the maturation of neurons expressing other neurotransmitters (5). As a result of these neurotransmitter disturbances elicited by the perinatal exposure to cannabinoids, when animals matured, they exhibited deterioration in a variety of functions, in which these neurotransmitters are involved, such as motor activity, pain sensitivity, drug-seeking behavior, social interaction, sexual behavior, learning ability, stress response and neuroendocrine regulation (see 1,2 for review). The last evidence is the suggested role for the endocannabinoid system in neuron-glia cell interaction, which is a crucial event during brain development. In vitro studies (4) have demonstrated that glial cells express cannabinoid receptors (CB1 subtype or others) and their activation seems to play a role in specific functions of these cells, which are particularly relevant during development, such as stimulation of energy metabolism or immediate early gene expression (see key refs in 2). An attractive possibility is that endocannabinoids might play a role in the expression of neuronglial cell adhesion molecules (NgCAM), which play a key role in specific processes of neuronal development as neuronal migration or axonal elongation, but there is no evidence, to this date, on this possibility. In summary, although further studies will be necessary, there is robust evidence to support that, from an early age, the endocannabinoid system has all the necessary elements to play a fimctional role in specific events related to brain development, which would be different to its classic functions in the adult brain. The exact processes in which endocannabinoids are involved are not fully known and discovering these processes remain the major challenge for the future.
References [1] [2] [3] [4] [5]
Fernfindez-Ruizet al., Life Sciences 65, 725-736 (1999) Fernfindez-Ruizet al., Trends in Neurosciences 23, 14-20 (2000) Berrendero et al., Development 125, 3179-3188 (1998) Berrendero et al., Synapse 33, 181-191 (1999) Hernfindez et al., Brain Research 857, 56-65 (2000)