Imaging the Brain Marijuana Receptor: Development of a Radioligand that Binds to Cannabinoid CB1 Receptors In Vivo

Gatley, S. John; Lan, Ruoxi; Volkow, Nora D.; Pappas, Naomi; King, Payton; Wong, Christopher; Gifford, Andrew N.; Pyatt, B.E.; Dewey, Stephen L.; Makriyannis, Alexandros

doi:10.1046/j.1471-4159.1998.70010417.x

Cited by 116 publications

(79 citation statements)

References 27 publications

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“…with AM1241 (0.33 mg/kg) that were blocked by AM630 (1 mg/kg) but not by AM251 (1 mg/kg). In spite of CB 2 R being present in the CNS also under normal, non-pathological conditions (Gong et al 2006;Van Sickle et al 2005), above DD data suggest minimal, if any contribution of this cannabinoid receptor subtype for behaviors primarily related to CB 1 R activation/inactivation. Although we do not have a ready explanation for the U-shaped dose-response curve in tests with AM630, the results again indicate that a cannabinoid ligand administered in pure DMSO do not necessarily lead to reduced drinking.…”

Section: Discussionmentioning

confidence: 77%

“…By comparison, test results with rimonabant in DMSO did not seem to differ substantially from tests where rimonabant was delivered as a suspension (as revealed by similar and nonsignificant ED 50 values for the two sets of tests). However, it is possible that enhanced uptake from the peritoneal cavity coupled with the drug's ability to more readily penetrate the blood-brain barrier, resulting in a comparatively rapid increase in brain drug concentrations (Gatley et al 1998), might explain the unconditioned effects. DMSO alone exerted a modest but statistically significant reduction in fluid intake.…”

Section: Discussionmentioning

confidence: 99%

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Discriminative stimulus effects of the cannabinoid CB1 receptor antagonist rimonabant in rats

Järbe

Vadivel

et al. 2008

Psychopharmacology

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Objective-To examine the discriminative stimulus effects of the cannabinoid CB 1 receptor (CB 1 R) antagonist/inverse agonist rimonabant (SR141716A) using a discriminated taste aversion (DTA) procedure.Materials and methods-Groups of rats were trained to discriminate between drug (5.6 or 3 mg/kg) and vehicle in DTA (t′=20 min). The 30-min drinking opportunity after rimonabant pretreatment was followed by injection of lithium chloride (120 mg/kg) in the experimental (EXP) animals. When offered fluid after vehicle pretreatment, EXP animals subsequently were given intraperitoneal saline (NaCl, 10 ml/kg). Post-drinking treatment for controls (CONT) was NaCl irrespective of the pretreatment condition (rimonabant or vehicle). Tests examined other doses and drugs (t′=20 min).Results-The rimonabant analog AM251 (1 to 5.6 mg/kg) substituted for rimonabant. AM281 also appeared to substitute, but interpretation is complicated by unconditioned effects (drinking suppressed also in the CONT group). The CB 2 R antagonists SR144528 (18 and 30 mg/kg), AM630 (1 to 10 mg/kg), and the CB 1 R agonist methanandamide (mAEA, 3 and 10 mg/kg) did not substitute. There was a dose-related attenuation of the rimonabant-induced suppression of saccharin drinking when Δ9-tetrahydrocannabinol (Δ9-THC; 0.3 to 5.6 mg/kg), but not mAEA (1 to 10 mg/kg), was given together with rimonabant (3 mg/kg). Unconditioned effects occurred with the mAEA-rimonabant combination, not evident for combinations of rimonabant and Δ9-THC. mAEA (10 mg/kg) plus AM251 (5.6 mg/kg) resulted in strong unconditioned effects.Conclusion-Rimonabant induces a discriminative stimulus in DTA that continues to show potential for further examination of cannabinoid receptor antagonism.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Discriminative stimulus effects of the cannabinoid CB1 receptor antagonist rimonabant in rats

Järbe

Vadivel

et al. 2008

Psychopharmacology

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“…In contrast, the presence of functional α7 nACh receptors in principal neurons of either the hippocampus or the dentate gyrus is controversial, as observations suggesting functional α7 nACh receptors in hippocampal gultamatergic neurons have not been replicated by others (Frazier et al, 1998b;Khiroug et al, 2003;Sudweeks and Yakel, 2000). Activation of α7 nACh receptors located on interneurons within the stratum (s.) oriens mediates strong excitatory effects that result in an increase of GABAergic neurotransmission (Jones and Yakel, 1997;Alkondon et al, 1998; Frazier et al, 1998a,b;McQuiston and Madison, 1999;Shao and Yakel, 2000;Sudweeks and Yakel, 2000;Buhler and Dunwiddie, 2002;Khiroug et al, 2003).Hippocampal GABAergic neurotransmission is also regulated by the cannabinoid receptor type 1 (CB1) receptors, which are highly expressed in hippocampal interneurons (Mailleux and Vanderhaeghen, 1992;Matsuda et al, 1993;Gatley et al, 1998;Tsou et al, 1998). These CB1 interneurons contain cholecystokinin (CCK) (Katona et al, 1999;Marsicano and Lutz, 1999;Tsou et al, 1999) and co-express the subunit A of the 5-HT 3 R (Hermann et al, 2002;Morales and Backman, 2002;Morales et al, 2004).…”

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confidence: 99%

“…Hippocampal GABAergic neurotransmission is also regulated by the cannabinoid receptor type 1 (CB1) receptors, which are highly expressed in hippocampal interneurons (Mailleux and Vanderhaeghen, 1992;Matsuda et al, 1993;Gatley et al, 1998;Tsou et al, 1998). These CB1 interneurons contain cholecystokinin (CCK) (Katona et al, 1999;Marsicano and Lutz, 1999;Tsou et al, 1999) and co-express the subunit A of the 5-HT 3 R (Hermann et al, 2002;Morales and Backman, 2002;Morales et al, 2004).…”

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confidence: 99%

Hippocampal interneurons co-express transcripts encoding the α7 nicotinic receptor subunit and the cannabinoid receptor 1

2008

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The notion of functional interactions between the α7 nicotinic acetylcholine (α7 nACh) and the cannabinoid systems is emerging from recent in vitro and in vivo studies. Both the α7 nACh receptor and the cannabinoid receptor 1 (CB1) are highly expressed in the hippocampus. To begin addressing possible anatomical interactions between the α7 nACh and the cannabinoid systems in the rat hippocampus, we investigated the distribution of neurons expressing α7 nACh mRNA in relation to those containing CB1 mRNA. By in situ hybridization we found that the α7 nACh mRNA is diffusely expressed in principal neurons and is highly expressed in a subset of interneurons. We observed that the pattern of distribution of hippocampal interneurons co-expressing transcripts encoding α7 nACh and glutamate decarboxylase (GAD; synthesizing enzyme of GABA) closely resembles the one displayed by interneurons expressing CB1 mRNA. By double in situ hybridization we established that the majority of hippocampal interneurons expressing α7 nACh mRNA have high levels of CB1 mRNA. As CB1 interneurons contain cholecystokinin (CCK), we investigated the degree of cellular co-expression of α7 nACh mRNA and CCK, and found that the cellular co-existence of α7 nACh and CCK varies within the different layers of the hippocampus.In summary, we established that most of the hippocampal α7 nACh expressing interneurons are endowed with CB1 mRNA. We found that these α7 nACh/CB1 interneurons are the major subpopulation of hippocampal interneurons expressing CB1 mRNA. The α7 nACh expressing interneurons represent half of the detected population of CCK containing neurons in the hippocampus. Since it is well established that the vast majority of hippocampal interneurons expressing CB1 mRNA have 5-HT type 3 (5-HT 3 ) receptors, we conclude that these hippocampal α7 nACh/5HT 3 /CB1/CCK interneurons correspond to those previously postulated to relay inputs from diverse cortical and subcortical regions about emotional, motivational, and physiological states. KeywordsCB1; 5-HT3 receptors; 5-HT; CCK; Alzheimer's disease; schizophrenia Nicotinic acetylcholine (nACh) receptors are members of the superfamily of ligand-gated ion channels that the includes the GABA receptors (GABA A and GABA C ), the glycine receptor and the 5-HT type 3 receptor (5-HT 3 R). In the nervous system, several subunits of the nACh receptor have been identified, including nine α subunits (α2-α10) and three β subunits (β2-β4) (Sargent, 1993;McGehee and Role, 1995 (Sargent, 1993;McGehee and Role, 1995). Electrophysiological, pharmacological and genetic approaches demonstrated that the homomeric α7-nACh receptor has a high affinity for α-bungarotoxin (Couturier et al., 1990;Séguéla et al., 1993;Chen and Patrick, 1997;Orr-Urtreger et al., 1997). The high affinity of the α7-nACh receptor for α-bungarotoxin has been used to map the distribution of this receptor in several brain areas, including the hippocampus (Hunt and Schmidt, 1978;Freedman et al., 1993;Fabian-Fine et al., 2001). Although mRNA enco...

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“…1) and induc- (Portier et al, 1999). In mammalian neuronal cells, CB modulation of N-and P/Q-type ion channels is altered by SR 141716A (Twitchell et al, 1997), an analog of AM 281 (Gatley et al, 1998). Thus, the reversal/inhibition by CB receptor antagonists of NAE 14:0-induced responses in tobacco cell suspensions and leaves suggests the parallel existence of a mammalian-like endocannabinoid system where NAE 14:0 mediates its function by binding to a CB receptor-like binding protein.…”

Section: Discussionmentioning

confidence: 99%

N-Acylethanolamine Signaling in Tobacco Is Mediated by a Membrane-Associated, High-Affinity Binding Protein

et al. 2003

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N-Acylethanolamines (NAEs) are fatty acid derivatives found as minor constituents of animal and plant tissues, and their levels increase 10- to 50-fold in tobacco (Nicotiana tabacum) leaves treated with fungal elicitors. Infiltration of tobacco leaves with submicromolar to micromolar concentrations ofN-myristoylethanolamine (NAE 14:0) resulted in an increase in relative phenylalanine ammonia-lyase (PAL) transcript abundance within 8 h after infiltration, and this PAL activation was reduced after co-infiltration with cannabinoid receptor antagonists (AM 281 and SR 144528). A saturable, high-affinity specific binding activity for [3H]NAE 14:0 was identified in suspension-cultured tobacco cells and in microsomes from tobacco leaves (apparent K d of 74 and 35 nm,respectively); cannabinoid receptor antagonists reduced or eliminated specific [3H]NAE 14:0 binding, consistent with the physiological response. N-Oleoylethanolamine activatedPAL2 expression in leaves and diminished [3H]NAE 14:0 binding in microsomes, whereasN-linoleoylethanolamine did not activatePAL2 expression in leaves, and did not affect [3H]NAE 14:0 binding in microsomes. The nonionic detergent dodecylmaltoside solubilized functional [3H]NAE 14:0-binding activity from tobacco microsomal membranes. The dodecylmaltoside-solubilized NAE-binding activity retained similar, but not identical, binding properties to the NAE-binding protein(s) in intact tobacco microsomes. Additionally, high-affinity saturable NAE-binding proteins were identified in microsomes isolated from Arabidopsis and Medicago truncatula tissues, indicating the general prevalence of these binding proteins in plant membranes. We propose that plants possess an NAE-signaling pathway with functional similarities to the “endocannabinoid” pathway of animal systems and that this pathway, in part, participates in xylanase elicitor perception in tobacco.

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Imaging the Brain Marijuana Receptor: Development of a Radioligand that Binds to Cannabinoid CB1 Receptors In Vivo

Cited by 116 publications

References 27 publications

Discriminative stimulus effects of the cannabinoid CB1 receptor antagonist rimonabant in rats

Discriminative stimulus effects of the cannabinoid CB1 receptor antagonist rimonabant in rats

Hippocampal interneurons co-express transcripts encoding the α7 nicotinic receptor subunit and the cannabinoid receptor 1

N-Acylethanolamine Signaling in Tobacco Is Mediated by a Membrane-Associated, High-Affinity Binding Protein

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