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      Cannabinoid Receptor 1 and Fatty Acid Amide Hydrolase Contribute to Operant Sensation Seeking in Mice

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          Abstract

          A large body of evidence in humans and preclinical models supports a role for the endocannabinoid system in the proper execution of motivated or goal-directed behaviors. Operant sensation seeking (OSS) is a task that uses varied sensory stimuli as a reinforcer to maintain operant responding in mice. The purpose of the studies in this report was to begin to explore the role of endocannabinoid signaling in OSS utilizing cannabinoid receptor 1 (CB1R) and fatty acid amide hydrolase (FAAH) knock out mice. Compared to wild type littermate controls, CB1R knock out mice exhibited significantly fewer active responses and earned significantly fewer reinforcers in fixed ratio and progressive ratio schedules. On the other hand, FAAH knock out mice exhibited increased active responses and earned more reinforcers than wild type littermates in fixed ratio but not progressive ratio schedules. These findings support the role of endocannabinoid signaling in motivated behaviors and also expand our understanding of the signaling processes involved in OSS.

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          Most cited references 52

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          Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy.

          Drug self-administration studies have recently employed progressive ratio (PR) schedules to examine psychostimulant and opiate reinforcement. This review addresses the technical, statistical, and theoretical issues related to the use of the PR schedule in self-administration studies in rats. Session parameters adopted for use in our laboratory and the considerations relevant to them are described. The strengths and weaknesses of the PR schedule are also discussed.
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            Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase.

            The medicinal properties of marijuana have been recognized for centuries, but clinical and societal acceptance of this drug of abuse as a potential therapeutic agent remains fiercely debated. An attractive alternative to marijuana-based therapeutics would be to target the molecular pathways that mediate the effects of this drug. To date, these neural signaling pathways have been shown to comprise a cannabinoid receptor (CB(1)) that binds the active constituent of marijuana, tetrahydrocannabinol (THC), and a postulated endogenous CB(1) ligand anandamide. Although anandamide binds and activates the CB(1) receptor in vitro, this compound induces only weak and transient cannabinoid behavioral effects in vivo, possibly a result of its rapid catabolism. Here we show that mice lacking the enzyme fatty acid amide hydrolase (FAAH(-/-)) are severely impaired in their ability to degrade anandamide and when treated with this compound, exhibit an array of intense CB(1)-dependent behavioral responses, including hypomotility, analgesia, catalepsy, and hypothermia. FAAH(-/-)-mice possess 15-fold augmented endogenous brain levels of anandamide and display reduced pain sensation that is reversed by the CB(1) antagonist SR141716A. Collectively, these results indicate that FAAH is a key regulator of anandamide signaling in vivo, setting an endogenous cannabinoid tone that modulates pain perception. FAAH may therefore represent an attractive pharmaceutical target for the treatment of pain and neuropsychiatric disorders.
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              Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain.

              The anatomical distribution and density of cannabinoid receptors in the human brain was studied in one fetal (33 weeks gestation), two neonatal (aged three to six months) and eight adult (aged 21-81 years) human cases using quantitative receptor autoradiography following in vitro labelling of sections with the synthetic cannabinoid agonist [3H]CP55,940. Cannabinoid receptors were distributed in a heterogeneous fashion throughout the adult human brain and spinal cord. The allocortex contained very high concentrations of cannabinoid receptor binding sites in the dentate gyrus, Ammons's horn and subiculum of the hippocampal formation; high concentrations of receptors were also present in the entorhinal cortex and amygdaloid complex. Cannabinoid receptor binding sites were also present throughout all regions of the neocortex, where they showed a marked variation in density between the primary, secondary and associational cortical regions: the greatest densities of receptors were present in the associational cortical regions of the frontal and limbic lobes, with moderate densities in the secondary sensory and motor cortical regions, and with the lowest densities of receptors in the primary sensory and motor cortical regions. Relatively high concentrations of cannabinoid receptors were consistently seen in cortical regions of the left (dominant) hemisphere, known to be associated with verbal language functions. In all of the cortical regions, the pattern and density of receptor labelling followed the neocortical laminar organization, with the greatest density of receptors localized in two discrete bands--a clearly delineated narrow superficial band which coincided with lamina I and a deeper broader, conspicuous band of labelling which corresponded to laminae V and VI. Labelling in the intervening cortical laminae (II-IV) showed lower densities, with a well delineated narrow band of label in the middle of laminae IV in the associational cortical regions. The thalamus showed a distinctive heterogeneous distribution of cannabinoid receptors, with the highest concentration of receptors localized in the mediodorsal nucleus, anterior nuclear complex, and in the midline and intralaminar complex of nuclei, i.e. in thalamic nuclei which have connectional affiliations with the associational cortical areas. The basal ganglia showed a distinctive heterogeneous pattern of receptor binding, with the very highest concentrations in the globus pallidus internus, moderate concentrations in the globus pallidus externus and ventral pallidum, and moderately low levels of binding throughout the striatal complex. In the midbrain, some of the highest levels of cannabinoid receptor binding sites in the human brain were present in the substantia nigra pars reticulata, with very low levels of labelling in all other midbrain areas. The highest densities of cannabinoid receptor binding in the hindbrain were localized in the molecular layer of the cerebellar cortex and the dorsal motor nucleus of the vagus, with moderate densities of receptors in the nucleus of the solitary tract. The spinal cord showed very low levels of receptor binding. Studies on the distribution of cannabinoid receptors in the fetal and neonatal human brain showed similar patterns of receptor distribution to that observed in the adult human brain, except that the density of receptor binding was generally markedly higher, especially in the basal ganglia and substantia nigra. The pattern of cannabinoid receptor labelling in the striatum showed a striking patchy pattern of organization which was especially conspicuous in the fetal brain. These results show that cannabinoid receptor binding sites in the human brain are localized mainly in: forebrain areas associated with higher cognitive functions; forebrain, midbrain and hindbrain areas associated with the control of movement; and in hindbrain areas associated with the control of motor and sensory functions of the autonomic nervous system. (AB
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                27 July 2017
                August 2017
                : 18
                : 8
                Affiliations
                Department of Pharmacology and Toxicology and Neuroscience Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; ahelfand@ 123456mcw.edu
                Author notes
                [* ]Correspondence: colsen@ 123456mcw.edu (C.M.O.); chillard@ 123456mcw.edu (C.J.H.); Tel.: +1-414-955-8493 (C.J.H.)
                ijms-18-01635
                10.3390/ijms18081635
                5578025
                28749428
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                Categories
                Article

                Molecular biology

                behavior, knock out, reward, motivation, novelty seeking

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