Chapter 12 - Cannabinoid Receptors in Brain: Pharmacogenetics, Neuropharmacology, Neurotoxicology, and Potential Therapeutic Applications

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Much progress has been achieved in cannabinoid research. A major breakthrough in marijuana-cannabinoid research has been the discovery of a previously unknown but elaborate endogenous endocannabinoid system (ECS), complete with endocannabinoids and enzymes for their biosynthesis and degradation with genes encoding two distinct cannabinoid (CB1 and CB2) receptors (CBRs) that are activated by endocannabinoids, cannabinoids, and marijuana use. Physical and genetic localization of the CBR genes CNR1 and CNR2 have been mapped to chromosome 6 and 1, respectively. A number of variations in CBR genes have been associated with human disorders including osteoporosis, attention deficit hyperactivity disorder (ADHD), posttraumatic stress disorder (PTSD), drug dependency, obesity, and depression. Other family of lipid receptors including vanilloid (VR1) and lysophosphatidic acid (LPA) receptors appear to be related to the CBRs at the phylogenetic level. The ubiquitous abundance and differential distribution of the ECS in the human body and brain along with the coupling to many signal transduction pathways may explain the effects in most biological system and the myriad behavioral effects associated with smoking marijuana. The neuropharmacological and neuroprotective features of phytocannabinoids and endocannabinoid associated neurogenesis have revealed roles for the use of cannabinoids in neurodegenerative pathologies with less neurotoxicity. The remarkable progress in understanding the biological actions of marijuana and cannabinoids have provided much richer results than previously appreciated cannabinoid genomics and raised a number of critical issues on the molecular mechanisms of cannabinoid induced behavioral and biochemical alterations. These advances will allow specific therapeutic targeting of the different components of the ECS in health and disease. This review focuses on these recent advances in cannabinoid genomics and the surprising new fundamental roles that the ECS plays in the retrograde signaling associated with cannabinoid inhibition of neurotransmitter release to the genetic basis of the effects of marijuana use and pharmacotherpeutic applications and limitations. Much evidence is provided for the complex CNR1 and CNR2 gene structures and their associated regulatory elements. Thus, understanding the ECS in the human body and brain will contribute to elucidating this natural regulatory mechanism in health and disease.

Introduction

This review presents the remarkable new understanding that the cellular, biochemical, and behavioral responses to marijuana, which remains one of the most widely used and abused drugs in the world, are coded in our genes. The discovery that specific gene codes for cannabinoid receptors (CBRs) that are activated by marijuana use, and that the human body makes its own marijuana-like substances—endocannabinoids (Onaivi et al., 1996, Onaivi et al., 2006b)—that also activates CBRs have provided surprising new knowledge about cannabinoid genomic and proteomic profiles. These remarkable advances in understanding the biological actions of marijuana, cannabinoids, and endocannabinoids, is unraveling the genetic basis of marijuana use and the implication in human health and disease. In the era of personalized medicine, we are eager to understand how to utilize cannabinoid pharmacotherapeutic agents based on our new knowledge of the genetic basis of cannabinoid and endocannabinoid action. We know that the two well-characterized cannabinoid CB1 and CB2 receptors are encoded by CNR1 and CNR2 genes that have been mapped to human chromosome 6 and 1, respectively. A number of variations in CBR genes have been associated with human disorders including osteoporosis (Karsak et al., 2005, Sipe et al., 2005), ADHD (Lu et al., 2008), posttraumatic stress disorder (PTSD) (Lu et al., 2008), drug dependency (Onaivi et al., 2006b), obesity (Cota et al., 2003, Jesudason and Wittert, 2008), and depression (Onaivi et al., 2006a, Serra and Fratta, 2007). Thus, because of the ubiquitous distribution and role of the endocannabinoid system in the regulation of a variety of normal human physiology, drugs that are targeted to different aspects of this system are already benefiting cancer subjects and those with AIDs and metabolic syndromes (Jesudason and Wittert, 2008). In the coming era of personalized medicine, genetic variants and haplotypes in CNR1 and CNR2 genes associated with obesity or addiction phenotypes may help identify specific targets in conditions of endocannabinoid dysfunction.

Our previous investigations had defined a number of features of the CNR1 gene's structure, regulation, and variation (Zhang et al., 2004), but many of these features still remain poorly defined. Nevertheless, we and others have now demonstrated and reported that variants of the CNR1 gene are associated with a number of disorders and substance abuse vulnerability in diverse ethnic groups including European–American, African–American, and Japanese subjects (Zhang et al., 2004). Most strikingly, variants of CNR genes co-occur with other genetic variations and share biological susceptibility that underlies comorbidity in many neuropsychiatric disturbances (Palomo et al., 2007). Thus, emerging evidence indicates that the endocannabinoid system exerts a powerful modulatory action on retrograde signaling associated with inhibition of synaptic transmission (Lovinger, 2008, Onaivi et al., 2006b). Interestingly, a role for variations in CNR1 gene has been associated with striatal responses to happy, but not to disgust, faces (Chakrabarti et al., 2006) with implication that functional variation of CNR genotypes may be associated with disturbances of the brain involving emotional and social stimuli, such as autism (Chakrabarti et al., 2006) and depression (Domschke et al., 2008; Onaivi et al., 2008a). This review focuses on these recent advances in cannabinoid genomics and the surprising new fundamental roles that the endogenous endocannabinoid system (ECS) plays in the genetic basis of the effects of marijuana use. The powerful influence of cannabinoid-induced retrograde signaling modulates GABAergic and glutamatergic systems indicate that the main excitatory and inhibitory systems are in part under the influence of the endocannabinoid system. Additional evidence is provided for the complex CNR1 and CNR2 gene structures and their associated regulatory elements. Therefore, understanding the ECS in the human body and brain will contribute to elucidating this natural regulatory mechanism in health and disease.

Section snippets

Cannabinoid Genomics

Most of the physiological effects of smoking marijuana are probably mediated via CBRs, actions at other non-CBRs, and nonreceptor mechanism(s). Thus, the genetic basis of marijuana use and perhaps dependence may be associated at least in part to their effects on these G-protein-coupled CBRs. The presently known CBRs and their gene transcripts can now be analyzed in human blood samples (Onaivi et al., 1999), fetal brain (Mato et al., 2003, Wang et al., 2003), placenta (Park et al., 2003), uterus

Cannabinoid Neuropharmacology, Neurogenesis, Neurotoxicology, and Neuroprotective Properties

The neuropharmacological and neuroprotective features of phytocannabinoids (de Lago and Fernandez-Ruiz, 2007) and endocannabinoid associated neurogenesis (Goncalves et al., 2008) have revealed roles for the use of cannabinoids in neurodegenerative pathologies with less neurotoxicity. A role for CB2-Rs and not for CB1-Rs has been reported in the regulation of adult subventricular zone neurogenesis in an age-dependent manner (Goncalves et al., 2008). Acute toxicity studies show marijuana use or

Chromosomal Mapping of the CNR Genes

The two well-documented human CBR CNR genes and of many other mammalian species have been mapped to their respective chromosomes. Human CNR1 and CNR2 genes have been mapped to chromosome 6q14-q15 and 1p34-p35, respectively. Using genetic linkage mapping and chromosomal in situ hybridization the genomic location of the human CNR gene was determined, thus confirming the linkage analysis and defining a precise alignment of the genetic and cytogenetic maps (Hoehe et al., 1991). These investigators

Polymorphic Structure of CNR Genes

Although two CBR G-protein coupled receptor (GPCR) subtypes have been cloned and well characterized, studies now indicate the functional existence of splice variations of CB1- and CB2-Rs. New information about CNR genes and their allelic variants in humans and rodents is adding to our understanding of vulnerabilities to addictions and other neuropsychiatric disorders and the genetic basis of marijuana use and addiction in vulnerable individuals. Some of the complexities are however due to our

Genes Encoding Endocannabinoid Transporter(s) as Pharmacotherapeutic Targets

Although there is evidence from functional studies for the existence of some form of cannabinoid transporter(s), their identity, sequence information, and biological characteristics at the molecular level are unknown. This is therefore “a difficult issue to handle,” as concluded by the review on anandamide transport (Glaser et al., 2005). Without a molecular identity and with the different experimental approaches in assay conditions that support or refute the existence of a transporter for

Variations in Cannabinoid Receptor Genes: Functional and Pharmacotherapeutic Implications

There is accumulating physiological evidence for the existence of other subtypes CBRs different from the currently known CB1 and CB2 receptors. The vanilloid receptor 1 (VRI), the site at which capsaicin in hot chili peppers acts, is a site that anandamide is a full agonist. As anandamide is a partial agonist at the CBRs, some have suggested that vanilloid (VR1) receptor be classified as a CBR subtype—may be CB3. In fact the endocannabinoid that is a full agonist at the CBRs is 2-arachidonyl

Genetic Basis of Cannabis use and Dependence

The question of physical and psychological addiction to marijuana is no longer a debate as the significant progress in marijuana-cannabinoid research have applied modern techniques using new molecular probes that were previously unavailable to resolve the issue of addiction to marijuana. There is substantial evidence in favor of heritable factors influencing the liability to cannabis use behaviors (Agrawal et al., 2008). Furthermore, previous twin studies indicate that there is a role of

Functional Implication of Cannabinoid Pharmacotherapeutics

The use of cannabis for both recreational and medicinal purposes dates back for thousands of years. In recent times there has been increased attention that marijuana should be legalized for medicinal use in AIDS, cancer, obesity, multiple sclerosis, and other medical conditions where patients might benefit from the pharmacological effects of cannabis. Synthetic cannabinoids such as dronabinol, marinol, and nabilone already have an established use as antiemetics in nausea and vomiting associated

Conclusions and Future Directions

The recent significant progress on marijuana cannabinoid research has lead to new understanding about the biological effects and the unique therapeutic possibilities of targeting the endocannabinoid system which are activated by cannabinoids, endocannabinoids, and marijuana use. In just a few years since the discovery of endocannabinoids that serve as cannabinoids in vivo, these lipid signaling molecules and endolipids have been shown to participate in a broad array of physiological and

Acknowledgments

I acknowledge support from Center for Research, Dean of Science and Health, Student Workers Fund, and the Provost office at William Paterson University for the assigned release time. I am indebted to Dr. Adriana Patricia Tagliaferro for her patience during the preparation of this chapter and her generous support. I am also associated as a guest researcher with NIDA-NIH and indebted to collaborators including, Drs. Ishiguro, Liu, and Uhl, and others across the globe, present and past students,

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